Novel HUWE1-Related Neurodevelopmental Disorder: Genotypic and Phenotypic Expansion

The HUWE1 gene plays a crucial role in mediating embryonic development as well as the differentiation and proliferation of neural cells. Variants in the HUWE1 are closely associated with intellectual developmental disorder. This study is designed to characterize the clinical phenotype of neurodevelopmental disorder in a cohort of seven children associated with variants in the HUWE1.

Blood samples of seven children with neurodevelopmental disorders and their parents were collected for trio whole exome sequencing. HUWE1 (NM_031407) variants were confirmed by Sanger sequencing.

A total of 7 children were diagnosed as HUWE1-related neurodevelopmental disorder, involving three girls and four boys. All these HUWE1 variants were missense variants (four newly detected HUWE1 variant sites). This study suggested that HUWE1 variants posed varying influences on the facial features, height and speech, social and gross motor skills. Specifically, children with the p. Gly4310Arg variant presented malocclusion-associated chewing and swallowing difficulties.

Our findings further broaden the genotypic-phenotypic spectrum of HUWE1 variants and highlight the crucial role of the HECT domain in the pathogenicity of HUWE1 gene variants. Moreover, children with HUWE1 variants exhibited certain symptoms of attention-deficit/hyperactivity disorder (ADHD), social dysfunction and abnormal chewing function, which warrant further investigation.