Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing
Background: Elevated TCRαβ+CD4−CD8− double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot...
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2023 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: The journal of allergy and clinical immunology - Amsterdam [u.a.] : Elsevier, 1971, 153, Seite 297-308.e12 |
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| Übergeordnetes Werk: |
volume:153 ; pages:297-308.e12 |
| DOI / URN: |
10.1016/j.jaci.2023.11.006 |
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| Katalog-ID: |
ELV066425964 |
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| 008 | 240106s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.jaci.2023.11.006 |2 doi | |
| 035 | |a (DE-627)ELV066425964 | ||
| 035 | |a (ELSEVIER)S0091-6749(23)01462-8 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 082 | 0 | 4 | |a 610 |q VZ |
| 084 | |a 44.45 |2 bkl | ||
| 084 | |a 44.78 |2 bkl | ||
| 100 | 1 | |a Rensing-Ehl, Anne |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing |
| 264 | 1 | |c 2023 | |
| 336 | |a nicht spezifiziert |b zzz |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Background: Elevated TCRαβ+CD4−CD8− double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U).Objective: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway–related genes could explain these cases.Methods: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway–related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH).Results: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous “loss-of-expression” FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH.Conclusion: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing. | ||
| 650 | 4 | |a ALPS | |
| 650 | 4 | |a ALPS-U | |
| 650 | 4 | |a FAS | |
| 650 | 4 | |a FADD | |
| 650 | 4 | |a loss of heterozygosity | |
| 650 | 4 | |a somatic mutations | |
| 650 | 4 | |a promoter | |
| 650 | 4 | |a genetic defect accumulation | |
| 650 | 4 | |a double-negative T cells | |
| 650 | 4 | |a DNT | |
| 700 | 1 | |a Lorenz, Myriam Ricarda |e verfasserin |4 aut | |
| 700 | 1 | |a Führer, Marita |e verfasserin |4 aut | |
| 700 | 1 | |a Willenbacher, Wolfgang |e verfasserin |4 aut | |
| 700 | 1 | |a Willenbacher, Ella |e verfasserin |4 aut | |
| 700 | 1 | |a Sopper, Sieghart |e verfasserin |4 aut | |
| 700 | 1 | |a Abinun, Mario |e verfasserin |4 aut | |
| 700 | 1 | |a Maccari, Maria Elena |e verfasserin |4 aut | |
| 700 | 1 | |a König, Christoph |e verfasserin |4 aut | |
| 700 | 1 | |a Haegele, Pauline |e verfasserin |4 aut | |
| 700 | 1 | |a Fuchs, Sebastian |e verfasserin |4 aut | |
| 700 | 1 | |a Castro, Carla |e verfasserin |4 aut | |
| 700 | 1 | |a Kury, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Pelle, Olivier |e verfasserin |4 aut | |
| 700 | 1 | |a Klemann, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Heeg, Maximilian |e verfasserin |4 aut | |
| 700 | 1 | |a Thalhammer, Julian |e verfasserin |4 aut | |
| 700 | 1 | |a Wegehaupt, Oliver |e verfasserin |4 aut | |
| 700 | 1 | |a Fischer, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Goldacker, Sigune |e verfasserin |4 aut | |
| 700 | 1 | |a Schulte, Björn |e verfasserin |4 aut | |
| 700 | 1 | |a Biskup, Saskia |e verfasserin |4 aut | |
| 700 | 1 | |a Chatelain, Philippe |e verfasserin |4 aut | |
| 700 | 1 | |a Schuster, Volker |e verfasserin |4 aut | |
| 700 | 1 | |a Warnatz, Klaus |e verfasserin |4 aut | |
| 700 | 1 | |a Grimbacher, Bodo |e verfasserin |4 aut | |
| 700 | 1 | |a Meinhardt, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Holzinger, Dirk |e verfasserin |4 aut | |
| 700 | 1 | |a Oommen, Prasad Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Hinze, Tanja |e verfasserin |4 aut | |
| 700 | 1 | |a Hebart, Holger |e verfasserin |4 aut | |
| 700 | 1 | |a Seeger, Karlheinz |e verfasserin |4 aut | |
| 700 | 1 | |a Lehmberg, Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Leahy, Timothy Ronan |e verfasserin |4 aut | |
| 700 | 1 | |a Claviez, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a Vieth, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Schilling, Freimut H. |e verfasserin |4 aut | |
