Detection of mosaic variants using genome sequencing in a large pediatric cohort

被引：6

作者：

Odgis, Jacqueline A. A. ^{[1
]}

Gallagher, Katie M. M. ^{[2
,14
]}

Rehman, Atteeq U. U. ^{[3
]}

Marathe, Priya N. N. ^{[1
]}

Bonini, Katherine E. E. ^{[1
]}

Sebastin, Monisha ^{[2
]}

Di Biase, Miranda ^{[2
]}

Brown, Kaitlyn ^{[2
,15
]}

Kelly, Nicole R. R. ^{[2
]}

Ramos, Michelle A. A. ^{[4
,5
]}

Thomas-Wilson, Amanda ^{[3
]}

Guha, Saurav ^{[3
]}

Okur, Volkan ^{[3
]}

Ganapathi, Mythily ^{[3
,6
]}

Elkhoury, Lama ^{[7
]}

Edelmann, Lisa ^{[7
]}

Zinberg, Randi E. E. ^{[8
,9
]}

Abul-Husn, Noura S. S. ^{[1
,8
,10
,16
]}

Diaz, George A. A. ^{[8
,11
]}

Greally, John M. M. ^{[2
]}

Suckiel, Sabrina A. A. ^{[1
,10
]}

Jobanputra, Vaidehi ^{[3
,6
]}

Horowitz, Carol R. R. ^{[4
,5
,10
]}

Kenny, Eimear E. E. ^{[1
,8
,10
]}

Wasserstein, Melissa P. P. ^{[2
]}

Gelb, Bruce D. D. ^{[8
,11
,12
,13
]}

机构：

[1] Icahn Sch Med Mt Sinai, Inst Genom Hlth, New York, NY USA

[2] Albert Einstein Coll Med, Childrens Hosp Montefiore, Montefiore Med Ctr, Dept Pediat,Div Pediat Genet Med, New York, NY USA

[3] New York Genome Ctr, Mol Diagnost, New York, NY USA

[4] Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, New York, NY USA

[5] Icahn Sch Med Mt Sinai, Inst Hlth Equ Res, New York, NY USA

[6] Columbia Univ Med Ctr, Dept Pathol & Cell Biol, New York, NY USA

[7] Sema4, Stamford, CT USA

[8] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY USA

[9] Icahn Sch Med Mt Sinai, Dept Obstet Gynecol & Reprod Sci, New York, NY USA

[10] Icahn Sch Med Mt Sinai, Dept Med, New York, NY USA

[11] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY USA

[12] Mindich Child Hlth & Dev Inst, Icahn Sch Med Mt Sinai, New York, NY USA

[13] Icahn Sch Med Mt Sinai, One Gustave Levy Pl,Box1040, New York, NY 10029 USA

[14] Sarah Lawrence Coll, Grad Program Human Genet, Bronxville, NY USA

[15] Illumina Inc, San Diego, CA USA

[16] 23andMe Inc, Sunnyvale, CA USA

来源：

AMERICAN JOURNAL OF MEDICAL GENETICS PART A | 2023年 / 191卷 / 03期

基金：

美国国家卫生研究院;

关键词：

genome sequencing; genomic medicine; mosaicism; pediatric genetics; whole genome sequencing; JOINT CONSENSUS RECOMMENDATION; AUTISM SPECTRUM DISORDER; MEDICAL GENETICS; AMERICAN-COLLEGE; INTELLECTUAL DISABILITY; MUTATIONS; STANDARDS; GUIDELINES;

D O I：

10.1002/ajmg.a.63062

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The increased use of next-generation sequencing has expanded our understanding of the involvement and prevalence of mosaicism in genetic disorders. We describe a total of eleven cases: nine in which mosaic variants detected by genome sequencing (GS) and/or targeted gene panels (TGPs) were considered to be causative for the proband's phenotype, and two of apparent parental mosaicism. Variants were identified in the following genes: PHACTR1, SCN8A, KCNT1, CDKL5, NEXMIF, CUX1, TSC2, GABRB2, and SMARCB1. In addition, we identified one large duplication including three genes, UBE3A, GABRB3, and MAGEL2, and one large deletion including deletion of ARFGAP1, EEF1A2, CHRNA4, and KCNQ2. All patients were enrolled in the NYCKidSeq study, a research program studying the communication of genomic information in clinical care, as well as the clinical utility and diagnostic yield of GS for children with suspected genetic disorders in diverse populations in New York City. We observed variability in the correlation between reported variant allele fraction and the severity of the patient's phenotype, although we were not able to determine the mosaicism percentage in clinically relevant tissue(s). Although our study was not sufficiently powered to assess differences in mosaicism detection between the two testing modalities, we saw a trend toward better detection by GS as compared with TGP testing. This case series supports the importance of mosaicism in childhood-onset genetic conditions and informs guidelines for laboratory and clinical interpretation of mosaic variants detected by GS.

引用

页码：699 / 710

页数：12

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