1. Academic Validation
  2. A novel splice variant in EMC1 is associated with cerebellar atrophy, visual impairment, psychomotor retardation with epilepsy

A novel splice variant in EMC1 is associated with cerebellar atrophy, visual impairment, psychomotor retardation with epilepsy

  • Mol Genet Genomic Med. 2018 Mar;6(2):282-287. doi: 10.1002/mgg3.352.
Thenral S Geetha 1 Lokesh Lingappa 2 Abhishek Ravindra Jain 2 Hridya Govindan 1 Nitin Mandloi 1 Sakthivel Murugan 1 Ravi Gupta 1 Ramprasad Vedam 1
Affiliations

Affiliations

  • 1 Medgenome Labs, Bommasandra, Bangalore, India.
  • 2 Rainbow Hospital, Hyderabad, India.
Abstract

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.

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