A novel partial duplication in OPHN1, associated with vermis cerebellar hypoplasia, seizures and developmental delay

Abstract

Pathogenic variants in the Oligophrenin 1 gene (OPHN1) cause an X-linked intellectual disability syndrome with a phenotype typically consisting of cerebellar hypoplasia, ventriculomegaly, seizures, facial dysmorphism, speech delay, and sometimes behavioral difficulties. OPHN1 is located in Xq12 and encodes a Rho-GTPase activating protein that regulates various cellular processes such as endocytosis, dendritic growth, morphology, synaptic localization, plasticity, and function. This study describes a male patient with global developmental delay, cerebellar hypoplasia, and other neuroanatomical findings suggestive of a Dandy-Walker malformation. A clinical pontocerebellar hypoplasia panel revealed a partial duplication from exon 7 to exon 15 in OPHN1 which was maternally inherited. PCR-Sanger sequencing of cDNA showed a truncating frameshift in the OPHN1 transcript.Further, transcript level analysis of OPHN1 showed a 75% reduction in the total expression in the patient in comparison to controls. Presumably, this leads to a similar decrease in the level of OPHN1 protein resulting in the observed phenotype. This is the first report of a partial duplication of exons 7–15 in OPHN1 in a patient with strabismus, speech delay, dysmorphic facial features, epilepsy, an autism-like phenotype, and developmental delay.