Insight into Haploinsufficiency of the ERBB4 Gene: Expanding the Spectrum of Associated Phenotypes

The ERBB4 gene encodes a tyrosine kinase receptor for neuregulins and EGF family members, and plays a crucial role in various neurobiological processes. At present, the phenotypic manifestations of genetic variants that disrupt ERBB4 gene function (null variants) are not well established.

A search for new patients with null variants in ERBB4 was initiated through an international data-sharing collaboration via GeneMatcher, and by searching the databases Decipher and ClinVar. Diagnosis had been performed using chromosomal microarray analysis, whole-exome sequencing, or whole-genome sequencing.

Twenty-four new patients from 13 unrelated families with null variants in ERBB4 were identified. Genetic findings included single- or multiple-exon deletions in eight families, a reciprocal translocation disrupting ERBB4 in one family, and sequence variants in four. Variants arose de novo in four probands, were inherited in eight, and had an unknown inheritance pattern in one. Co-segregation of variants with clinical manifestations was observed within families. The predominant clinical features included neurodevelopmental disorders (intellectual disability, neurodevelopmental delay, autism spectrum disorder, and attention deficit hyperactivity disorder), speech delay, challenging behaviors, hypotonia, psychiatric conditions and seizures.

This study represents the largest case series of patients with neurological disorders and null variants in the ERBB4 gene. Our findings support haploinsufficiency as the most plausible pathophysiological mechanism underlying ERBB4-related disorders and broaden the spectrum of associated phenotypes. Autism spectrum disorders and psychiatric manifestations have emerged as frequent, previously underrecognized features. Penetrance appears to be high but incomplete, and expressivity is highly variable, with a tendency toward intrafamilial phenotypic conservation.