Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Guillem de Valles-Ibáñez [verfasserIn] Ana Esteve-Solé [verfasserIn] Mònica Piquer [verfasserIn] E. Azucena González-Navarro [verfasserIn] Jessica Hernandez-Rodriguez [verfasserIn] Hafid Laayouni [verfasserIn] Eva González-Roca [verfasserIn] Ana María Plaza-Martin [verfasserIn] Ángela Deyà-Martínez [verfasserIn] Andrea Martín-Nalda [verfasserIn] Mónica Martínez-Gallo [verfasserIn] Marina García-Prat [verfasserIn] Lucía del Pino-Molina [verfasserIn] Ivón Cuscó [verfasserIn] Marta Codina-Solà [verfasserIn] Laura Batlle-Masó [verfasserIn] Manuel Solís-Moruno [verfasserIn] Tomàs Marquès-Bonet [verfasserIn] Elena Bosch [verfasserIn] Eduardo López-Granados [verfasserIn] Juan Ignacio Aróstegui [verfasserIn] Pere Soler-Palacín [verfasserIn] Roger Colobran [verfasserIn] Jordi Yagüe [verfasserIn] Laia Alsina [verfasserIn] Manel Juan [verfasserIn] Ferran Casals [verfasserIn] |
|---|
| Format: |
E-Artikel |
|---|---|
| Sprache: |
Englisch |
| Erschienen: |
2018 |
|---|
| Schlagwörter: |
|---|
| Übergeordnetes Werk: |
In: Frontiers in Immunology - Frontiers Media S.A., 2011, 9(2018) |
|---|---|
| Übergeordnetes Werk: |
volume:9 ; year:2018 |
| Links: |
|---|
| DOI / URN: |
10.3389/fimmu.2018.00636 |
|---|
| Katalog-ID: |
DOAJ038882566 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | DOAJ038882566 | ||
| 003 | DE-627 | ||
| 005 | 20230502205638.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 230227s2018 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3389/fimmu.2018.00636 |2 doi | |
| 035 | |a (DE-627)DOAJ038882566 | ||
| 035 | |a (DE-599)DOAJ101b88bc2f1f4640aaf1b70c55b35578 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 050 | 0 | |a RC581-607 | |
| 100 | 0 | |a Guillem de Valles-Ibáñez |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond |
| 264 | 1 | |c 2018 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15–24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls. | ||
| 650 | 4 | |a common variable immunodeficiency | |
| 650 | 4 | |a primary immunodeficiency | |
| 650 | 4 | |a exome sequencing | |
| 650 | 4 | |a loss-of-function | |
| 650 | 4 | |a rare disease genetics | |
| 653 | 0 | |a Immunologic diseases. Allergy | |
| 700 | 0 | |a Ana Esteve-Solé |e verfasserin |4 aut | |
| 700 | 0 | |a Ana Esteve-Solé |e verfasserin |4 aut | |
| 700 | 0 | |a Mònica Piquer |e verfasserin |4 aut | |
| 700 | 0 | |a Mònica Piquer |e verfasserin |4 aut | |
| 700 | 0 | |a E. Azucena González-Navarro |e verfasserin |4 aut | |
| 700 | 0 | |a E. Azucena González-Navarro |e verfasserin |4 aut | |
| 700 | 0 | |a Jessica Hernandez-Rodriguez |e verfasserin |4 aut | |
| 700 | 0 | |a Hafid Laayouni |e verfasserin |4 aut | |
| 700 | 0 | |a Hafid Laayouni |e verfasserin |4 aut | |
| 700 | 0 | |a Eva González-Roca |e verfasserin |4 aut | |
| 700 | 0 | |a Eva González-Roca |e verfasserin |4 aut | |
| 700 | 0 | |a Ana María Plaza-Martin |e verfasserin |4 aut | |
| 700 | 0 | |a Ana María Plaza-Martin |e verfasserin |4 aut | |
| 700 | 0 | |a Ángela Deyà-Martínez |e verfasserin |4 aut | |
| 700 | 0 | |a Ángela Deyà-Martínez |e verfasserin |4 aut | |
| 700 | 0 | |a Andrea Martín-Nalda |e verfasserin |4 aut | |
| 700 | 0 | |a Andrea Martín-Nalda |e verfasserin |4 aut | |
| 700 | 0 | |a Mónica Martínez-Gallo |e verfasserin |4 aut | |
| 700 | 0 | |a Mónica Martínez-Gallo |e verfasserin |4 aut | |
| 700 | 0 | |a Mónica Martínez-Gallo |e verfasserin |4 aut | |
| 700 | 0 | |a Marina García-Prat |e verfasserin |4 aut | |
| 700 | 0 | |a Marina García-Prat |e verfasserin |4 aut | |
| 700 | 0 | |a Lucía del Pino-Molina |e verfasserin |4 aut | |
| 700 | 0 | |a Ivón Cuscó |e verfasserin |4 aut | |
| 700 | 0 | |a Ivón Cuscó |e verfasserin |4 aut | |
| 700 | 0 | |a Marta Codina-Solà |e verfasserin |4 aut | |
| 700 | 0 | |a Marta Codina-Solà |e verfasserin |4 aut | |
| 700 | 0 | |a Laura Batlle-Masó |e verfasserin |4 aut | |
| 700 | 0 | |a Laura Batlle-Masó |e verfasserin |4 aut | |
| 700 | 0 | |a Manuel Solís-Moruno |e verfasserin |4 aut | |
| 700 | 0 | |a Manuel Solís-Moruno |e verfasserin |4 aut | |
| 700 | 0 | |a Tomàs Marquès-Bonet |e verfasserin |4 aut | |
| 700 | 0 | |a Tomàs Marquès-Bonet |e verfasserin |4 aut | |
| 700 | 0 | |a Tomàs Marquès-Bonet |e verfasserin |4 aut | |
| 700 | 0 | |a Elena Bosch |e verfasserin |4 aut | |
| 700 | 0 | |a Eduardo López-Granados |e verfasserin |4 aut | |
| 700 | 0 | |a Juan Ignacio Aróstegui |e verfasserin |4 aut | |
| 700 | 0 | |a Juan Ignacio Aróstegui |e verfasserin |4 aut | |
| 700 | 0 | |a Pere Soler-Palacín |e verfasserin |4 aut | |
| 700 | 0 | |a Pere Soler-Palacín |e verfasserin |4 aut | |
| 700 | 0 | |a Roger Colobran |e verfasserin |4 aut | |
| 700 | 0 | |a Roger Colobran |e verfasserin |4 aut | |
| 700 | 0 | |a Roger Colobran |e verfasserin |4 aut | |
| 700 | 0 | |a Jordi Yagüe |e verfasserin |4 aut | |
| 700 | 0 | |a Jordi Yagüe |e verfasserin |4 aut | |
