Deletion 2p16.1p15, USP34 and XPO1 genes

Deletion 2p16.1p15 is a relatively rare abnormality reported so far in ~50 patients.  Most affected persons show microcephaly, growth delay, spectrum of dysmorphic features (hypertelorism, down slanting palpebral fissures, broad nasal root, short philtrum, high palate) and intellectual disability. Many patients also reveal hearing impairment, hypotonia and autism spectrum disorder. Some of them also have seizures. Comparison of the deleted segments showed that a minimal lost segment included two neighboring genes – USP34 and XPO1. It became clear that one of these genes or interaction between causal genes play the crucial role in the origin of clinical abnormalities (Miceli et al., 2023). In that context it is important to compare phenotypic manifestations of patients with del 2p16.1p15 syndrome and patients with mutations in the USP34 and XPO1 genes.

Van Oirsouw et al. (2025) examined 22 individuals with different heterozygous mutations in the XPO1 gene. Half of these persons have loss-of-function variants, 10 had missence variants and 1 had in-frame deletion variant. Developmental delay was reported in 19 out of 22 patients, dysmorphic features were found in 20 patients, microcephaly in 14, epilepsy in 4, hypotonia in 14, etc. Basically patients with mutations in the XPO1 gene show significant overlap with persons with 2p16.1p15 deletions. Therefore, loss of the XPO1 gene significantly contributes to the phenotypic picture in patients with deletions. Experimental knockdown of the emb gene (the ortholog of the XPO1 in Drosophila) showed impaired cognitive function in habituation.

At the same time Wigoda et al. (2026) presented an examination of 6 patients with heterozygous point mutations in the USP34 gene. All these patients had global developmental delay, speech delay and dysmorphic features including down slanting palpebral fissures, hypertelorism, short philtrum, wide mouth, micrognathia. Small digital abnormalities (tapering fingers, clinodactyly, etc.) were mentioned in 4/6 patients. Autistic features were reported in 4/6 patients, hearing impairment was noted in 3/6 patients. Remarkable similarity between manifestations in patients with 2p16.1p15 deletions and with point mutations in the USP34 gene allowed us to consider this gene also as a main factor contributing to the clinical picture of persons with deletions.

Analysis of manifestations in each of the studied genes shows that actions of both genes and interaction between these genes are necessary for the clinical picture of the 2p16.1p15 deletion syndrome.

REFERENCES

Miceli M., Failla P., Saccuzzo L. et al. “Trait-driven analysis of the 2p15p16.1 microdeletion syndrome suggests a complex pattern of interactions between candidate genes”. “Genes & Genomics” 2023, v. 45, 491-505.

Van Oirsouw A.S.E., Nedbalova P., Hancarova M. et al. “Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder”. “Genetics in Medicine” 2025, v. 27 (11): 101555.

Wigoda H., Khan A., Mendelsohn B.A. et al. “USP34 haploinsufficiency as a cause of neurodevelopmental phenotypes”. “Clinical Genetics” 2026, v. 110 (3), 315-324.

Chromosome Disorder Outreach Inc. medical geneticist and medical advisor Dr. Iosif Lurie M.D. Ph.D examines newly published research studies to locate the most important and relevant for our members. Synopses of these articles are then posted to our website’s research pages. Review by Dr. Iosif Lurie.

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