| 700 | 1 | |a Fuchs, Ilka |e verfasserin |4 aut | |
| 700 | 1 | |a Groß, Miriam |e verfasserin |4 aut | |
| 700 | 1 | |a Rieux-Laucat, Frederic |e verfasserin |4 aut | |
| 700 | 1 | |a Magerus, Aude |e verfasserin |4 aut | |
| 700 | 1 | |a Speckmann, Carsten |e verfasserin |4 aut | |
| 700 | 1 | |a Schwarz, Klaus |e verfasserin |4 aut | |
| 700 | 1 | |a Ehl, Stephan |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The journal of allergy and clinical immunology |d Amsterdam [u.a.] : Elsevier, 1971 |g 153, Seite 297-308.e12 |h Online-Ressource |w (DE-627)32045553X |w (DE-600)2006613-2 |w (DE-576)094478864 |x 1097-6825 |7 nnns |
| 773 | 1 | 8 | |g volume:153 |g pages:297-308.e12 |
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| 912 | |a GBV_ILN_161 | ||
| 912 | |a GBV_ILN_168 | ||
| 912 | |a GBV_ILN_170 | ||
| 912 | |a GBV_ILN_187 | ||
| 912 | |a GBV_ILN_206 | ||
| 912 | |a GBV_ILN_213 | ||
| 912 | |a GBV_ILN_224 | ||
| 912 | |a GBV_ILN_230 | ||
| 912 | |a GBV_ILN_285 | ||
| 912 | |a GBV_ILN_293 | ||
| 912 | |a GBV_ILN_370 | ||
| 912 | |a GBV_ILN_602 | ||
| 912 | |a GBV_ILN_702 | ||
| 912 | |a GBV_ILN_2001 | ||
| 912 | |a GBV_ILN_2003 | ||
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| 912 | |a GBV_ILN_2010 | ||
| 912 | |a GBV_ILN_2011 | ||
| 912 | |a GBV_ILN_2014 | ||
| 912 | |a GBV_ILN_2015 | ||
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| 912 | |a GBV_ILN_2025 | ||
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| 912 | |a GBV_ILN_2034 | ||
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| 912 | |a GBV_ILN_2055 | ||
| 912 | |a GBV_ILN_2056 | ||
| 912 | |a GBV_ILN_2059 | ||
| 912 | |a GBV_ILN_2061 | ||
| 912 | |a GBV_ILN_2064 | ||
| 912 | |a GBV_ILN_2088 | ||
| 912 | |a GBV_ILN_2106 | ||
| 912 | |a GBV_ILN_2110 | ||
| 912 | |a GBV_ILN_2111 | ||
| 912 | |a GBV_ILN_2112 | ||
| 912 | |a GBV_ILN_2122 | ||
| 912 | |a GBV_ILN_2129 | ||
| 912 | |a GBV_ILN_2143 | ||
| 912 | |a GBV_ILN_2152 | ||
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| 912 | |a GBV_ILN_4313 | ||
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| 912 | |a GBV_ILN_4325 | ||
| 912 | |a GBV_ILN_4326 | ||
| 912 | |a GBV_ILN_4333 | ||
| 912 | |a GBV_ILN_4334 | ||
| 912 | |a GBV_ILN_4338 | ||
| 912 | |a GBV_ILN_4367 | ||
| 912 | |a GBV_ILN_4393 | ||
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| 936 | b | k | |a 44.45 |j Immunologie |q VZ |
| 936 | b | k | |a 44.78 |j Immunkrankheiten |q VZ |
| 951 | |a AR | ||
| 952 | |d 153 |h 297-308.e12 | ||
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10.1016/j.jaci.2023.11.006 doi (DE-627)ELV066425964 (ELSEVIER)S0091-6749(23)01462-8 DE-627 ger DE-627 rda eng 610 VZ 44.45 bkl 44.78 bkl Rensing-Ehl, Anne verfasserin aut Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Elevated TCRαβ+CD4−CD8− double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U).Objective: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway–related genes could explain these cases.Methods: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway–related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH).Results: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous “loss-of-expression” FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH.Conclusion: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing. ALPS ALPS-U FAS FADD loss of heterozygosity somatic mutations promoter genetic defect accumulation double-negative T cells DNT Lorenz, Myriam Ricarda verfasserin aut Führer, Marita verfasserin aut Willenbacher, Wolfgang verfasserin aut Willenbacher, Ella verfasserin aut Sopper, Sieghart verfasserin aut Abinun, Mario verfasserin aut Maccari, Maria Elena verfasserin aut König, Christoph verfasserin aut Haegele, Pauline verfasserin aut Fuchs, Sebastian verfasserin aut Castro, Carla verfasserin aut Kury, Patrick verfasserin aut Pelle, Olivier verfasserin aut Klemann, Christian verfasserin aut Heeg, Maximilian verfasserin aut Thalhammer, Julian verfasserin aut Wegehaupt, Oliver verfasserin aut