| 700 | 0 | |a Laia Alsina |e verfasserin |4 aut | |
| 700 | 0 | |a Laia Alsina |e verfasserin |4 aut | |
| 700 | 0 | |a Manel Juan |e verfasserin |4 aut | |
| 700 | 0 | |a Manel Juan |e verfasserin |4 aut | |
| 700 | 0 | |a Ferran Casals |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i In |t Frontiers in Immunology |d Frontiers Media S.A., 2011 |g 9(2018) |w (DE-627)657998354 |w (DE-600)2606827-8 |x 16643224 |7 nnns |
| 773 | 1 | 8 | |g volume:9 |g year:2018 |
| 856 | 4 | 0 | |u https://doi.org/10.3389/fimmu.2018.00636 |z kostenfrei |
| 856 | 4 | 0 | |u https://doaj.org/article/101b88bc2f1f4640aaf1b70c55b35578 |z kostenfrei |
| 856 | 4 | 0 | |u http://journal.frontiersin.org/article/10.3389/fimmu.2018.00636/full |z kostenfrei |
| 856 | 4 | 2 | |u https://doaj.org/toc/1664-3224 |y Journal toc |z kostenfrei |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a SYSFLAG_A | ||
| 912 | |a GBV_DOAJ | ||
| 912 | |a SSG-OLC-PHA | ||
| 912 | |a GBV_ILN_11 | ||
| 912 | |a GBV_ILN_20 | ||
| 912 | |a GBV_ILN_22 | ||
| 912 | |a GBV_ILN_23 | ||
| 912 | |a GBV_ILN_24 | ||
| 912 | |a GBV_ILN_39 | ||
| 912 | |a GBV_ILN_40 | ||
| 912 | |a GBV_ILN_60 | ||
| 912 | |a GBV_ILN_62 | ||
| 912 | |a GBV_ILN_63 | ||
| 912 | |a GBV_ILN_65 | ||
| 912 | |a GBV_ILN_69 | ||
| 912 | |a GBV_ILN_73 | ||
| 912 | |a GBV_ILN_74 | ||
| 912 | |a GBV_ILN_95 | ||
| 912 | |a GBV_ILN_105 | ||
| 912 | |a GBV_ILN_110 | ||
| 912 | |a GBV_ILN_151 | ||
| 912 | |a GBV_ILN_161 | ||
| 912 | |a GBV_ILN_170 | ||
| 912 | |a GBV_ILN_206 | ||
| 912 | |a GBV_ILN_213 | ||
| 912 | |a GBV_ILN_230 | ||
| 912 | |a GBV_ILN_285 | ||
| 912 | |a GBV_ILN_293 | ||
| 912 | |a GBV_ILN_602 | ||
| 912 | |a GBV_ILN_2003 | ||
| 912 | |a GBV_ILN_2014 | ||
| 912 | |a GBV_ILN_4012 | ||
| 912 | |a GBV_ILN_4037 | ||
| 912 | |a GBV_ILN_4112 | ||
| 912 | |a GBV_ILN_4125 | ||
| 912 | |a GBV_ILN_4126 | ||
| 912 | |a GBV_ILN_4249 | ||
| 912 | |a GBV_ILN_4305 | ||
| 912 | |a GBV_ILN_4306 | ||
| 912 | |a GBV_ILN_4307 | ||
| 912 | |a GBV_ILN_4313 | ||
| 912 | |a GBV_ILN_4322 | ||
| 912 | |a GBV_ILN_4323 | ||
| 912 | |a GBV_ILN_4324 | ||
| 912 | |a GBV_ILN_4325 | ||
| 912 | |a GBV_ILN_4338 | ||
| 912 | |a GBV_ILN_4367 | ||
| 912 | |a GBV_ILN_4700 | ||
| 951 | |a AR | ||
| 952 | |d 9 |j 2018 | ||
| author_variant |
g d v i gdvi a e s aes a e s aes m p mp m p mp e a g n eagn e a g n eagn j h r jhr h l hl h l hl e g r egr e g r egr a m p m ampm a m p m ampm á d m ádm á d m ádm a m n amn a m n amn m m g mmg m m g mmg m m g mmg m g p mgp m g p mgp l d p m ldpm i c ic i c ic m c s mcs m c s mcs l b m lbm l b m lbm m s m msm m s m msm t m b tmb t m b tmb t m b tmb e b eb e l g elg j i a jia j i a jia p s p psp p s p psp r c rc r c rc r c rc j y jy j y jy l a la l a la m j mj m j mj f c fc |
|---|---|
| matchkey_str |
article:16643224:2018----::vlaighgntcocmovralimndfcecmn |
| hierarchy_sort_str |
2018 |
| callnumber-subject-code |
RC |
| publishDate |
2018 |
| allfields |
10.3389/fimmu.2018.00636 doi (DE-627)DOAJ038882566 (DE-599)DOAJ101b88bc2f1f4640aaf1b70c55b35578 DE-627 ger DE-627 rakwb eng RC581-607 Guillem de Valles-Ibáñez verfasserin aut Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15–24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls. common variable immunodeficiency primary immunodeficiency exome sequencing loss-of-function rare disease genetics Immunologic diseases. Allergy Ana Esteve-Solé verfasserin aut Ana Esteve-Solé verfasserin aut Mònica Piquer verfasserin aut Mònica Piquer verfasserin aut E. Azucena González-Navarro verfasserin aut E. Azucena González-Navarro verfasserin aut Jessica Hernandez-Rodriguez verfasserin aut Hafid Laayouni verfasserin aut Hafid Laayouni verfasserin aut Eva González-Roca verfasserin aut Eva González-Roca verfasserin aut Ana María Plaza-Martin verfasserin aut Ana María Plaza-Martin verfasserin aut Ángela Deyà-Martínez verfasserin aut Ángela Deyà-Martínez verfasserin aut Andrea Martín-Nalda verfasserin aut Andrea Martín-Nalda verfasserin aut Mónica Martínez-Gallo verfasserin aut Mónica Martínez-Gallo verfasserin aut Mónica Martínez-Gallo verfasserin aut Marina García-Prat verfasserin aut Marina García-Prat verfasserin aut Lucía del Pino-Molina verfasserin aut Ivón Cuscó verfasserin aut Ivón Cuscó verfasserin aut Marta Codina-Solà verfasserin aut Marta Codina-Solà verfasserin aut Laura Batlle-Masó verfasserin aut Laura Batlle-Masó verfasserin aut Manuel Solís-Moruno verfasserin aut Manuel Solís-Moruno verfasserin aut Tomàs Marquès-Bonet verfasserin aut Tomàs Marquès-Bonet verfasserin aut Tomàs Marquès-Bonet verfasserin aut Elena Bosch verfasserin aut Eduardo López-Granados verfasserin aut Juan Ignacio Aróstegui verfasserin aut Juan Ignacio Aróstegui verfasserin aut Pere Soler-Palacín verfasserin aut Pere Soler-Palacín verfasserin aut Roger Colobran verfasserin aut Roger Colobran verfasserin aut Roger Colobran verfasserin aut Jordi Yagüe verfasserin aut Jordi Yagüe verfasserin aut Laia Alsina verfasserin aut Laia Alsina verfasserin aut Manel Juan verfasserin aut Manel Juan verfasserin aut Ferran Casals verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 9(2018) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:9 year:2018 https://doi.org/10.3389/fimmu.2018.00636 kostenfrei https://doaj.org/article/101b88bc2f1f4640aaf1b70c55b35578 kostenfrei http://journal.frontiersin.org/article/10.3389/fimmu.2018.00636/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2018 |
