CHMP1A – Pontocerebellar Hypoplasia Type 8

Pontocerebellar hypoplasia type 8 (PCH8) is a rare autosomal recessive neurodegenerative disorder caused by biallelic CHMP1A variants and is characterized by prenatal polyhydramnios, mild ventriculomegaly, severe cerebellar hypoplasia with vermis and hemispheric reduction, a thin corpus callosum, postnatal hypotonia, global developmental delay, dental crowding, increased tendon reflexes, skeletal malformations, and recurrent pulmonary infections.

In a single patient, whole exome and genome sequencing identified compound heterozygous CHMP1A variants: c.53>C (p.Leu18Pro) and a deletion of exon 1. cDNA analysis confirmed that the exon 1 deletion abolished CHMP1A expression, and zebrafish base editing of c.53>C (p.Leu18Pro) produced cerebellar and pontine dysplasia paralleling the human presentation (PMID:37789895).

Given only one proband with supportive functional data, the clinical validity of CHMP1A in Pontocerebellar Hypoplasia Type 8 remains Limited; genetic evidence is Limited, and functional assays provide Moderate support. Screening of CHMP1A should be considered in patients presenting with characteristic PCH8 features to facilitate diagnosis and genetic counselling.

References

• Frontiers in Neurology • 2023 • Novel bi-allelic variants of CHMP1A contribute to pontocerebellar hypoplasia type 8: additional clinical and genetic evidence. PMID:37789895

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