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

Jacqueline A Odgis¹, Katie M Gallagher², Atteeq U Rehman³, Priya N Marathe¹, Katherine E Bonini¹, Monisha Sebastin², Miranda Di Biase², Kaitlyn Brown², Nicole R Kelly², Michelle A Ramos^{4

5}, Amanda Thomas-Wilson³, Saurav Guha³, Volkan Okur³, Mythily Ganapathi^{3

6}, Lama Elkhoury⁷, Lisa Edelmann⁷, Randi E Zinberg^{8

9}, Noura S Abul-Husn^{1

8

10}, George A Diaz^{8

11}, John M Greally², Sabrina A Suckiel^{1

10}, Vaidehi Jobanputra^{3

6}, Carol R Horowitz^{4

5

10}, Eimear E Kenny^{1

8

10}, Melissa P Wasserstein², Bruce D Gelb^{8

11

12}

Affiliations

¹ The Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
² Division of Pediatric Genetic Medicine, Department of Pediatrics, Children's Hospital at Montefiore/Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA.
³ Molecular Diagnostics, New York Genome Center, New York, New York, USA.
⁴ Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁵ Institute for Health Equity Research, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁶ Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.
⁷ Sema4, Stamford, Connecticut, USA.
⁸ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁹ Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁰ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹¹ Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹² Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

PMID: 36563179
PMCID: PMC10266700
DOI: 10.1002/ajmg.a.63062

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

Jacqueline A Odgis et al. Am J Med Genet A. 2023 Mar.

. 2023 Mar;191(3):699-710.

doi: 10.1002/ajmg.a.63062. Epub 2022 Dec 23.

Authors

Affiliations

¹ The Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
² Division of Pediatric Genetic Medicine, Department of Pediatrics, Children's Hospital at Montefiore/Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA.
³ Molecular Diagnostics, New York Genome Center, New York, New York, USA.
⁴ Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁵ Institute for Health Equity Research, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁶ Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.
⁷ Sema4, Stamford, Connecticut, USA.
⁸ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁹ Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁰ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹¹ Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹² Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

PMID: 36563179
PMCID: PMC10266700
DOI: 10.1002/ajmg.a.63062

Abstract

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.

Keywords: genome sequencing; genomic medicine; mosaicism; pediatric genetics; whole genome sequencing.

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Conflict of interest statement

Conflicts of Interest

N.S.A.-H. is an employee and equity holder of 23andMe; serves as a scientific advisory board member for Allelica; received personal fees from Genentech, Allelica, and 23andMe; received research funding from Akcea; and was previously employed by Regeneron Pharmaceuticals.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources