Ataxia and cerebellar anomalies - narrow panel

Gene: INPP4A

Green List (high evidence)

Comment on list classification: There is sufficient evidence available (15 patients from 11 families) for the promotion of this gene to green rating in the next GMS update.

Created: 13 Aug 2025, 5:59 p.m. | Last Modified: 13 Aug 2025, 5:59 p.m.

Panel Version: 8.15

PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 13 patients from 10 families were reported with cerebellar hypoplasia from neuroimaging. Nine of these patients had LoF variants downstream of exon 4, while the other four had missense variants.

There is also functional evidence available in support of the disease association. Preliminary fibroblast cell lines from an affected individual showed disruption of endocytic pathways as the likely mechanism of disease. All mouse models displayed a phenotype mirroring human INPP4A-related neurodevelopmental disorder.

PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs*22). They presented with global developmental delay, short stature, microcephaly, limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies.
Sources: Literature

Created: 13 Aug 2025, 5:57 p.m. | Last Modified: 13 Aug 2025, 7:14 p.m.

Panel Version: 8.15

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
neurodevelopmental disorder, MONDO:0700092; Cerebellar hypoplasia, HP:0001321

Publications

• 39315527
• 40748307
• 40772914