Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders

Abstract

BackgroundVariants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined.MethodsMolecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2-related neurodevelopmental disorder.ResultsWe identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain.ConclusionWe provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management.

The Roles of NEDD4 Subfamily of HECT E3 Ubiquitin Ligases in Neurodevelopment and Neurodegeneration

“…Mice lacking p73 expression show severe neurodevelopmental abnormalities with hippocampal dysgenesis [ 81 ]. Recently, de novo mutations in the HECW2 gene have been identified in patients with neurodevelopmental diseases, including epilepsy, intellectual deficiency and macrocephaly [ 82 , 83 , 84 , 85 ].…”

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). …”

“…All the variants in HECW2 associated with an autosomal dominant disease are heterozygous missense variants, and most of them are clustering at the last third of the protein (27/32 are located between aa 1000 and 1572), and more specifically in C‐terminal HECT domain (19/32 are located between aa 1216 and 1572). Furthermore, HECW2 is intolerant to haploinsufficiency and loss‐of‐function (LOF), and hypomorphic variants (nonsense, frameshift, or variant in the catalytic cysteine 1540) with LOF have not been described to date (Acharya et al, 2021). This suggests that these missense variants could act through a gain‐of‐function (GOF) or dominant negative (DN) mechanism (Acharya et al, 2021; Backwell & Marsh, 2022).…”