Severe microcephaly

Gene: INPP4A

Green List (high evidence)

Comment on list classification: There are 11 patients from eight unrelated families reported with biallelic INPP4A variants and severe microcephaly. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 13 Aug 2025, 7:01 p.m. | Last Modified: 13 Aug 2025, 7:01 p.m.

Panel Version: 8.11

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. 15 patients from 10 families presented with microcephaly, of which 11 patients from eight families had severe microcephaly (OFC < -3 SD below mean). Three of these 15 patients had nonsense variants in exon 4, nine patients had LoF variants downstream of exon 4, while the remaining three 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:40772914 (2025) reported a 34-month old female patient with the same biallelic variant that was reported in family 7 from PMID:39315527 (c.981del/ p.Asp328Ilefs*4) and with INPP4A-related disorder. The severity of microcephaly was not provided in the report.

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 (severity not reported), limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies.
Sources: Literature

Created: 13 Aug 2025, 6:58 p.m. | Last Modified: 13 Aug 2025, 7:15 p.m.

Panel Version: 8.11

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149

Publications

• 39315527
• 40748307
• 40772914