A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing

Background Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. Methods To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. Results We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. Conclusions In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Cao, Ye [verfasserIn] Tokita, Mari J. Chen, Edward S. Ghosh, Rajarshi Chen, Tiansheng Feng, Yanming Gorman, Elizabeth Gibellini, Federica Ward, Patricia A. Braxton, Alicia Wang, Xia Meng, Linyan Xiao, Rui Bi, Weimin Xia, Fan Eng, Christine M. Yang, Yaping Gambin, Tomasz Shaw, Chad Liu, Pengfei Stankiewicz, Pawel

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Schlagwörter:	AOH CpG site Somatic mosaicism Genotype-phenotype correlation PI3K-AKT-mTOR pathway RASopathies UPD

Anmerkung:	© The Author(s). 2019

Übergeordnetes Werk:	Enthalten in: Genome medicine - London : BioMed Central, 2009, 11(2019), 1 vom: 26. Juli
Übergeordnetes Werk:	volume:11 ; year:2019 ; number:1 ; day:26 ; month:07

Links:	Volltext

DOI / URN:	10.1186/s13073-019-0658-2

Katalog-ID:	SPR030673763

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520			\|a Background Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. Methods To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. Results We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. Conclusions In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort.
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allfields	10.1186/s13073-019-0658-2 doi (DE-627)SPR030673763 (SPR)s13073-019-0658-2-e DE-627 ger DE-627 rakwb eng Cao, Ye verfasserin aut A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 Background Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. Methods To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. Results We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. Conclusions In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort. AOH (dpeaa)DE-He213 CpG site (dpeaa)DE-He213 Somatic mosaicism (dpeaa)DE-He213 Genotype-phenotype correlation (dpeaa)DE-He213 PI3K-AKT-mTOR pathway (dpeaa)DE-He213 RASopathies (dpeaa)DE-He213 UPD (dpeaa)DE-He213 Tokita, Mari J. aut Chen, Edward S. aut Ghosh, Rajarshi aut Chen, Tiansheng aut Feng, Yanming aut Gorman, Elizabeth aut Gibellini, Federica aut Ward, Patricia A. aut Braxton, Alicia aut Wang, Xia aut Meng, Linyan aut Xiao, Rui aut Bi, Weimin aut Xia, Fan aut Eng, Christine M. aut Yang, Yaping aut Gambin, Tomasz aut Shaw, Chad aut Liu, Pengfei aut Stankiewicz, Pawel (orcid)0000-0002-6456-7490 aut Enthalten in Genome medicine London : BioMed Central, 2009 11(2019), 1 vom: 26. Juli (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:11 year:2019 number:1 day:26 month:07 https://dx.doi.org/10.1186/s13073-019-0658-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 11 2019 1 26 07
spelling	10.1186/s13073-019-0658-2 doi (DE-627)SPR030673763 (SPR)s13073-019-0658-2-e DE-627 ger DE-627 rakwb eng Cao, Ye verfasserin aut A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 Background Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. Methods To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. Results We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. Conclusions In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort. AOH (dpeaa)DE-He213 CpG site (dpeaa)DE-He213 Somatic mosaicism (dpeaa)DE-He213 Genotype-phenotype correlation (dpeaa)DE-He213 PI3K-AKT-mTOR pathway (dpeaa)DE-He213 RASopathies (dpeaa)DE-He213 UPD (dpeaa)DE-He213 Tokita, Mari J. aut Chen, Edward S. aut Ghosh, Rajarshi aut Chen, Tiansheng aut Feng, Yanming aut Gorman, Elizabeth aut Gibellini, Federica aut Ward, Patricia A. aut Braxton, Alicia aut Wang, Xia aut Meng, Linyan aut Xiao, Rui aut Bi, Weimin aut Xia, Fan aut Eng, Christine M. aut Yang, Yaping aut Gambin, Tomasz aut Shaw, Chad aut Liu, Pengfei aut Stankiewicz, Pawel (orcid)0000-0002-6456-7490 aut Enthalten in Genome medicine London : BioMed Central, 2009 11(2019), 1 vom: 26. Juli (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:11 year:2019 number:1 day:26 month:07 https://dx.doi.org/10.1186/s13073-019-0658-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 11 2019 1 26 07
