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Intellectual disability

Gene: INPP4A

Amber List (moderate evidence)
INPP4A (inositol polyphosphate-4-phosphatase type I A)
EnsemblGeneIds (GRCh38): ENSG00000040933
EnsemblGeneIds (GRCh37): ENSG00000040933
OMIM: 600916, Gene2Phenotype
INPP4A is in 6 panels

7 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

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, 29 patients presented with severe or profound intellectual disability/ global developmental delay. Hence, this gene should be promoted to green rating in the next GMS update.
Created: 13 Aug 2025, 3:44 p.m. | Last Modified: 13 Aug 2025, 3:44 p.m.
Panel Version: 9.61

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071

Publications

Created: 13 Aug 2025, 2:53 p.m.
Last Modified: 13 Aug 2025, 2:53 p.m.
Panel version: 9.60

Eleanor Williams (Genomics England Curator)

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
Created: 9 Feb 2025, 9:52 p.m.
Last Modified: 9 Feb 2025, 9:55 p.m.
Panel version: 8.78

Arina Puzriakova (Genomics England Curator)

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
Created: 30 Apr 2021, 3:44 p.m.
Last Modified: 30 Apr 2021, 3:44 p.m.
Panel version: 3.1050

Zornitza Stark (Australian Genomics)

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

Created: 16 Apr 2021, 9:27 a.m.
Last Modified: 16 Apr 2021, 9:27 a.m.
Panel version: 3.1018

Caroline Wright (Sanger)

Red List (low evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
AUTOSOMAL RECESSIVE MENTAL RETARDATION

Publications

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

Olivia Niblock (Genomics England Curator)

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

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

Panel version: Imported from Intellectual disability update Oct 2017 panel version 0.6

Lu Raymond (university of cambridge )

Red List (low evidence)

Created: 23 Feb 2016, 11:05 a.m.

Panel version: 0.306

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • neurodevelopmental disorder, MONDO:0700092
  • intellectual disability, MONDO:0001071
Tags
Q1_25_ promote_green
OMIM
600916
Clinvar variants
Variants in INPP4A
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

13 Aug 2025, Gel status: 2

Entity classified by Genomics England curator

Achchuthan Shanmugasundram (Genomics England Curator)

Gene: inpp4a has been classified as Amber List (Moderate Evidence).

13 Aug 2025, Gel status: 2

Set Phenotypes

Achchuthan Shanmugasundram (Genomics England Curator)

Phenotypes for gene: INPP4A were changed from Intellectual disability; Seizures to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071

13 Aug 2025, Gel status: 2

Set publications

Achchuthan Shanmugasundram (Genomics England Curator)

Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524; 36653678; 39315527; 4074830740772914

13 Aug 2025, Gel status: 2

Set publications

Achchuthan Shanmugasundram (Genomics England Curator)

Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524; 36653678

9 Feb 2025, Gel status: 2

Added Tag

Eleanor Williams (Genomics England Curator)

Tag Q1_25_ promote_green tag was added to gene: INPP4A.

9 Feb 2025, Gel status: 2

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: INPP4A were set to 21937992; 31978615; 31938306; 25338135; 20011524

9 Feb 2025, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: inpp4a has been classified as Amber List (Moderate Evidence).

30 Apr 2021, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: INPP4A were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Intellectual disability; Seizures

30 Apr 2021, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: INPP4A were set to 21937992

30 Apr 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: inpp4a has been classified as Amber List (Moderate Evidence).

12 Mar 2018, Gel status: 1

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

INPP4A was added to Intellectual disabilitypanel. Sources: Expert Review Red

13 Nov 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

INPP4A was created by ellenmcdonagh