| spelling |
10.3389/fimmu.2018.00636 doi (DE-627)DOAJ038882566 (DE-599)DOAJ101b88bc2f1f4640aaf1b70c55b35578 DE-627 ger DE-627 rakwb eng RC581-607 Guillem de Valles-Ibáñez verfasserin aut Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15–24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls. common variable immunodeficiency primary immunodeficiency exome sequencing loss-of-function rare disease genetics Immunologic diseases. Allergy Ana Esteve-Solé verfasserin aut Ana Esteve-Solé verfasserin aut Mònica Piquer verfasserin aut Mònica Piquer verfasserin aut E. Azucena González-Navarro verfasserin aut E. Azucena González-Navarro verfasserin aut Jessica Hernandez-Rodriguez verfasserin aut Hafid Laayouni verfasserin aut Hafid Laayouni verfasserin aut Eva González-Roca verfasserin aut Eva González-Roca verfasserin aut Ana María Plaza-Martin verfasserin aut Ana María Plaza-Martin verfasserin aut Ángela Deyà-Martínez verfasserin aut Ángela Deyà-Martínez verfasserin aut Andrea Martín-Nalda verfasserin aut Andrea Martín-Nalda verfasserin aut Mónica Martínez-Gallo verfasserin aut Mónica Martínez-Gallo verfasserin aut Mónica Martínez-Gallo verfasserin aut Marina García-Prat verfasserin aut Marina García-Prat verfasserin aut Lucía del Pino-Molina verfasserin aut Ivón Cuscó verfasserin aut Ivón Cuscó verfasserin aut Marta Codina-Solà verfasserin aut Marta Codina-Solà verfasserin aut Laura Batlle-Masó verfasserin aut Laura Batlle-Masó verfasserin aut Manuel Solís-Moruno verfasserin aut Manuel Solís-Moruno verfasserin aut Tomàs Marquès-Bonet verfasserin aut Tomàs Marquès-Bonet verfasserin aut Tomàs Marquès-Bonet verfasserin aut Elena Bosch verfasserin aut Eduardo López-Granados verfasserin aut Juan Ignacio Aróstegui verfasserin aut Juan Ignacio Aróstegui verfasserin aut Pere Soler-Palacín verfasserin aut Pere Soler-Palacín verfasserin aut Roger Colobran verfasserin aut Roger Colobran verfasserin aut Roger Colobran verfasserin aut Jordi Yagüe verfasserin aut Jordi Yagüe verfasserin aut Laia Alsina verfasserin aut Laia Alsina verfasserin aut Manel Juan verfasserin aut Manel Juan verfasserin aut Ferran Casals verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 9(2018) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:9 year:2018 https://doi.org/10.3389/fimmu.2018.00636 kostenfrei https://doaj.org/article/101b88bc2f1f4640aaf1b70c55b35578 kostenfrei http://journal.frontiersin.org/article/10.3389/fimmu.2018.00636/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2018 |
| allfields_unstemmed |
10.3389/fimmu.2018.00636 doi (DE-627)DOAJ038882566 (DE-599)DOAJ101b88bc2f1f4640aaf1b70c55b35578 DE-627 ger DE-627 rakwb eng RC581-607 Guillem de Valles-Ibáñez verfasserin aut Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15–24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls. common variable immunodeficiency primary immunodeficiency exome sequencing loss-of-function rare disease genetics Immunologic diseases. Allergy Ana Esteve-Solé verfasserin aut Ana Esteve-Solé verfasserin aut Mònica Piquer verfasserin aut Mònica Piquer verfasserin aut E. Azucena González-Navarro verfasserin aut E. Azucena González-Navarro verfasserin aut Jessica Hernandez-Rodriguez verfasserin aut Hafid Laayouni verfasserin aut Hafid Laayouni verfasserin aut Eva González-Roca verfasserin aut Eva González-Roca verfasserin aut Ana María Plaza-Martin verfasserin aut Ana María Plaza-Martin verfasserin aut Ángela Deyà-Martínez verfasserin aut Ángela Deyà-Martínez verfasserin aut Andrea Martín-Nalda verfasserin aut Andrea Martín-Nalda verfasserin aut Mónica Martínez-Gallo verfasserin aut Mónica Martínez-Gallo verfasserin aut Mónica Martínez-Gallo verfasserin aut Marina García-Prat verfasserin aut Marina García-Prat verfasserin aut Lucía del Pino-Molina verfasserin aut Ivón Cuscó verfasserin aut Ivón Cuscó verfasserin aut Marta Codina-Solà verfasserin aut Marta Codina-Solà verfasserin aut Laura Batlle-Masó verfasserin aut Laura Batlle-Masó verfasserin aut Manuel Solís-Moruno verfasserin aut Manuel Solís-Moruno verfasserin aut Tomàs Marquès-Bonet verfasserin aut Tomàs Marquès-Bonet verfasserin aut Tomàs Marquès-Bonet verfasserin aut Elena Bosch verfasserin aut Eduardo López-Granados verfasserin aut Juan Ignacio Aróstegui verfasserin aut Juan Ignacio Aróstegui verfasserin aut Pere Soler-Palacín verfasserin aut Pere Soler-Palacín verfasserin aut Roger Colobran verfasserin aut Roger Colobran verfasserin aut Roger Colobran verfasserin aut Jordi Yagüe verfasserin aut Jordi Yagüe verfasserin aut Laia Alsina verfasserin aut Laia Alsina verfasserin aut Manel Juan verfasserin aut Manel Juan verfasserin aut Ferran Casals verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 9(2018) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:9 year:2018 https://doi.org/10.3389/fimmu.2018.00636 kostenfrei https://doaj.org/article/101b88bc2f1f4640aaf1b70c55b35578 kostenfrei http://journal.frontiersin.org/article/10.3389/fimmu.2018.00636/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2018 |