Fischer, Marco verfasserin aut Goldacker, Sigune verfasserin aut Schulte, Björn verfasserin aut Biskup, Saskia verfasserin aut Chatelain, Philippe verfasserin aut Schuster, Volker verfasserin aut Warnatz, Klaus verfasserin aut Grimbacher, Bodo verfasserin aut Meinhardt, Andrea verfasserin aut Holzinger, Dirk verfasserin aut Oommen, Prasad Thomas verfasserin aut Hinze, Tanja verfasserin aut Hebart, Holger verfasserin aut Seeger, Karlheinz verfasserin aut Lehmberg, Kai verfasserin aut Leahy, Timothy Ronan verfasserin aut Claviez, Alexander verfasserin aut Vieth, Simon verfasserin aut Schilling, Freimut H. verfasserin aut Fuchs, Ilka verfasserin aut Groß, Miriam verfasserin aut Rieux-Laucat, Frederic verfasserin aut Magerus, Aude verfasserin aut Speckmann, Carsten verfasserin aut Schwarz, Klaus verfasserin aut Ehl, Stephan verfasserin aut Enthalten in The journal of allergy and clinical immunology Amsterdam [u.a.] : Elsevier, 1971 153, Seite 297-308.e12 Online-Ressource (DE-627)32045553X (DE-600)2006613-2 (DE-576)094478864 1097-6825 nnns volume:153 pages:297-308.e12 GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 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_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 44.45 Immunologie VZ 44.78 Immunkrankheiten VZ AR 153 297-308.e12 |
| spelling |
10.1016/j.jaci.2023.11.006 doi (DE-627)ELV066425964 (ELSEVIER)S0091-6749(23)01462-8 DE-627 ger DE-627 rda eng 610 VZ 44.45 bkl 44.78 bkl Rensing-Ehl, Anne verfasserin aut Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Elevated TCRαβ+CD4−CD8− double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U).Objective: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway–related genes could explain these cases.Methods: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway–related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH).Results: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous “loss-of-expression” FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH.Conclusion: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing. ALPS ALPS-U FAS FADD loss of heterozygosity somatic mutations promoter genetic defect accumulation double-negative T cells DNT Lorenz, Myriam Ricarda verfasserin aut Führer, Marita verfasserin aut Willenbacher, Wolfgang verfasserin aut Willenbacher, Ella verfasserin aut Sopper, Sieghart verfasserin aut Abinun, Mario verfasserin aut Maccari, Maria Elena verfasserin aut König, Christoph verfasserin aut Haegele, Pauline verfasserin aut Fuchs, Sebastian verfasserin aut Castro, Carla verfasserin aut Kury, Patrick verfasserin aut Pelle, Olivier verfasserin aut Klemann, Christian verfasserin aut Heeg, Maximilian verfasserin aut Thalhammer, Julian verfasserin aut Wegehaupt, Oliver verfasserin aut Fischer, Marco verfasserin aut Goldacker, Sigune verfasserin aut Schulte, Björn verfasserin aut Biskup, Saskia verfasserin aut Chatelain, Philippe verfasserin aut Schuster, Volker verfasserin aut Warnatz, Klaus verfasserin aut Grimbacher, Bodo verfasserin aut Meinhardt, Andrea verfasserin aut Holzinger, Dirk verfasserin aut Oommen, Prasad Thomas verfasserin aut Hinze, Tanja verfasserin aut Hebart, Holger verfasserin aut Seeger, Karlheinz verfasserin aut Lehmberg, Kai verfasserin aut Leahy, Timothy Ronan verfasserin aut Claviez, Alexander verfasserin aut Vieth, Simon verfasserin aut Schilling, Freimut H. verfasserin aut Fuchs, Ilka verfasserin aut Groß, Miriam verfasserin aut Rieux-Laucat, Frederic verfasserin aut Magerus, Aude verfasserin aut Speckmann, Carsten verfasserin aut Schwarz, Klaus verfasserin aut Ehl, Stephan verfasserin aut Enthalten in The journal of allergy and clinical immunology Amsterdam [u.a.] : Elsevier, 1971 153, Seite 297-308.e12 Online-Ressource (DE-627)32045553X (DE-600)2006613-2 (DE-576)094478864 1097-6825 nnns volume:153 pages:297-308.e12 GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 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_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 44.45 Immunologie VZ 44.78 Immunkrankheiten VZ AR 153 297-308.e12 |
| allfields_unstemmed |
