Resolving adolescence-onset progressive myoclonic epilepsy with variable phenotypes using whole exome sequencing

Muhammad Ilyas; Rafaqat Ishaq; Khajista Tahira; Sadiq Noor Khan; Ataullah; Fayaz Ahmad; Umme Habiba; Aatika Minhas; Ghazala Kaukab Raja; Pakeeza Arzoo Shaiq

Objective: Progressive myoclonic epilepsies (PMEs) are a group of neurodegenerative disorders most commonly affecting adolescents. It is characterized by generalized myoclonic epilepsy, ataxia, cognitive deficits, and dementia. To date, several PMEs associated genes have been identified with specific phenotypes. However, CLN6 variants with variable phenotypes have not been described with adolescence-onset PMEs in Pakistan. In the current study, we described three individuals affected with autosomal recessive adolescence-onset PMEs from a multiplex Pakistani family with substantially variable clinical phenotypes.Methods: Whole Exome Sequencing (WES) was performed in the proband followed by Sanger sequencing to identify the causative variant(s) which was later verified using bi-directional Sanger sequencing. Results: We identified a homozygous recessive CLN6 variant c.768C>G (p.Asp256Glu) which resides at the TM6-TM7 loop domain of CLN6 a hotspot for CLN6 variants that is currently thought to be typical for PMEs.Conclusion: This study supports and expands the phenotypic spectrum of CLN6 mutations and the importance of considering CLN6 variant c.768C>G in diagnosing adolescence onset progressive myoclonic epilepsy. Moreover, it also indicates variable pathology among these patients with the same CLN6genotype strongly contributes to clinical heterogeneity.