| allfieldsGer |
10.3389/fimmu.2018.00636 doi (DE-627)DOAJ038882566 (DE-599)DOAJ101b88bc2f1f4640aaf1b70c55b35578 DE-627 ger DE-627 rakwb eng RC581-607 Guillem de Valles-Ibáñez verfasserin aut Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15–24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls. common variable immunodeficiency primary immunodeficiency exome sequencing loss-of-function rare disease genetics Immunologic diseases. Allergy Ana Esteve-Solé verfasserin aut Ana Esteve-Solé verfasserin aut Mònica Piquer verfasserin aut Mònica Piquer verfasserin aut E. Azucena González-Navarro verfasserin aut E. Azucena González-Navarro verfasserin aut Jessica Hernandez-Rodriguez verfasserin aut Hafid Laayouni verfasserin aut Hafid Laayouni verfasserin aut Eva González-Roca verfasserin aut Eva González-Roca verfasserin aut Ana María Plaza-Martin verfasserin aut Ana María Plaza-Martin verfasserin aut Ángela Deyà-Martínez verfasserin aut Ángela Deyà-Martínez verfasserin aut Andrea Martín-Nalda verfasserin aut Andrea Martín-Nalda verfasserin aut Mónica Martínez-Gallo verfasserin aut Mónica Martínez-Gallo verfasserin aut Mónica Martínez-Gallo verfasserin aut Marina García-Prat verfasserin aut Marina García-Prat verfasserin aut Lucía del Pino-Molina verfasserin aut Ivón Cuscó verfasserin aut Ivón Cuscó verfasserin aut Marta Codina-Solà verfasserin aut Marta Codina-Solà verfasserin aut Laura Batlle-Masó verfasserin aut Laura Batlle-Masó verfasserin aut Manuel Solís-Moruno verfasserin aut Manuel Solís-Moruno verfasserin aut Tomàs Marquès-Bonet verfasserin aut Tomàs Marquès-Bonet verfasserin aut Tomàs Marquès-Bonet verfasserin aut Elena Bosch verfasserin aut Eduardo López-Granados verfasserin aut Juan Ignacio Aróstegui verfasserin aut Juan Ignacio Aróstegui verfasserin aut Pere Soler-Palacín verfasserin aut Pere Soler-Palacín verfasserin aut Roger Colobran verfasserin aut Roger Colobran verfasserin aut Roger Colobran verfasserin aut Jordi Yagüe verfasserin aut Jordi Yagüe verfasserin aut Laia Alsina verfasserin aut Laia Alsina verfasserin aut Manel Juan verfasserin aut Manel Juan verfasserin aut Ferran Casals verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 9(2018) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:9 year:2018 https://doi.org/10.3389/fimmu.2018.00636 kostenfrei https://doaj.org/article/101b88bc2f1f4640aaf1b70c55b35578 kostenfrei http://journal.frontiersin.org/article/10.3389/fimmu.2018.00636/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2018 |
| allfieldsSound |
10.3389/fimmu.2018.00636 doi (DE-627)DOAJ038882566 (DE-599)DOAJ101b88bc2f1f4640aaf1b70c55b35578 DE-627 ger DE-627 rakwb eng RC581-607 Guillem de Valles-Ibáñez verfasserin aut Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15–24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls. common variable immunodeficiency primary immunodeficiency exome sequencing loss-of-function rare disease genetics Immunologic diseases. Allergy Ana Esteve-Solé verfasserin aut Ana Esteve-Solé verfasserin aut Mònica Piquer verfasserin aut Mònica Piquer verfasserin aut E. Azucena González-Navarro verfasserin aut E. Azucena González-Navarro verfasserin aut Jessica Hernandez-Rodriguez verfasserin aut Hafid Laayouni verfasserin aut Hafid Laayouni verfasserin aut Eva González-Roca verfasserin aut Eva González-Roca verfasserin aut Ana María Plaza-Martin verfasserin aut Ana María Plaza-Martin verfasserin aut Ángela Deyà-Martínez verfasserin aut Ángela Deyà-Martínez verfasserin aut Andrea Martín-Nalda verfasserin aut Andrea Martín-Nalda verfasserin aut Mónica Martínez-Gallo verfasserin aut Mónica Martínez-Gallo verfasserin aut Mónica Martínez-Gallo verfasserin aut Marina García-Prat verfasserin aut Marina García-Prat verfasserin aut Lucía del Pino-Molina verfasserin aut Ivón Cuscó verfasserin aut Ivón Cuscó verfasserin aut Marta Codina-Solà verfasserin aut Marta Codina-Solà verfasserin aut Laura Batlle-Masó verfasserin aut Laura Batlle-Masó verfasserin aut Manuel Solís-Moruno verfasserin aut Manuel Solís-Moruno verfasserin aut Tomàs Marquès-Bonet verfasserin aut Tomàs Marquès-Bonet verfasserin aut Tomàs Marquès-Bonet verfasserin aut Elena Bosch verfasserin aut Eduardo