10.1016/j.jaci.2023.11.006 doi (DE-627)ELV066425964 (ELSEVIER)S0091-6749(23)01462-8 DE-627 ger DE-627 rda eng 610 VZ 44.45 bkl 44.78 bkl Rensing-Ehl, Anne verfasserin aut Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Elevated TCRαβ+CD4−CD8− double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U).Objective: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway–related genes could explain these cases.Methods: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway–related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH).Results: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous “loss-of-expression” FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH.Conclusion: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing. ALPS ALPS-U FAS FADD loss of heterozygosity somatic mutations promoter genetic defect accumulation double-negative T cells DNT Lorenz, Myriam Ricarda verfasserin aut Führer, Marita verfasserin aut Willenbacher, Wolfgang verfasserin aut Willenbacher, Ella verfasserin aut Sopper, Sieghart verfasserin aut Abinun, Mario verfasserin aut Maccari, Maria Elena verfasserin aut König, Christoph verfasserin aut Haegele, Pauline verfasserin aut Fuchs, Sebastian verfasserin aut Castro, Carla verfasserin aut Kury, Patrick verfasserin aut Pelle, Olivier verfasserin aut Klemann, Christian verfasserin aut Heeg, Maximilian verfasserin aut Thalhammer, Julian verfasserin aut Wegehaupt, Oliver verfasserin aut Fischer, Marco verfasserin aut Goldacker, Sigune verfasserin aut Schulte, Björn verfasserin aut Biskup, Saskia verfasserin aut Chatelain, Philippe verfasserin aut Schuster, Volker verfasserin aut Warnatz, Klaus verfasserin aut Grimbacher, Bodo verfasserin aut Meinhardt, Andrea verfasserin aut Holzinger, Dirk verfasserin aut Oommen, Prasad Thomas verfasserin aut Hinze, Tanja verfasserin aut Hebart, Holger verfasserin aut Seeger, Karlheinz verfasserin aut Lehmberg, Kai verfasserin aut Leahy, Timothy Ronan verfasserin aut Claviez, Alexander verfasserin aut Vieth, Simon verfasserin aut Schilling, Freimut H. verfasserin aut Fuchs, Ilka verfasserin aut Groß, Miriam verfasserin aut Rieux-Laucat, Frederic verfasserin aut Magerus, Aude verfasserin aut Speckmann, Carsten verfasserin aut Schwarz, Klaus verfasserin aut Ehl, Stephan verfasserin aut Enthalten in The journal of allergy and clinical immunology Amsterdam [u.a.] : Elsevier, 1971 153, Seite 297-308.e12 Online-Ressource (DE-627)32045553X (DE-600)2006613-2 (DE-576)094478864 1097-6825 nnns volume:153 pages:297-308.e12 GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 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_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 44.45 Immunologie VZ 44.78 Immunkrankheiten VZ AR 153 297-308.e12 |
| allfieldsGer |
10.1016/j.jaci.2023.11.006 doi (DE-627)ELV066425964 (ELSEVIER)S0091-6749(23)01462-8 DE-627 ger DE-627 rda eng 610 VZ 44.45 bkl 44.78 bkl Rensing-Ehl, Anne verfasserin aut Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Elevated TCRαβ+CD4−CD8− double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U).Objective: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway–related genes could explain these cases.Methods: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway–related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH).Results: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous “loss-of-expression” FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH.Conclusion: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing. ALPS ALPS-U FAS FADD loss of heterozygosity somatic mutations promoter genetic defect accumulation double-negative T cells DNT Lorenz, Myriam Ricarda verfasserin aut Führer, Marita verfasserin aut Willenbacher, Wolfgang verfasserin aut Willenbacher, Ella verfasserin aut Sopper, Sieghart verfasserin aut Abinun, Mario verfasserin aut Maccari, Maria Elena verfasserin aut König, Christoph verfasserin aut Haegele, Pauline verfasserin aut Fuchs, Sebastian verfasserin aut Castro, Carla verfasserin aut Kury, Patrick verfasserin aut Pelle, Olivier verfasserin aut