Early onset or syndromic epilepsy

Gene: INPP4A

Green List (high evidence)

Comment on list classification: There are a total of 33 patients from 19 unrelated families reported with biallelic INPP4A variants and a neurodevelopmental disorder. Of these, 13 patients from 12 families presented with seizures. Hence, this gene should be promoted to green rating in the next GMS update.

Created: 13 Aug 2025, 5:18 p.m. | Last Modified: 13 Aug 2025, 5:18 p.m.

Panel Version: 8.21

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
neurodevelopmental disorder, MONDO:0700092; epilepsy, MONDO:0005027

Publications

• 39315527
• 40748307
• 40772914

Comment on list classification: Leaving as amber, but with a recommendation to promote to green following GMS approval.

Created: 9 Feb 2025, 9:53 p.m. | Last Modified: 9 Feb 2025, 9:53 p.m.

Panel Version: 8.79

More information about previously reported cases and additional cases:

PMID: 21937992 Najmabadi et al 2011 - Report 3 related Iranian probands with moderate intellectual disability and a homozyous 1 bp deletion leading to a frameshift variant in INPP4A:D915fs. No detailed phenotype information, although stated as non-syndromic.

PMIDs: 25338135 - Sheffer et al 2015 - child from healthy consanguineous Arab Moslem parents, found to have hindbrain malformations at 4 months of age. No eye blinking in response to light. Started to have myoclonic seizures at 8 months. The patient had no developmental milestones and was cortically blind. At 15 months, head circumference was 39.5 cm (<3 SD for age). A homozygous frame-shift mutation c.1581 del256, p.Glu528Ilefs*22 in exon 15 of INPP4A was found. It segregated within the family.

PMID: 31978615 - Banihashemi et al 2020 - 5 individuals with severe intellectual disability from an extended Arab Iranian family and patients were born from consanguineous marriages. Patients presented at ages 2-4 years. Brain MRIs were normal. However, EEGs was abnormal due to the presence of generalized slowing waves with no epileptiform discharge. Only IV-2 had myoclonic seizures during infancy. A homozygous nonsense variant INPP4A c.115 C > T; p.Gln39X variant was identified, which segregated with the phenotype in the family (9 unaffected members were either heterozygous or wild type homozygous).

PMID: 36653678 - Hecher et al 2023 - 2-year-old girl whose parents were a healthy consanguineous Turkish couple with microcephaly (OFC of 27.5 cm (− 2.88 z) at birth), severe developmental delay, myoclonic seizures, and pontocerebellar hypoplasia, carrying the novel homozygous INPP4A frameshift variant c.2840del/p.(Gly947Glufs*12) (NM_001134224.2).

There are now 4 families in which homozygous variants in INPP4A are reported in probands with severe intellectual disability. Myoclonic seizures are reported in some patients from an early age, but this is alongside brain abnormalities in 2 cases, suggesting that the seizures are not the only cause for the intellectual disability.

See also review by Medyanik et al 2025 PMID: 39858526.

Created: 9 Feb 2025, 9:52 p.m. | Last Modified: 9 Feb 2025, 9:55 p.m.

Panel Version: 8.80

Comment on list classification: Upgraded from Red to Amber. 2 unrelated families with severe ID and biallelic variants in this gene reported to date (PMIDs: 25338135; 31978615)

Created: 30 Apr 2021, 3:44 p.m. | Last Modified: 30 Apr 2021, 3:44 p.m.

Panel Version: 3.1050

I don't know

Two families reported with bi-allelic variants and a neurological phenotype. Supportive mouse model and expression data.

Created: 16 Apr 2021, 9:27 a.m. | Last Modified: 16 Apr 2021, 9:27 a.m.

Panel Version: 3.1018

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual disability

Publications

• 31978615
• 31938306
• 25338135
• 20011524

Red List (low evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
AUTOSOMAL RECESSIVE MENTAL RETARDATION

Publications

• 21937992

Red List (low evidence)

Gene2Phenotype lists Autosomal Recessive Mental Retardation as a phenotype of variants in this gene, however there are no literature papers linking variants in this gene to Intellectual Disability, nor is there evidence in any of the 4 sources

Created: 31 Oct 2017, 10:36 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Red List (low evidence)