<scp> <i>MINPP1</i> </scp> ‐Related Pontocerebellar Hypoplasia in Five New Patients: Identification of Three Novel Variants and Further Phenotype Delineation

Abstract

MINPP1-related pontocerebellar hypoplasia (PCH) is a rare neurodevelopmental disorder characterized by microcephaly, profound developmental delay, and a distinct neuroimaging pattern. To date, only 21 patients from 13 unrelated families have been reported. Herein, we describe five patients from four Egyptian families with homozygous MINPP1 variants. All patients presented with global developmental delay, microcephaly, hypotonia, nystagmus, severe motor impairment, seizures, and intellectual disability. Interestingly, all patients exhibited dysmorphic facies, characterized by a high forehead, long philtrum, smooth philtrum, thin upper lip vermilion, broad chin, and low-set ears. Additional variable findings were optic atrophy, strabismus, feeding difficulties, and genital anomalies. Brain MRI showed cerebellar and pontine hypoplasia, thin corpus callosum, cortical atrophic changes, white matter signal, enlarged ventricles, and striking basal ganglia hypoplasia. Exome sequencing identified four MINPP1 variants, including three novel variants (p.Trp68Ter, p.Trp141Ter, and p.Val434_Gln435dup). All variants are localized within functionally critical domains of the protein and were either absent or extremely rare in public databases. Our study increases the number of affected individuals with MINPP1 variants and reinforces the clinical and brain imaging features of the disorder. In addition, the specific facial gestalt noted in our patients along with the basal ganglia changes appear characteristic and might point to the diagnosis of this type of PCH.