Klemann, Christian verfasserin aut Heeg, Maximilian verfasserin aut Thalhammer, Julian verfasserin aut Wegehaupt, Oliver verfasserin aut Fischer, Marco verfasserin aut Goldacker, Sigune verfasserin aut Schulte, Björn verfasserin aut Biskup, Saskia verfasserin aut Chatelain, Philippe verfasserin aut Schuster, Volker verfasserin aut Warnatz, Klaus verfasserin aut Grimbacher, Bodo verfasserin aut Meinhardt, Andrea verfasserin aut Holzinger, Dirk verfasserin aut Oommen, Prasad Thomas verfasserin aut Hinze, Tanja verfasserin aut Hebart, Holger verfasserin aut Seeger, Karlheinz verfasserin aut Lehmberg, Kai verfasserin aut Leahy, Timothy Ronan verfasserin aut Claviez, Alexander verfasserin aut Vieth, Simon verfasserin aut Schilling, Freimut H. verfasserin aut Fuchs, Ilka verfasserin aut Groß, Miriam verfasserin aut Rieux-Laucat, Frederic verfasserin aut Magerus, Aude verfasserin aut Speckmann, Carsten verfasserin aut Schwarz, Klaus verfasserin aut Ehl, Stephan verfasserin aut Enthalten in The journal of allergy and clinical immunology Amsterdam [u.a.] : Elsevier, 1971 153, Seite 297-308.e12 Online-Ressource (DE-627)32045553X (DE-600)2006613-2 (DE-576)094478864 1097-6825 nnns volume:153 pages:297-308.e12 GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 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_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 44.45 Immunologie VZ 44.78 Immunkrankheiten VZ AR 153 297-308.e12 |
| allfieldsSound |
10.1016/j.jaci.2023.11.006 doi (DE-627)ELV066425964 (ELSEVIER)S0091-6749(23)01462-8 DE-627 ger DE-627 rda eng 610 VZ 44.45 bkl 44.78 bkl Rensing-Ehl, Anne verfasserin aut Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Elevated TCRαβ+CD4−CD8− double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U).Objective: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway–related genes could explain these cases.Methods: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway–related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH).Results: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous “loss-of-expression” FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH.Conclusion: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing. ALPS ALPS-U FAS FADD loss of heterozygosity somatic mutations promoter genetic defect accumulation double-negative T cells DNT Lorenz, Myriam Ricarda verfasserin aut Führer, Marita verfasserin aut Willenbacher, Wolfgang verfasserin aut Willenbacher, Ella verfasserin aut Sopper, Sieghart verfasserin aut Abinun, Mario verfasserin aut Maccari, Maria Elena verfasserin aut König, Christoph verfasserin aut Haegele, Pauline verfasserin aut Fuchs, Sebastian verfasserin aut Castro, Carla verfasserin aut Kury, Patrick verfasserin aut Pelle, Olivier verfasserin aut Klemann, Christian verfasserin aut Heeg, Maximilian verfasserin aut Thalhammer, Julian verfasserin aut Wegehaupt, Oliver verfasserin aut Fischer, Marco verfasserin aut Goldacker, Sigune verfasserin aut Schulte, Björn verfasserin aut Biskup, Saskia verfasserin aut Chatelain, Philippe verfasserin aut Schuster, Volker verfasserin aut Warnatz, Klaus verfasserin aut Grimbacher, Bodo verfasserin aut Meinhardt, Andrea verfasserin aut Holzinger, Dirk verfasserin aut Oommen, Prasad Thomas verfasserin aut Hinze, Tanja verfasserin aut Hebart, Holger verfasserin aut Seeger, Karlheinz verfasserin aut Lehmberg, Kai verfasserin aut Leahy, Timothy Ronan verfasserin aut Claviez, Alexander verfasserin aut Vieth, Simon verfasserin aut Schilling, Freimut H. verfasserin aut Fuchs, Ilka verfasserin aut Groß, Miriam verfasserin aut Rieux-Laucat, Frederic verfasserin aut Magerus, Aude verfasserin aut Speckmann, Carsten verfasserin aut Schwarz, Klaus verfasserin aut Ehl, Stephan verfasserin aut Enthalten in The journal of allergy and clinical immunology Amsterdam [u.a.] : Elsevier, 1971 153, Seite 297-308.e12 Online-Ressource (DE-627)32045553X (DE-600)2006613-2 (DE-576)094478864 1097-6825 nnns volume:153 pages:297-308.e12 GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 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_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 44.45 Immunologie VZ 44.78 Immunkrankheiten VZ AR 153 297-308.e12 |
