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Intellectual disability
Gene: ENTPD1

ENTPD1 (ectonucleoside triphosphate diphosphohydrolase 1)
EnsemblGeneIds (GRCh38): ENSG00000138185
EnsemblGeneIds (GRCh37): ENSG00000138185
OMIM: 601752, Gene2Phenotype
ENTPD1 is in 8 panels

6 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There is sufficient evidence for this gene to be promoted to Green rating at the next major update.
Created: 16 May 2023, 10:03 a.m. | Last Modified: 16 May 2023, 10:03 a.m.

Panel Version: 5.121

As reviewed by Konstantinos Varvagiannis, PMID:35471564 reported 27 cases from 17 families with biallelic variants in ENTPD1 and with a complex childhood-onset neurodevelopmental disorder characterised by intellectual disability/ developmental delay and spastic paraplegia in all individuals, white matter abnormalities in 12 individuals and epilepsy in 7 individuals.

PMID:35758610 reported two siblings with biallelic variants in ENTPD1. The proband was mildly intellectually disabled and her brother was moderately clinically disabled based on clinical observations.

In addition, this gene has been associated with autosomal recessive intellectual developmental disorder in Gene2phenotype with 'limited' rating and ID has been included as part of the SPG64 phenotype in OMIM.
Created: 16 May 2023, 9:58 a.m. | Last Modified: 16 May 2023, 10:57 a.m.

Panel Version: 5.123

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 64, autosomal recessive, OMIM:615683

Publications

Created: 16 May 2023, 9:53 a.m.
Last Modified: 16 May 2023, 10:57 a.m.
Panel version: 5.122

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Biallelic ENTPD1 pathogenic variants cause Spastic paraplegia 64, autosomal recessive (# 615683) with DD/ID being a universal feature as suggested by the study by Calame, Herman et al. Epilepsy was also reported in 7 unrelated individuals so far with supporting evidence also from mouse model.

Consider upgrade to green rating in the ID panel, inclusion in the epilepsy panel (amber/green). Also consider adding this gene in panels for white matter disorders (which does not appear to be the case so far).

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Calame, Herman et al (2022 - PMID:35471564) describe the phenotype of 27 individuals (from 17 unrelated families) with biallelic ENTPD1 pathogenic variants. The authors collected additional information from previously reported cases and summarize the core features of the disorder.

As they highlight, the disorder has a childhood onset, with DD/ID as a universal feature (27/27 or 36/36 considering cases from the literature), progressive spastic paraparesis (36/36) [On neurological examination, abnormal reflexes were common with hyperreflexia (8/36), hyporeflexia (5/36), areflexia (3/36) or both hyperreflexia and hypo/areflexia in 20, suggesting mixed upper and lower motor neuron dysfunction]. Other features included dysarthria (in 20/27 or 27/36 overall), white matter abnormalities on brain imaging (12/22 or 15/28, in 12-13 signal abnormalities in posterior limb of internal capsule), or dysmorphisms (13/27). Some individuals had evidence of neurocognitive regression (18/27 or 21/36). Epilepsy was reported in 7 unrelated individuals within the cohort (likely 7/25 as for 2 sibs from Fam11, this was NA). Previous studies had not reported this feature.

ENTPD1 encodes ectonucleoside triphosphate diphosphohydrolase 1, involved in hydrolysis of ATP to ADP (and ADP to AMP).

While previous studies identified 5 distinct variants (2 missense and 3 pLoF), the authors describe 12 novel variants 10 of which pLoF (stopgain, stoploss, splicing) and 2 missense (one SNV and one MNV).

In silico predictions were in favor of a deleterious effect. Almost all variants were ultrarare or absent from gnomAD, although 4 were recurrent ones [NM_001776.6]: c.1109T>A / p.(Leu370*) (possibly recurrent mutation found in 4 families from Persia/Poland), c.574-6_574-3del, c.770_771del / p.(Gly257Glufs*18) (possibly founder allele from the Iberian peninsula), c.1041del / p.(Ile348Phefs*19) (?founder allele in Persia).

Variant studies:
- c.574-6_574-3del : was shown to result to skipping (complete absence) of exon 6 (RNA extracted from a whole blood sample, followed by cDNA synthesis and Sanger seq using different primer sets).
- c.401T>G / p.Met134Arg : RT-qPCR of mRNA from patient lymphoblasts showed significantly reduced mRNA levels in individuals homozygous for this variant. Protein levels were also markedly decreased upon Western blot. ENTPD1 is essential for hydrolysis of ATP to ADP and ADP to AMP, with impairment of ATPase and ADPase activity (significantly decreased phosphate production) in patient lymphoblasts.
- c.185T>G / p.Leu62* : As ENTPD1 (also known as CD39) is highly expressed in lymphocytes and polymorphonuclear leukocytes, the authors used flow cytometry on whole blood from individuals hmz for this variant, carrier parents and controls, demonstrating complete absence of ENTPD1 positive cells in affected individuals. Immunohistochemistry for ENTPD1 using paraffin sections of sural nerve demonstrated complete absence of endo and epineural vascular staining (/lack of expression).

