The elucidation of the intrafamilial phenotypic heterogeneity of neurodevelopmental disorders by trio-based exome sequencing
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| Year of publication | 2023 |
| Type | Conference abstract |
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| Description | The intrafamilial phenotypic heterogeneity of neurodevelopmental disorders represents a challenging issue in the molecular diagnostics of paediatric NDDs and subsequent genetic counselling. Trio-based ES serves as the unique solution to identify multiple genetic hits and explain their contribution to the clinical manifestation of NDDs. Our study included 89 paediatric patients with NDDs and MCA and their parents. The strategy of trio-based ES utilized the commercial kit Human Core Exome (Twist Biosciences), Illumina NovaSeq 6000 and in-house bioinformatic pipeline. Trio-based ES has elucidated 49% of paediatric NDDs (44/89), including recurrent and novel causative gene variants affecting the central nervous system development and functioning. The detailed variant prioritization and analysis uncovered the familial occurrence of causative variants in “OMIM-morbid” genes in fourteen paediatric patients from twelve families. Familial causative variants in “OMIM-morbid” genes or CNVs were detected in seven patients from six families whereas the variable combinations of causative variants in “OMIM-morbid” genes and rare CNVs encompassing “OMIM-morbid” genes were identified in seven patients from six families. The segregation analyses were performed in other familial members, including those with the clinical manifestation of NDDs. The intrafamilial phenotypic heterogeneity of NDDs may be explained by “two-“ or “multiple-hit” model for NDDs or by dual diagnosis. Our results shed light on the genetic basis of this phenomenon and demonstrate how trio-based ES can facilitate the molecular diagnostics of paediatric NDDs. Supported by Ministry of Health of the Czech Republic, grant nr. NU20-07-00145, and conceptual development of research organization (FNBr, 65269705). |
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