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Enthalten in The journal of allergy and clinical immunology 153, Seite 297-308.e12 volume:153 pages:297-308.e12 |
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ALPS ALPS-U FAS FADD loss of heterozygosity somatic mutations promoter genetic defect accumulation double-negative T cells DNT |
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Rensing-Ehl, Anne @@aut@@ Lorenz, Myriam Ricarda @@aut@@ Führer, Marita @@aut@@ Willenbacher, Wolfgang @@aut@@ Willenbacher, Ella @@aut@@ Sopper, Sieghart @@aut@@ Abinun, Mario @@aut@@ Maccari, Maria Elena @@aut@@ König, Christoph @@aut@@ Haegele, Pauline @@aut@@ Fuchs, Sebastian @@aut@@ Castro, Carla @@aut@@ Kury, Patrick @@aut@@ Pelle, Olivier @@aut@@ Klemann, Christian @@aut@@ Heeg, Maximilian @@aut@@ Thalhammer, Julian @@aut@@ Wegehaupt, Oliver @@aut@@ Fischer, Marco @@aut@@ Goldacker, Sigune @@aut@@ Schulte, Björn @@aut@@ Biskup, Saskia @@aut@@ Chatelain, Philippe @@aut@@ Schuster, Volker @@aut@@ Warnatz, Klaus @@aut@@ Grimbacher, Bodo @@aut@@ Meinhardt, Andrea @@aut@@ Holzinger, Dirk @@aut@@ Oommen, Prasad Thomas @@aut@@ Hinze, Tanja @@aut@@ Hebart, Holger @@aut@@ Seeger, Karlheinz @@aut@@ Lehmberg, Kai @@aut@@ Leahy, Timothy Ronan @@aut@@ Claviez, Alexander @@aut@@ Vieth, Simon @@aut@@ Schilling, Freimut H. @@aut@@ Fuchs, Ilka @@aut@@ Groß, Miriam @@aut@@ Rieux-Laucat, Frederic @@aut@@ Magerus, Aude @@aut@@ Speckmann, Carsten @@aut@@ Schwarz, Klaus @@aut@@ Ehl, Stephan @@aut@@ |
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englisch |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">ELV066425964</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240106093254.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">240106s2023 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1016/j.jaci.2023.11.006</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)ELV066425964</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(ELSEVIER)S0091-6749(23)01462-8</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">rda</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">610</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">44.45</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">44.78</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Rensing-Ehl, Anne</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">zzz</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">Background: Elevated TCRαβ+CD4−CD8− double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U).Objective: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway–related genes could explain these cases.Methods: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway–related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH).Results: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous “loss-of-expression” FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH.Conclusion: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">ALPS</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">ALPS-U</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">FAS</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">FADD</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">loss of heterozygosity</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">somatic mutations</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">promoter</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">genetic defect 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Rensing-Ehl, Anne |
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Rensing-Ehl, Anne ddc 610 bkl 44.45 bkl 44.78 misc ALPS misc ALPS-U misc FAS misc FADD misc loss of heterozygosity misc somatic mutations misc promoter misc genetic defect accumulation misc double-negative T cells misc DNT Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing |
