A novel likely pathogenic heterozygous HECW2 missense variant in a family with variable expressivity of neurodevelopmental delay, hypotonia, and epileptiform EEG patterns.

1. Dezember 2021

Heide EC1, Puk O2, Biskup S2 3, Krahn A1, Rauf E1, Kreilkamp BAK1 4, Paulus W5, Focke NK1


Pathogenic variants in HECW2 are extremely rare. So far, only 19 cases have been reported. They were associated with epilepsy, intellectual disability, absent language, hypotonia, and autism. As these cases were all de novo mutations, mostly presenting without identical variants, variable expressivity has never been investigated. Here, we describe the first family with the same novel variant in HECW2. A 19-year old female patient presented with bursts of generalized spike-wave discharges and intellectual disability. We performed next-generation-sequencing, to detect the genetic cause. Next-generation-sequencing revealed a novel likely pathogenic variant in HECW2 (c.3571C>T; p.Arg1191Trp) in the index patient, her mother and brother. They showed some similar phenotypic patterns with intellectual disability, hypotonia and generalized epileptiform patterns. However, the mother was less severely affected and epileptiform patterns were less frequent. The brother presented with additional autistic features. In contrast to previous cases, the speech of all individuals was only mildly impaired. This is the first case report of a family with the same novel likely pathogenic variant in HECW2 and as such provides insight into the phenotypic variability of this mutation. The expressivity of symptoms may be so mild that genetic and EEG analysis are needed to disclose the correct diagnosis.