López-Granados verfasserin aut Juan Ignacio Aróstegui verfasserin aut Juan Ignacio Aróstegui verfasserin aut Pere Soler-Palacín verfasserin aut Pere Soler-Palacín verfasserin aut Roger Colobran verfasserin aut Roger Colobran verfasserin aut Roger Colobran verfasserin aut Jordi Yagüe verfasserin aut Jordi Yagüe verfasserin aut Laia Alsina verfasserin aut Laia Alsina verfasserin aut Manel Juan verfasserin aut Manel Juan verfasserin aut Ferran Casals verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 9(2018) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:9 year:2018 https://doi.org/10.3389/fimmu.2018.00636 kostenfrei https://doaj.org/article/101b88bc2f1f4640aaf1b70c55b35578 kostenfrei http://journal.frontiersin.org/article/10.3389/fimmu.2018.00636/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2018 |
| language |
English |
| source |
In Frontiers in Immunology 9(2018) volume:9 year:2018 |
| sourceStr |
In Frontiers in Immunology 9(2018) volume:9 year:2018 |
| format_phy_str_mv |
Article |
| institution |
findex.gbv.de |
| topic_facet |
common variable immunodeficiency primary immunodeficiency exome sequencing loss-of-function rare disease genetics Immunologic diseases. Allergy |
| isfreeaccess_bool |
true |
| container_title |
Frontiers in Immunology |
| authorswithroles_txt_mv |
Guillem de Valles-Ibáñez @@aut@@ Ana Esteve-Solé @@aut@@ Mònica Piquer @@aut@@ E. Azucena González-Navarro @@aut@@ Jessica Hernandez-Rodriguez @@aut@@ Hafid Laayouni @@aut@@ Eva González-Roca @@aut@@ Ana María Plaza-Martin @@aut@@ Ángela Deyà-Martínez @@aut@@ Andrea Martín-Nalda @@aut@@ Mónica Martínez-Gallo @@aut@@ Marina García-Prat @@aut@@ Lucía del Pino-Molina @@aut@@ Ivón Cuscó @@aut@@ Marta Codina-Solà @@aut@@ Laura Batlle-Masó @@aut@@ Manuel Solís-Moruno @@aut@@ Tomàs Marquès-Bonet @@aut@@ Elena Bosch @@aut@@ Eduardo López-Granados @@aut@@ Juan Ignacio Aróstegui @@aut@@ Pere Soler-Palacín @@aut@@ Roger Colobran @@aut@@ Jordi Yagüe @@aut@@ Laia Alsina @@aut@@ Manel Juan @@aut@@ Ferran Casals @@aut@@ |
| publishDateDaySort_date |
2018-01-01T00:00:00Z |
| hierarchy_top_id |
657998354 |
| id |
DOAJ038882566 |
| language_de |
englisch |
| fullrecord |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ038882566</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230502205638.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230227s2018 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.3389/fimmu.2018.00636</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ038882566</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ101b88bc2f1f4640aaf1b70c55b35578</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">RC581-607</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Guillem de Valles-Ibáñez</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2018</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15–24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">common variable immunodeficiency</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">primary immunodeficiency</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">exome sequencing</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">loss-of-function</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">rare disease genetics</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Immunologic diseases. Allergy</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ana Esteve-Solé</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ana Esteve-Solé</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Mònica Piquer</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Mònica Piquer</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">E. Azucena González-Navarro</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">E. Azucena González-Navarro</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jessica Hernandez-Rodriguez</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Hafid Laayouni</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Hafid Laayouni</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Eva González-Roca</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Eva González-Roca</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ana María Plaza-Martin</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ana María Plaza-Martin</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ángela Deyà-Martínez</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ángela Deyà-Martínez</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Andrea Martín-Nalda</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Andrea Martín-Nalda</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Mónica Martínez-Gallo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Mónica Martínez-Gallo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Mónica Martínez-Gallo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Marina