De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual...

Area of Science:

• Genetics and Genomics
• Neuroscience
• Developmental Biology

Background:

• WD40 repeat-containing proteins are a large, evolutionarily conserved family crucial for various cellular functions.
• WDR37, a member of this family, has not been previously linked to human disease.
• De novo variants in genes are a significant cause of rare pediatric neurodevelopmental disorders.

Purpose of the Study:

• To investigate the role of WDR37 in human health and disease.
• To identify the genetic cause of a novel syndromic neurological disorder in pediatric patients.
• To elucidate the functional consequences of WDR37 variants using a model organism.

Main Methods:

• Whole-exome sequencing to identify de novo variants in five pediatric probands.
• Phenotypic analysis of affected individuals, noting epilepsy, colobomas, facial dysmorphology, developmental delay, and cerebellar hypoplasia.
• Generation of a null allele in Drosophila melanogaster (CG12333/wdr37) to model disease phenotypes and rescue experiments using human WDR37 cDNA.

Main Results:

• Five pediatric probands presented with de novo variants in WDR37, exhibiting a consistent set of neurological and developmental phenotypes.
• Drosophila WDR37 null mutants displayed bang sensitivity (seizure-like behavior) and impaired motor function (grip strength defects).
• Human WDR37 variants failed to rescue the observed Drosophila phenotypes, indicating a loss-of-function mechanism.

Conclusions:

• De novo variants in WDR37 are associated with a novel syndromic neurological disorder characterized by epilepsy, developmental delay, and specific physical features.
• WDR37 plays a critical, conserved role in neurological function and development.
• The findings establish WDR37 as a disease-associated gene and provide a foundation for understanding this new neurodevelopmental disorder.