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610 VZ 44.45 bkl 44.78 bkl Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing ALPS ALPS-U FAS FADD loss of heterozygosity somatic mutations promoter genetic defect accumulation double-negative T cells DNT |
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Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing |
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Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing |
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Rensing-Ehl, Anne Lorenz, Myriam Ricarda Führer, Marita Willenbacher, Wolfgang Willenbacher, Ella Sopper, Sieghart Abinun, Mario Maccari, Maria Elena König, Christoph Haegele, Pauline Fuchs, Sebastian Castro, Carla Kury, Patrick Pelle, Olivier Klemann, Christian Heeg, Maximilian Thalhammer, Julian Wegehaupt, Oliver Fischer, Marco Goldacker, Sigune Schulte, Björn Biskup, Saskia Chatelain, Philippe Schuster, Volker Warnatz, Klaus Grimbacher, Bodo Meinhardt, Andrea Holzinger, Dirk Oommen, Prasad Thomas Hinze, Tanja Hebart, Holger Seeger, Karlheinz Lehmberg, Kai Leahy, Timothy Ronan Claviez, Alexander Vieth, Simon Schilling, Freimut H. Fuchs, Ilka Groß, Miriam Rieux-Laucat, Frederic Magerus, Aude Speckmann, Carsten Schwarz, Klaus Ehl, Stephan |
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Rensing-Ehl, Anne |
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10.1016/j.jaci.2023.11.006 |
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abnormal biomarkers predict complex fas or fadd defects missed by exome sequencing |
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Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing |
| abstract |
Background: Elevated TCRαβ+CD4−CD8− double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U).Objective: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway–related genes could explain these cases.Methods: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway–related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH).Results: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous “loss-of-expression” FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH.Conclusion: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing. |
| abstractGer |
Background: Elevated TCRαβ+CD4−CD8− double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U).Objective: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway–related genes could explain these cases.Methods: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway–related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH).Results: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous “loss-of-expression” FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH.Conclusion: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing. |
| abstract_unstemmed |
Background: Elevated TCRαβ+CD4−CD8− double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U).Objective: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway–related genes could explain these cases.Methods: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway–related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH).Results: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous “loss-of-expression” FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH.Conclusion: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing. |
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Lorenz, Myriam Ricarda Führer, Marita Willenbacher, Wolfgang Willenbacher, Ella Sopper, Sieghart Abinun, Mario Maccari, Maria Elena König, Christoph Haegele, Pauline Fuchs, Sebastian Castro, Carla Kury, Patrick Pelle, Olivier Klemann, Christian Heeg, Maximilian Thalhammer, Julian Wegehaupt, Oliver Fischer, Marco Goldacker, Sigune Schulte, Björn Biskup, Saskia Chatelain, Philippe Schuster, Volker Warnatz, Klaus Grimbacher, Bodo Meinhardt, Andrea Holzinger, Dirk Oommen, Prasad Thomas Hinze, Tanja Hebart, Holger Seeger, Karlheinz Lehmberg, Kai Leahy, Timothy Ronan Claviez, Alexander Vieth, Simon Schilling, Freimut H. Fuchs, Ilka Groß, Miriam Rieux-Laucat, Frederic Magerus, Aude Speckmann, Carsten Schwarz, Klaus Ehl, Stephan |
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