TY - JOUR
T1 - Detection of mosaic variants using genome sequencing in a large pediatric cohort
AU - Odgis, Jacqueline A.
AU - Gallagher, Katie M.
AU - Rehman, Atteeq U.
AU - Marathe, Priya N.
AU - Bonini, Katherine E.
AU - Sebastin, Monisha
AU - Di Biase, Miranda
AU - Brown, Kaitlyn
AU - Kelly, Nicole R.
AU - Ramos, Michelle A.
AU - Thomas-Wilson, Amanda
AU - Guha, Saurav
AU - Okur, Volkan
AU - Ganapathi, Mythily
AU - Elkhoury, Lama
AU - Edelmann, Lisa
AU - Zinberg, Randi E.
AU - Abul-Husn, Noura S.
AU - Diaz, George A.
AU - Greally, John M.
AU - Suckiel, Sabrina A.
AU - Jobanputra, Vaidehi
AU - Horowitz, Carol R.
AU - Kenny, Eimear E.
AU - Wasserstein, Melissa P.
AU - Gelb, Bruce D.
N1 - Funding Information:
The NYCKidSeq project is a genomic medicine research program studying the communication of genomic information in the clinic, and the clinical utility and diagnostic yield of GS in children with suspected genetic disorders in a large cohort of racially and ethnically diverse families in New York City (Odgis et al., 2021 ; Sebastin et al., 2022 ). NYCKidSeq is a member‐site of the Clinical Sequencing Evidence‐Generating Research (CSER2) consortium, jointly funded by the National Human Genome Research Institute and the National Institute of Minority Health and Health Disparities (NIMHD). Through this study, GS and/or targeted gene panel (TGP) testing was performed in a total of 1,054 children and young adults (0–21 years of age) suspected of having an underlying genetic etiology for their neurologic, cardiovascular, or immunologic disorder. We describe a total of eleven cases, nine cases in which apparently mosaic variants were detected and considered to be causative for the proband's phenotype, and two in which inherited variants were present as mosaic in the parental samples. The aim of this case series is to contribute to increasing evidence for the role of mosaicism in childhood‐onset genetic conditions and to inform guidelines for laboratory and clinical interpretation of mosaic variants detected by GS. de novo
Funding Information:
The authors would like to thank the Mount Sinai Genomics Stakeholder Board who have advised us on all aspects of the project as well as our referring providers and all who facilitated our engagement with our participating families. We also offer our profound gratitude to the children and parents who participated in NYCKidSeq, without whom this research would not be possible.
Funding Information:
Research reported in this publication was supported by the National Human Genome Research Institute (NHGRI) and the National Institute on Minority Health and Health Disparities (NIMHD) of the National Institutes of Health under Award Number U01HG009610. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2022 Wiley Periodicals LLC.
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
KW - genome sequencing
KW - genomic medicine
KW - mosaicism
KW - pediatric genetics
KW - whole genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85145037569&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.63062
DO - 10.1002/ajmg.a.63062
M3 - Article
C2 - 36563179
AN - SCOPUS:85145037569
SN - 1552-4825
VL - 191
SP - 699
EP - 710
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 3
ER -