allfields_unstemmed	10.1186/s13073-019-0658-2 doi (DE-627)SPR030673763 (SPR)s13073-019-0658-2-e DE-627 ger DE-627 rakwb eng Cao, Ye verfasserin aut A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 Background Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. Methods To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. Results We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. Conclusions In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort. AOH (dpeaa)DE-He213 CpG site (dpeaa)DE-He213 Somatic mosaicism (dpeaa)DE-He213 Genotype-phenotype correlation (dpeaa)DE-He213 PI3K-AKT-mTOR pathway (dpeaa)DE-He213 RASopathies (dpeaa)DE-He213 UPD (dpeaa)DE-He213 Tokita, Mari J. aut Chen, Edward S. aut Ghosh, Rajarshi aut Chen, Tiansheng aut Feng, Yanming aut Gorman, Elizabeth aut Gibellini, Federica aut Ward, Patricia A. aut Braxton, Alicia aut Wang, Xia aut Meng, Linyan aut Xiao, Rui aut Bi, Weimin aut Xia, Fan aut Eng, Christine M. aut Yang, Yaping aut Gambin, Tomasz aut Shaw, Chad aut Liu, Pengfei aut Stankiewicz, Pawel (orcid)0000-0002-6456-7490 aut Enthalten in Genome medicine London : BioMed Central, 2009 11(2019), 1 vom: 26. Juli (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:11 year:2019 number:1 day:26 month:07 https://dx.doi.org/10.1186/s13073-019-0658-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 11 2019 1 26 07
allfieldsGer	10.1186/s13073-019-0658-2 doi (DE-627)SPR030673763 (SPR)s13073-019-0658-2-e DE-627 ger DE-627 rakwb eng Cao, Ye verfasserin aut A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 Background Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. Methods To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. Results We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. Conclusions In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort. AOH (dpeaa)DE-He213 CpG site (dpeaa)DE-He213 Somatic mosaicism (dpeaa)DE-He213 Genotype-phenotype correlation (dpeaa)DE-He213 PI3K-AKT-mTOR pathway (dpeaa)DE-He213 RASopathies (dpeaa)DE-He213 UPD (dpeaa)DE-He213 Tokita, Mari J. aut Chen, Edward S. aut Ghosh, Rajarshi aut Chen, Tiansheng aut Feng, Yanming aut Gorman, Elizabeth aut Gibellini, Federica aut Ward, Patricia A. aut Braxton, Alicia aut Wang, Xia aut Meng, Linyan aut Xiao, Rui aut Bi, Weimin aut Xia, Fan aut Eng, Christine M. aut Yang, Yaping aut Gambin, Tomasz aut Shaw, Chad aut Liu, Pengfei aut Stankiewicz, Pawel (orcid)0000-0002-6456-7490 aut Enthalten in Genome medicine London : BioMed Central, 2009 11(2019), 1 vom: 26. Juli (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:11 year:2019 number:1 day:26 month:07 https://dx.doi.org/10.1186/s13073-019-0658-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 11 2019 1 26 07
allfieldsSound	10.1186/s13073-019-0658-2 doi (DE-627)SPR030673763 (SPR)s13073-019-0658-2-e DE-627 ger DE-627 rakwb eng Cao, Ye verfasserin aut A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 Background Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. Methods To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. Results We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. Conclusions In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort. AOH (dpeaa)DE-He213 CpG site (dpeaa)DE-He213 Somatic mosaicism (dpeaa)DE-He213 Genotype-phenotype correlation (dpeaa)DE-He213 PI3K-AKT-mTOR pathway (dpeaa)DE-He213 RASopathies (dpeaa)DE-He213 UPD (dpeaa)DE-He213 Tokita, Mari J. aut Chen, Edward S. aut Ghosh, Rajarshi aut Chen, Tiansheng aut Feng, Yanming aut Gorman, Elizabeth aut Gibellini, Federica aut Ward, Patricia A. aut Braxton, Alicia aut Wang, Xia aut Meng, Linyan aut Xiao, Rui aut Bi, Weimin aut Xia, Fan aut Eng, Christine M. aut Yang, Yaping aut Gambin, Tomasz aut Shaw, Chad aut Liu, Pengfei aut Stankiewicz, Pawel (orcid)0000-0002-6456-7490 aut Enthalten in Genome medicine London : BioMed Central, 2009 11(2019), 1 vom: 26. Juli (DE-627)594424275 (DE-600)2484394-5 1756-994X nnns volume:11 year:2019 number:1 day:26 month:07 https://dx.doi.org/10.1186/s13073-019-0658-2 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 11 2019 1 26 07
language	English
source	Enthalten in Genome medicine 11(2019), 1 vom: 26. Juli volume:11 year:2019 number:1 day:26 month:07
sourceStr	Enthalten in Genome medicine 11(2019), 1 vom: 26. Juli volume:11 year:2019 number:1 day:26 month:07
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	AOH CpG site Somatic mosaicism Genotype-phenotype correlation PI3K-AKT-mTOR pathway RASopathies UPD
isfreeaccess_bool	true
container_title	Genome medicine
authorswithroles_txt_mv	Cao, Ye @@aut@@ Tokita, Mari J. @@aut@@ Chen, Edward S. @@aut@@ Ghosh, Rajarshi @@aut@@ Chen, Tiansheng @@aut@@ Feng, Yanming @@aut@@ Gorman, Elizabeth @@aut@@ Gibellini, Federica @@aut@@ Ward, Patricia A. @@aut@@ Braxton, Alicia @@aut@@ Wang, Xia @@aut@@ Meng, Linyan @@aut@@ Xiao, Rui @@aut@@ Bi, Weimin @@aut@@ Xia, Fan @@aut@@ Eng, Christine M. @@aut@@ Yang, Yaping @@aut@@ Gambin, Tomasz @@aut@@ Shaw, Chad @@aut@@ Liu, Pengfei @@aut@@ Stankiewicz, Pawel @@aut@@