García-Prat</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Marina García-Prat</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Lucía del Pino-Molina</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ivón Cuscó</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ivón Cuscó</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Marta Codina-Solà</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Marta Codina-Solà</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Laura Batlle-Masó</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Laura Batlle-Masó</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Manuel Solís-Moruno</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Manuel Solís-Moruno</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Tomàs Marquès-Bonet</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Tomàs Marquès-Bonet</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Tomàs Marquès-Bonet</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Elena Bosch</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Eduardo López-Granados</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Juan Ignacio Aróstegui</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Juan Ignacio Aróstegui</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Pere Soler-Palacín</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Pere Soler-Palacín</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Roger Colobran</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Roger Colobran</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Roger Colobran</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jordi Yagüe</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jordi Yagüe</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Laia Alsina</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Laia Alsina</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Manel Juan</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Manel Juan</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ferran Casals</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">Frontiers in Immunology</subfield><subfield code="d">Frontiers Media S.A., 2011</subfield><subfield code="g">9(2018)</subfield><subfield code="w">(DE-627)657998354</subfield><subfield code="w">(DE-600)2606827-8</subfield><subfield code="x">16643224</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:9</subfield><subfield code="g">year:2018</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.3389/fimmu.2018.00636</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/101b88bc2f1f4640aaf1b70c55b35578</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">http://journal.frontiersin.org/article/10.3389/fimmu.2018.00636/full</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/1664-3224</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_DOAJ</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_11</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2003</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">9</subfield><subfield code="j">2018</subfield></datafield></record></collection>
|
| callnumber-first |
R - Medicine |
| author |
Guillem de Valles-Ibáñez |
| spellingShingle |
Guillem de Valles-Ibáñez misc RC581-607 misc common variable immunodeficiency misc primary immunodeficiency misc exome sequencing misc loss-of-function misc rare disease genetics misc Immunologic diseases. Allergy Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond |
| authorStr |
Guillem de Valles-Ibáñez |
| ppnlink_with_tag_str_mv |
@@773@@(DE-627)657998354 |
| format |
electronic Article |
| delete_txt_mv |
keep |
| author_role |
aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut |
| collection |
DOAJ |
| remote_str |
true |
| callnumber-label |
RC581-607 |
| illustrated |
Not Illustrated |
| issn |
16643224 |
| topic_title |
RC581-607 Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond common variable immunodeficiency primary immunodeficiency exome sequencing loss-of-function rare disease genetics |
| topic |
misc RC581-607 misc common variable immunodeficiency misc primary immunodeficiency misc exome sequencing misc loss-of-function misc rare disease genetics misc Immunologic diseases. Allergy |
| topic_unstemmed |
misc RC581-607 misc common variable immunodeficiency misc primary immunodeficiency misc exome sequencing misc loss-of-function misc rare disease genetics misc Immunologic diseases. Allergy |
| topic_browse |
misc RC581-607 misc common variable immunodeficiency misc primary immunodeficiency misc exome sequencing misc loss-of-function misc rare disease genetics misc Immunologic diseases. Allergy |
| format_facet |
Elektronische Aufsätze Aufsätze Elektronische Ressource |
| format_main_str_mv |
Text Zeitschrift/Artikel |
| carriertype_str_mv |
cr |
| hierarchy_parent_title |
Frontiers in Immunology |
| hierarchy_parent_id |
657998354 |
