Identification of the rare compound heterozygous variants in the NEB gene in a Korean family with intellectual disability, epilepsy and early-childhood-onset generalized muscle weakness.

Abstract

We examined a Korean family with complex phenotypes characterized by intellectual

disability, epilepsy and early-childhood-onset generalized muscle weakness. Since

we did not find any abnormality using several conventional genetic tests for

detection of chromosomal aberrations, gene copy number variations and

mitochondrial gene mutations, we aimed to identify disease-causing genetic

alteration(s) in this family. We conducted whole-exome sequencing (WES) in this

family. After filtering the WES data, we compared five exome sequences of two

affected siblings, one unaffected sibling and the unaffected parents, and we

determined the allele frequency of the identified variants in an Asian

population. Finally, we selected one candidate variant pair which is unique in

the patients and corresponds to an autosomal recessive genetic model. The two

affected siblings had the same compound heterozygous variation in the NEB gene

encoding nebulin, which was composed of two different missense variants:

c.2603T>C (p.L868P) in exon 27 and c.21340C>T (p.R7114W) in exon 143. We

confirmed these variations by Sanger sequencing. On the basis of the fundamental

role of nebulin in the brain and skeletal muscles, we concluded that this

compound heterozygous NEB variation may be a sound candidate for the

disease-causing mutation in this family. Since the patients are characterized by

generalized muscle weakness together with neurodevelopmental phenotypes, it is

suggested that NEB mutations could manifest more diverse phenotypes than those

previously described.