ClinVar Genomic variation as it relates to human health

In a 16-year-old boy, born of consanguineous Saudi parents, with recurrent metabolic crises with variable encephalomyopathic features and neurologic regression (MECREN; 618416), (618416), Shamseldin et al. (2016) identified a homozygous c.871A-G transition (c.871A-G, NM_178526) in the SLC25A42 gene, resulting in an asn291-to-asp (N291D) substitution at a highly conserved residue. The mutation, which was found by exome analysis, segregated with the disorder in the family and was not found in the ExAC database or in 700 in-house control exomes. Molecular modeling suggested that the N291 residue faces the interior of the substrate-binding groove. The mutation was unable to rescue the motor-deficit phenotype in zebrafish with morpholino knockdown of the slc25a42 gene, suggesting that the mutation resulted in a loss of function. Almannai et al. (2018) identified a homozygous N291D mutation in the SLC25A42 gene in 12 patients from 8 unrelated consanguineous Middle Eastern families with MECREN. The phenotype was highly variable, even within families, and the authors suggested that exogenous factors and stressors can modulate disease severity. Functional studies of the variant and studies of patient cells were not performed. The authors referred to N291D as a founder allele in this population. Iuso et al. (2019) identified a homozygous N291D mutation in a 6-year-old boy, born of consanguineous Saudi parents, with MECREN. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was found in heterozygous state in each unaffected parent, confirming segregation. Functional studies of the variant and studies of patient cells were not performed. (less)