| hierarchy_top_title |
Frontiers in Immunology |
| isfreeaccess_txt |
true |
| familylinks_str_mv |
(DE-627)657998354 (DE-600)2606827-8 |
| title |
Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond |
| ctrlnum |
(DE-627)DOAJ038882566 (DE-599)DOAJ101b88bc2f1f4640aaf1b70c55b35578 |
| title_full |
Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond |
| author_sort |
Guillem de Valles-Ibáñez |
| journal |
Frontiers in Immunology |
| journalStr |
Frontiers in Immunology |
| callnumber-first-code |
R |
| lang_code |
eng |
| isOA_bool |
true |
| recordtype |
marc |
| publishDateSort |
2018 |
| contenttype_str_mv |
txt |
| author_browse |
Guillem de Valles-Ibáñez Ana Esteve-Solé Mònica Piquer E. Azucena González-Navarro Jessica Hernandez-Rodriguez Hafid Laayouni Eva González-Roca Ana María Plaza-Martin Ángela Deyà-Martínez Andrea Martín-Nalda Mónica Martínez-Gallo Marina García-Prat Lucía del Pino-Molina Ivón Cuscó Marta Codina-Solà Laura Batlle-Masó Manuel Solís-Moruno Tomàs Marquès-Bonet Elena Bosch Eduardo López-Granados Juan Ignacio Aróstegui Pere Soler-Palacín Roger Colobran Jordi Yagüe Laia Alsina Manel Juan Ferran Casals |
| container_volume |
9 |
| class |
RC581-607 |
| format_se |
Elektronische Aufsätze |
| author-letter |
Guillem de Valles-Ibáñez |
| doi_str_mv |
10.3389/fimmu.2018.00636 |
| author2-role |
verfasserin |
| title_sort |
evaluating the genetics of common variable immunodeficiency: monogenetic model and beyond |
| callnumber |
RC581-607 |
| title_auth |
Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond |
| abstract |
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15–24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls. |
| abstractGer |
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15–24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls. |
| abstract_unstemmed |
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15–24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls. |
| collection_details |
GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 |
| title_short |
Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond |
| url |
https://doi.org/10.3389/fimmu.2018.00636 https://doaj.org/article/101b88bc2f1f4640aaf1b70c55b35578 http://journal.frontiersin.org/article/10.3389/fimmu.2018.00636/full https://doaj.org/toc/1664-3224 |
| remote_bool |
true |
| author2 |
Ana Esteve-Solé Mònica Piquer E. Azucena González-Navarro Jessica Hernandez-Rodriguez Hafid Laayouni Eva González-Roca Ana María Plaza-Martin Ángela Deyà-Martínez Andrea Martín-Nalda Mónica Martínez-Gallo Marina García-Prat Lucía del Pino-Molina Ivón Cuscó Marta Codina-Solà Laura Batlle-Masó Manuel Solís-Moruno Tomàs Marquès-Bonet Elena Bosch Eduardo López-Granados Juan Ignacio Aróstegui Pere Soler-Palacín Roger Colobran Jordi Yagüe Laia Alsina Manel Juan Ferran Casals |
| author2Str |
Ana Esteve-Solé Mònica Piquer E. Azucena González-Navarro Jessica Hernandez-Rodriguez Hafid Laayouni Eva González-Roca Ana María Plaza-Martin Ángela Deyà-Martínez Andrea Martín-Nalda Mónica Martínez-Gallo Marina García-Prat Lucía del Pino-Molina Ivón Cuscó Marta Codina-Solà Laura Batlle-Masó Manuel Solís-Moruno Tomàs Marquès-Bonet Elena Bosch Eduardo López-Granados Juan Ignacio Aróstegui Pere Soler-Palacín Roger Colobran Jordi Yagüe Laia Alsina Manel Juan Ferran Casals |
| ppnlink |
657998354 |
| callnumber-subject |
RC - Internal Medicine |
| mediatype_str_mv |
c |
| isOA_txt |
true |
| hochschulschrift_bool |
false |
| doi_str |
10.3389/fimmu.2018.00636 |
| callnumber-a |
RC581-607 |
| up_date |
2024-07-03T20:25:05.851Z |
| _version_ |
1803590886600212480 |
| fullrecord_marcxml |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ038882566</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230502205638.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230227s2018 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.3389/fimmu.2018.00636</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ038882566</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ101b88bc2f1f4640aaf1b70c55b35578</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">RC581-607</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Guillem de Valles-Ibáñez</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2018</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in LRBA, CTLA4, NFKB1, and PIK3R1, as well as other very likely causative variants in PRKCD, MAPK8, or DOCK8 among others. We experimentally validate the effect of the LRBA stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in CTLA4 producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15–24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">common variable immunodeficiency</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">primary immunodeficiency</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">exome