Deletion 2q34 and the ERBB4 gene

DELETION 2q34 and the ERBB4 gene. Many articles about patients with small deletions in the chromosome 2q34 area who have various neurodevelopmental problems but not serious structural defects have been published in recent years. Detailed examinations showed that all these persons have deletion of the ERBB4 gene, sometimes in association with deletions of several neighboring genes. Later it was shown that point mutations in the ERBB4 gene as well as small deletions affecting only parts of the ERBB4 gene may cause similar clinical consequences.

The ERBB4 gene is necessary for the production of a tyrosine kinase receptor, which plays a significant role in numerous neurobiological processes: development of neurons from neural stem cells, formation of contacts between neurons, functioning of neural circuits (Yang et al., 2019). It is not surprising that this gene has an extremely high expression in the brain. The gene itself includes 28 exons (segments of the gene containing instructions for the formation of the functional RNA molecules or proteins). This gene is suggested as one of the susceptibility genes for schizophrenia.

Currently at least 44 patients with deletions 2q34 involving the ERBB4 gene have been reported (Rasic et al., 2025; Mademont-Soler et al., 2026). There are a few families with balanced translocations, where one of the breakpoints disrupts the ERBB4 gene. The most common manifestations are developmental delay (21/44), behavioral problems (20/44), autism (10/44), and speech delay (6/44). Most of these patients reveal “challenging” behavior, which includes hyperactivity and aggressiveness. Several patients revealed or other psychotic manifestations. Mild dysmorphic features were reported in 5 patients. It was shown that patients with deletions completely encompassing the ERBB4 gene or affecting only several exons reveal similar clinical manifestations.

In several families deletions were inherited from the parents who mostly had some speech delay, learning disability or other relatively mild symptoms. At the same time several parents were clinically unaffected despite having the same deletions as their affected children. This is an evidence of incomplete penetrance of this deletion.

Mademont-Soler et al. (2026) presented 4 families with point mutations in the ERBB4 gene. These patients revealed the same manifestations as patients with deletions. In one of these 4 families mutation occurred de novo, in three others mutations were inherited from the affected parents.

REFERENCES

Mademont-Soler I. et al. Insight into haploinsufficiency of the ERBB4 gene: expanding the spectrum of associated phenotypes. J. Autism Devel. Disorders 2026, online.

Rasic M. et al. ERBB4 exonic deletions in patients with intellectual disability and speech developmental delay. 15th Balkan Congr. Hum. Genet. 2025, 86.

Yang J.-M. et al. ERBB4 deficits in chandelier cells of the medial prefrontal cortex confer cognitive dysfunctions: implications for schizophrenia. Cerebral Cortex 2019, v. 29(10), 4334-4346.