Autosomal recessive frameshift variant broadens HECW2-related disease spectrum

The HECW2 gene encodes a HECT (homologous to E6-AP carboxy terminus)-type E3 ubiquitin ligase that plays a critical role in neurodevelopment. Pathogenic variants in HECW2 are associated with a neurodevelopmental disorder characterized by hypotonia, seizures, and absent language (NDHSAL; OMIM #617268), typically inherited in an autosomal dominant pattern. However, recent evidence suggests that some variants in HECW2 gene may cause the disease with autosomal recessive inheritance.

Here, we report a 6-year-old female proband of consanguineous Afghan descent who presented with severe microcephaly, hypotonia, failure to thrive, recurrent seizures, global neurodevelopmental delay, and brain MRI findings of significant cerebral and cerebellar atrophy. Whole-exome sequencing revealed a novel homozygous frameshift variant in HECW2 (c.3601_3602insT, p.Y1201Lfs∗7, ClinVar: SCV006279594) in this patient. In silico analyses and Sanger validation confirmed the pathogenicity of this variant and its autosomal recessive inheritance, with both parents being heterozygous carriers but clinically unaffected. This frameshift variant likely results in nonsense-mediated decay (NMD) of the mRNA, suggesting a loss-of-function mechanism distinct from the mechanism implicated in missense variants that causing the disease with autosomal dominant inheritance.

This study expands the phenotype and genetic spectrum of HECW2-related disorders and highlights the importance of recognizing autosomal recessive inheritance patterns. The findings emphasize the need for comprehensive genetic analyses, especially in consanguineous populations, and underscore the value of considering null variants in HECW2 when evaluating severe neurodevelopmental phenotypes. Further studies exploring the molecular mechanisms of HECW2 variants are essential to deepen our understanding of its role in neurodevelopment and refine diagnostic and therapeutic approaches.