Background: Several genes have been implicated in a highly variable presentation of developmental delay with psychomotor retardation. Mutations in EMC1 gene have recently been reported. Herein, we describe a proband born of a consanguineous marriage, who presented with early infantile onset epilepsy, scaphocephaly, developmental delay, central hypotonia, muscle wasting, and severe cerebellar and brainstem atrophy.
Methods: Genetic testing in the proband was performed using custom clinical exome and targeted next-generation sequencing. This was followed by segregation analysis of the variant in the parents by Sanger sequencing and evaluation of the splice variant by RNA sequencing.
Results: Clinical exome sequencing identified a novel homozygous intronic splice variant in the EMC1 gene (chr1:19564510C>T, c.1212 + 1G>A, NM_015047.2). Neither population databases (ExAC and 1000 genomes) nor our internal database (n = 1,500) had reported this rare variant, predicted to affect the splicing. RNA sequencing data from the proband confirmed aberrant splicing with intron 11 retention, thereby introducing a stop codon in the resultant mRNA. This nonsense mutation is predicted to result in the premature termination of protein synthesis leading to loss of function of the EMC1 protein.
Conclusion: We report, for the first time the role of aberrant EMC1RNA splicing as a potential cause of disease pathogenesis. The severe epilepsy observed in our study expands the disease-associated phenotype and also emphasizes the need for comprehensive screening of intronic splice mutations.
Keywords: EMC1; Indian population; South Asian; clinical exome; developmental delay; epilepsy; psychomotor retardation; splice variant.
© 2017 MedGenome Labs Pvt. Ltd. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.