Familial cases of progressive myoclonic epilepsy caused by maternal somatic mosaicism of a recurrent KCNC1 p.Arg320His mutation

Abstract

Purpose: A recurrent de novo mutation in KCNC1 (c.959G > A, p.Arg320His) has been identified recently as one of the important genetic causes of progress myoclonic epilepsy (PME). The clinical phenotype resulting from this mutation has been named as myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK). This finding carries important clinical implications in that autosomal dominant inheritance and de novo occurrence need to be considered when conducting genetic tests in patients with PME. We present two familial cases of MEAK in siblings with a recurrent p.Arg320His mutation in KCNC1.

Method: Whole exome sequencing and subsequent Sanger sequencing were performed for the cases and their parents.

Results: A recurrent p.Arg320His mutation in KCNC1 was identified in the two brothers who showed characteristic features of MEAK: near normal early development, onset of myoclonus around 10 years of age, infrequent generalized tonic-clonic seizures, relatively mild cognitive impairment, and generalized epileptiform discharges. Interestingly, the asymptomatic mother was suspected as being mosaic for this mutation. This finding could lead to misleading inheritance patterns and make genetic diagnosis of PME more complicated.

Conclusions: Our familial MEAK cases show that consideration of parental mosaicism in addition to meticulous phenotyping is needed when conducting KCNC1 genetic testing.

Keywords: KCNC1; Parental mosaicism; Progressive myoclonic epilepsy.