Untargeted metabolomic analyses were performed in plasma samples from 3 affected individuals. Consistent patterns of metabolic abnormalities with alterations in lipid, nucleotide and carbohydrate metabolism were observed. Some metabolite patterns or biomarkers were indicative of inflammatory state, liver disease, insulin resistance / metabolic syndrome.

The authors cite previous mouse models suggesting hepatocellular disfunction, impaired glucose homeostasis and intestinal inflammation in ectonucleotidase deficiency (probably not specific to Entpd1). Further, the authors cite a study by Lanser et al for Entpd1-/- mice exhibiting proepileptogenic activity (2017 - PMID: 28742222 / “Disruption of the ATP/adenosine balance in CD39(-/-) mice is associated with handling-induced seizures”).

In vitro studies using a cellular model of sympathetic neurons (nerve growth factor-differentiated PC12 cells) provided evidence that ENTPD1 expression levels modulate exocytic and ischemic neurotransmitter release (cited PMID: 21325440)

Overall, the authors propose accessible diagnostic biomarkers for the disorder (e.g. flow cytometry on periperal blood cells, immunochemistry of peripheral nerve biopsies, T2 hyperintense signal in posterior limb of internal capsule, diminished ATP/ADP breakdown in lymphoblast assays, alteration in metabolic pathways) and discuss potential future developments (ASOs for splicing variant, antagonism for purinergic receptor P2X7, etc).
Created: 29 Apr 2022, 8:13 a.m. | Last Modified: 29 Apr 2022, 8:13 a.m.

Panel Version: 3.1561

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

35471564

Created: 29 Apr 2022, 8:13 a.m.
Last Modified: 29 Apr 2022, 8:13 a.m.
Panel version: 3.1561

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Created: 11 Oct 2023, 9:34 a.m. | Last Modified: 11 Oct 2023, 9:34 a.m.

Panel Version: 5.286

Comment on list classification: Upgraded from Red to Amber as there is some evidence of cognitive impairment associated with SPG64, but perhaps too mild in most cases to warrant inclusion on this panel. Cases are expected to be picked up via the HSP route which presents a more prominent feature of this disorder.
Created: 16 Aug 2021, 4:13 p.m. | Last Modified: 16 Aug 2021, 4:13 p.m.

Panel Version: 3.1226

Seven individuals from four unrelated families have been reported with SPG64 and biallelic variants in this gene. All affected patients presented some degree of cognitive impairment:

- PMID: 24482476 (2014): 2 sibs in one family (1242-IV) had borderline intelligence, while another 2 sibs in an unrelated family (WMD-1800-6) had moderate ID

- PMID: 29691679 (2018): 1 male who showed cognitive delay during the second year of life

- PMID: 30652007 (2019): 2 sisters both said to have moderate learning disability
Created: 16 Aug 2021, 4:08 p.m. | Last Modified: 16 Aug 2021, 4:08 p.m.

Panel Version: 3.1223

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 64, autosomal recessive, OMIM:615683

Publications

Created: 16 Aug 2021, 4:08 p.m.
Last Modified: 16 Aug 2021, 4:08 p.m.
Panel version: 5.286

Caroline Wright (Sanger)

Red List (low evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
AUTOSOMAL RECESSIVE MENTAL RETARDATION

Publications

21937992

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

Panel version: 0

Ellen McDonagh (Genomics England Curator)

Red List (low evidence)

Possible DD gene for AUTOSOMAL RECESSIVE MENTAL RETARDATION in Gene2Phenotype. Reported in Spastic paraplegia 64, autosomal recessive in OMIM. Only evidence identified in the literature is in PMID 21937992 is from another reference that knockout mice display abnormal synaptic transmitter release.
Created: 27 Oct 2017, 2:46 p.m.

Publications

21937992

Created: 27 Oct 2017, 2:46 p.m.

Panel version: Imported from Intellectual disability update Oct 2017 panel version 0.2

Lu Raymond (university of cambridge )

Red List (low evidence)

Created: 23 Feb 2016, 11:04 a.m.

Panel version: 0.306

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Green
NHS GMS

Phenotypes

Spastic paraplegia 64, autosomal recessive, OMIM:615683

OMIM

601752

Clinvar variants

Variants in ENTPD1

Penetrance

Complete

Publications

Panels with this gene

History Filter Activity

11 Oct 2023, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q2_23_promote_green was removed from gene: ENTPD1.

11 Oct 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to ENTPD1. Source Expert Review Green was added to ENTPD1. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

16 May 2023, Gel status: 2