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

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.

[1]  V. Jobanputra,et al.  eP236: TeleKidSeq: Incorporating telehealth into clinical care of children from diverse backgrounds undergoing clinical genome sequencing , 2022, Genetics in Medicine.

[2]  C. Boerkoel,et al.  Somatic mosaicism detected by genome-wide sequencing in 500 parent–child trios with suspected genetic disease: clinical and genetic counseling implications , 2021, Cold Spring Harbor molecular case studies.

[3]  H. Weiner,et al.  Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations. , 2021, Pediatric neurology.

[4]  Siobhan M. Dolan,et al.  The NYCKidSeq project: study protocol for a randomized controlled trial incorporating genomics into the clinical care of diverse New York City children , 2020, Trials.

[5]  Daniel C. Koboldt,et al.  Best practices for variant calling in clinical sequencing , 2020, Genome medicine.

[6]  R. Wilson,et al.  Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience , 2020, Cold Spring Harbor molecular case studies.

[7]  Hanlin Gao,et al.  The Value of Parental Testing by Next-Generation Sequencing Includes the Detection of Germline Mosaicism. , 2020, The Journal of molecular diagnostics : JMD.

[8]  R. Śmigiel,et al.  CDKL5 Deficiency Disorder—A Complex Epileptic Encephalopathy , 2020, Brain sciences.

[9]  N. Chémaly,et al.  Epilepsy with migrating focal seizures KCNT1 mutation hotspots and phenotype variability , 2020 .

[10]  S. South,et al.  Technical standards for the interpretation and reporting of constitutional copy number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) , 2019, Genetics in Medicine.

[11]  N. Boddaert,et al.  Epilepsy with migrating focal seizures , 2019, Neurology: Genetics.

[12]  Praveen K. Chandrasekharan,et al.  Infantile refractory seizures due to de novo KCNT 1 mutation , 2019, BMJ Case Reports.

[13]  E. Pestana-Knight,et al.  Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review. , 2019, Pediatric neurology.

[14]  J. Hentschel,et al.  Parental mosaicism in epilepsies due to alleged de novo variants , 2019, Epilepsia.

[15]  M. Jaatun,et al.  Epilepsy in tuberous sclerosis complex: Findings from the TOSCA Study , 2018, Epilepsia open.

[16]  Angela Marchi,et al.  Postictal electroencephalographic (EEG) suppression: A stereo‐EEG study of 100 focal to bilateral tonic–clonic seizures , 2018, Epilepsia.

[17]  K. Nagata,et al.  De novo PHACTR1 mutations in West syndrome and their pathophysiological effects , 2018, Brain : a journal of neurology.

[18]  I. Simonic,et al.  Haploinsufficiency of CUX1 Causes Nonsyndromic Global Developmental Delay With Possible Catch‐up Development , 2018, Annals of neurology.

[19]  G. Carvill,et al.  Parental Mosaicism in "De Novo" Epileptic Encephalopathies. , 2018, The New England journal of medicine.

[20]  K. B. Manheimer,et al.  Robust identification of mosaic variants in congenital heart disease , 2018, Human Genetics.

[21]  L. Shlush.  Age-related clonal hematopoiesis. , 2018, Blood.

[22]  Amanda S. Lindy,et al.  High frequency of mosaic pathogenic variants in genes causing epilepsy-related neurodevelopmental disorders , 2017, Genetics in Medicine.

[23]  A. Y. Ye,et al.  Genomic mosaicism in paternal sperm and multiple parental tissues in a Dravet syndrome cohort , 2017, Scientific Reports.

[24]  François Dubeau,et al.  High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. , 2017, American journal of human genetics.

[25]  Donald N Freed,et al.  The Contribution of Mosaic Variants to Autism Spectrum Disorder , 2016, PLoS genetics.

[26]  Arthur Wuster,et al.  Timing, rates and spectra of human germline mutation , 2015, Nature Genetics.

[27]  C. Walsh,et al.  Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms , 2015, Neuron.

[28]  L. Vissers,et al.  Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic Variation. , 2015, American journal of human genetics.

[29]  Y. Kuroda,et al.  Delineation of the KIAA2022 mutation phenotype: Two patients with X‐linked intellectual disability and distinctive features , 2015, American journal of medical genetics. Part A.

[30]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[31]  S. Dib-Hajj,et al.  De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy , 2015, Journal of Medical Genetics.

[32]  Leslie Cope,et al.  Clinical validation of KRAS, BRAF, and EGFR mutation detection using next-generation sequencing. , 2014, American journal of clinical pathology.

[33]  Wu We,et al.  American College of Medical Genetics Standards and Guidelines for Interpretation and Reporting of Postnatal Constitutional Copy Number Variants , 2014 .

[34]  S. Haas,et al.  Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth. , 2013, Human molecular genetics.

[35]  Leslie G. Biesecker,et al.  A genomic view of mosaicism and human disease , 2013, Nature Reviews Genetics.

[36]  B. V. van Bon,et al.  Diagnostic exome sequencing in persons with severe intellectual disability. , 2012, The New England journal of medicine.

[37]  S. South,et al.  American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants , 2011, Genetics in Medicine.

[38]  N. C. Schanen,et al.  The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13 , 2010, Neurobiology of Disease.

[39]  Laura K Conlin,et al.  Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis. , 2010, Human molecular genetics.