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

Abstract

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.

First splicing variant in HECW2 with an autosomal recessive pattern of inheritance and associated with NDHSAL

“…Recently, de novo variants in HECW2 have been recognized as a cause of a neurodevelopmental disorder with hypotonia, seizures, and absent language (NDHSAL; MIM# 617268) (Acharya et al, 2021; Berko et al, 2017; Halvardson et al, 2016; Heide et al, 2021; Kritioti et al, 2021; Lu et al, 2021; Nakamura et al, 2018; Peikes et al, 2021; Ullman et al, 2018; Yanagishita et al, 2021). They have also been associated to autism spectrum disorder (Iossifov et al, 2014; Krumm et al, 2015), developmental disorder (Deciphering Developmental Disorders Study 2015; Deciphering Developmental Disorders Study 2017), intellectual disability (Taşkıran et al, 2021), and epileptic encephalopathy (Euro et al, 2014; Hamdan et al, 2017).…”

“…Currently, 54 patients from 53 families with 32 missense variants in HECW2 have been published (Table 1). These variants showed an autosomal dominant pattern of inheritance, and most of them were de novo (Acharya et al, 2021; Berko et al, 2017; Deciphering Developmental Disorders Study 2015; Deciphering Developmental Disorders Study 2017; Euro et al, 2014; Halvardson et al, 2016; Hamdan et al, 2017; Heide et al, 2021; Iossifov et al, 2014; Kritioti et al, 2021; Krumm et al, 2015; Lu et al, 2021; Nakamura et al, 2018; Peikes et al, 2021; Taşkıran et al, 2021; Ullman et al, 2018; Yanagishita et al, 2021). Of these 32 variants, 18 are described as pathogenic and 7 as likely pathogenic, the rest being of uncertain significance.…”

“… Note : Krumm et al (2015); (3) Deciphering Developmental Disorders Study (2015); (4) Krumm et al (2015); (5) Halvardson et al (2016); (6) Berko et al (2017); (7) Deciphering Developmental Disorders Study (2017); (8) Hamdan et al (2017); (9) Nakamura et al (2018); (10) Ullman et al (2018); (11) Peikes et al (2021); (12) Lu et al (2021); (13) Taşkıran et al (2021); (14) Yanagishita et al (2021); (15) Acharya et al (2021); (16) Kritioti et al (2021); (17) Heide et al (2021); (18) Krami et al (2022). …”