The clinical benefit of trio-based whole-exome sequencing for the detection of rare pathogenic sequence variants in paediatric patients with undiagnosed neurodevelopmental disorders
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| Year of publication | 2022 |
| Type | Conference abstract |
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| Description | Thanks to more than 50% diagnostic yield the whole-exome sequencing (WES) has become an effective and powerful approach to identify molecular genetic causes of neurodevelopmental disorders (NDDs) and multiple congenital abnormalities (MCA). We present our experience with WES as an effective tool for the detection of rare and novel pathogenic sequence variant using the commercial kit Human Core Exome (Twist Biosciences) and Illumina NovaSeq 6000. Our pilot study included 45 families (trios or quatros) of children with severe NDDs and MCA. Using our in-house bioinformatic pipeline and unique algorithm for variant prioritization we identified recurrent de novo pathogenic sequence variants in clinically relevant SHANK3, GRIN1, NSD1, CDK13 genes, novel de novo pathogenic variants in KDM1A, KMT2E, GNAI1, MEIS2, SMARCA2, RAI1 and CHD8 genes, pathogenic X-linked variants in EDA and OPHN1 genes of maternal origin, pathogenic sequence variants in ZGRF1 of paternal origin and biallelic pathogenic sequence variants in the BLM gene. Moreover, two pathogenic sequence variants in the CTNNB1 and DYNC1H genes were present as low-level mosaicism in healthy fathers. All clinically important variants including secondary findings (in „ACMG“ genes) were manually verified using Sanger sequencing and interpreted based on relevant information in integrated databases of genomic variants, relevant scientific literature, and individual anamnesis. With an achieved diagnostic yield of 37.5% (18/48 children with NDDs and MCA), trio-based WES represents as an effective first-tier diagnostic test in the genetic evaluation of children with NDDs. Supported by Ministry of Health of the Czech Republic, grant nr. NU20-07-00145. All rights reserved. |
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