sequencing</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">loss-of-function</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">rare disease genetics</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Immunologic diseases. Allergy</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ana Esteve-Solé</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ana Esteve-Solé</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Mònica Piquer</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Mònica Piquer</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">E. Azucena González-Navarro</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">E. Azucena González-Navarro</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jessica Hernandez-Rodriguez</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Hafid Laayouni</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Hafid Laayouni</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Eva González-Roca</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Eva González-Roca</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ana María Plaza-Martin</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ana María Plaza-Martin</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ángela Deyà-Martínez</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ángela Deyà-Martínez</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Andrea Martín-Nalda</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Andrea Martín-Nalda</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Mónica Martínez-Gallo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Mónica Martínez-Gallo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Mónica Martínez-Gallo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Marina García-Prat</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Marina García-Prat</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Lucía del Pino-Molina</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ivón Cuscó</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ivón Cuscó</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Marta Codina-Solà</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Marta Codina-Solà</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Laura Batlle-Masó</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Laura Batlle-Masó</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Manuel Solís-Moruno</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Manuel Solís-Moruno</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Tomàs Marquès-Bonet</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Tomàs Marquès-Bonet</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Tomàs Marquès-Bonet</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Elena Bosch</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Eduardo López-Granados</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Juan Ignacio Aróstegui</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Juan Ignacio Aróstegui</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Pere Soler-Palacín</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Pere Soler-Palacín</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Roger Colobran</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Roger Colobran</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Roger Colobran</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jordi Yagüe</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Jordi Yagüe</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Laia Alsina</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Laia Alsina</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Manel Juan</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Manel Juan</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ferran Casals</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">Frontiers in Immunology</subfield><subfield code="d">Frontiers Media S.A., 2011</subfield><subfield code="g">9(2018)</subfield><subfield code="w">(DE-627)657998354</subfield><subfield code="w">(DE-600)2606827-8</subfield><subfield code="x">16643224</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:9</subfield><subfield code="g">year:2018</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.3389/fimmu.2018.00636</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/101b88bc2f1f4640aaf1b70c55b35578</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">http://journal.frontiersin.org/article/10.3389/fimmu.2018.00636/full</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/1664-3224</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_DOAJ</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_11</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2003</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">9</subfield><subfield code="j">2018</subfield></datafield></record></collection>
|
| score |
7.4032135 |