Parental germline mosaicism in SCN3A-related severe developmental disorder

Inuzuka, Luciana Midori; Macedo‐Souza, Lúcia Inês; Guerra-Peixe, Matheus; Pedreira, Christiane Cobas; Della-Ripa, Bruno; Delgado, Daniel Souza; Monteiro, Fabíola Paoli; Kitajima, João Paulo; Garzón, Eliana; Kok, Fernando

doi:10.1016/j.braindev.2020.12.013

Cited by 1 publication

(1 citation statement)

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“…There are other reasons for failure to identify a significant variant from parental ES of affected probands. These include non‐Mendelian inheritance, a de‐novo variant in the proband, recurrence of an autosomal dominant condition due to gonadal mosaicism, a variant located in a noncoding region, a structural variant, presence of a disease whose genetic etiology has not yet been identified, poor coverage in ES, filtering out of certain relevant variants by bioinformatic software, and nongenetic factors 18,19 …”

Section: Discussionmentioning

confidence: 99%

Retrospective diagnosis by parental testing in the next generation sequencing era and utility of reanalysis of exome data

et al. 2023

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Objective: Genetic diseases are an important cause of neonatal and childhood mortality. For couples with a history of demise of previous children, screening for carrier status can be done by exome sequencing (ES) of the parents. Our aim was to describe the clinical utility of "targeted parental ES" in such couples and to assess the utility of reanalysis of parental ES data. Method:We analyzed previous records, including ES reports, of 52 families with demise of previous offspring with a suspected genetic disorder. We also retrieved and reanalyzed raw data of parental ES in FASTQ format from the testing lab.Results: A potential diagnosis was obtained in 30/52 (57.7%) of couples. We found 38/70 (54.3%) novel variants in this cohort. Shared carrier status for more than one autosomal or X-linked recessive disorder was identified in 18% of couples. Reanalysis of raw data resulted in a reclassification of variants in 15% of cases. Conclusion:Targeted parental ES can be helpful for families with demise of previous offspring with a suspected genetic disorder. Key pointsWhat's already known about the topic? � Many genetic disorders can be rapidly identified by exome sequencing (ES), but this is not always done early in the course of illness due to cost constraints, and many children succumb to the illness before a molecular diagnosis is made.� ES of parents in such cases has a reported diagnostic yield of 38%-64%. What does this study add?� Parental ES had a diagnostic yield of 57.7%, supporting its usefulness for the evaluation of couples with a history of previous loss of offsprings due to a suspected genetic disorder.� Shared carrier status for more than one autosomal or X-linked recessive disorder was found in 18%, suggesting this should be considered with parental ES.� Reanalysis of parental exome data resulted in reclassification of variants in ~15%.

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Section: Discussionmentioning

confidence: 99%