publishDateDaySort_date	2019-07-26T00:00:00Z
hierarchy_top_id	594424275
id	SPR030673763
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">SPR030673763</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230520010423.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201007s2019 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s13073-019-0658-2</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR030673763</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s13073-019-0658-2-e</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="100" ind1="1" ind2=" "><subfield code="a">Cao, Ye</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="2"><subfield code="a">A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2019</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="500" ind1=" " ind2=" "><subfield code="a">© The Author(s). 2019</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Background Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. Methods To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. Results We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. Conclusions In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. 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author	Cao, Ye
spellingShingle	Cao, Ye misc AOH misc CpG site misc Somatic mosaicism misc Genotype-phenotype correlation misc PI3K-AKT-mTOR pathway misc RASopathies misc UPD A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing
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topic_title	A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing AOH (dpeaa)DE-He213 CpG site (dpeaa)DE-He213 Somatic mosaicism (dpeaa)DE-He213 Genotype-phenotype correlation (dpeaa)DE-He213 PI3K-AKT-mTOR pathway (dpeaa)DE-He213 RASopathies (dpeaa)DE-He213 UPD (dpeaa)DE-He213
topic	misc AOH misc CpG site misc Somatic mosaicism misc Genotype-phenotype correlation misc PI3K-AKT-mTOR pathway misc RASopathies misc UPD
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title	A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing
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title_full	A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing
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author_browse	Cao, Ye Tokita, Mari J. Chen, Edward S. Ghosh, Rajarshi Chen, Tiansheng Feng, Yanming Gorman, Elizabeth Gibellini, Federica Ward, Patricia A. Braxton, Alicia Wang, Xia Meng, Linyan Xiao, Rui Bi, Weimin Xia, Fan Eng, Christine M. Yang, Yaping Gambin, Tomasz Shaw, Chad Liu, Pengfei Stankiewicz, Pawel
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title_sort	clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing
title_auth	A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing
abstract	Background Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. Methods To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. Results We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. Conclusions In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort. © The Author(s). 2019
abstractGer	Background Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. Methods To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. Results We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. Conclusions In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort. © The Author(s). 2019
abstract_unstemmed	Background Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. Methods To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. Results We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. Conclusions In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort. © The Author(s). 2019
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title_short	A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing
url	https://dx.doi.org/10.1186/s13073-019-0658-2
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author2	Tokita, Mari J. Chen, Edward S. Ghosh, Rajarshi Chen, Tiansheng Feng, Yanming Gorman, Elizabeth Gibellini, Federica Ward, Patricia A. Braxton, Alicia Wang, Xia Meng, Linyan Xiao, Rui Bi, Weimin Xia, Fan Eng, Christine M. Yang, Yaping Gambin, Tomasz Shaw, Chad Liu, Pengfei Stankiewicz, Pawel
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To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. Methods To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. Results We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. Conclusions In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. 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A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing

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