Intellectual disability - microarray and sequencing
Gene: ENTPD1
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
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
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 disabilityCreated: 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
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
AUTOSOMAL RECESSIVE MENTAL RETARDATION
Publications
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
Tag Q2_23_promote_green was removed from gene: ENTPD1.
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)
Publications for gene: ENTPD1 were set to 21937992; 24482476; 29691679; 30652007; 35471564; 35758610
Publications for gene: ENTPD1 were set to 21937992; 24482476; 29691679; 30652007; 35471564; 35758610
Publications for gene: ENTPD1 were set to 21937992; 24482476; 29691679; 30652007; 35471564; 35758610
Publications for gene: ENTPD1 were set to 21937992; 24482476; 29691679; 30652007; 35471564
Tag Q2_23_promote_green tag was added to gene: ENTPD1.
Gene: entpd1 has been classified as Amber List (Moderate Evidence).
Publications for gene: ENTPD1 were set to 21937992; 24482476; 29691679; 30652007; 35471564
Publications for gene: ENTPD1 were set to 21937992; 24482476; 29691679; 30652007; 35471564
Publications for gene: ENTPD1 were set to 21937992; 24482476; 29691679; 30652007; 35471564
Publications for gene: ENTPD1 were set to 21937992; 24482476; 29691679; 30652007; 35471564
Publications for gene: ENTPD1 were set to 21937992; 24482476; 29691679; 30652007
Gene: entpd1 has been classified as Amber List (Moderate Evidence).
Gene: entpd1 has been classified as Amber List (Moderate Evidence).
Publications for gene: ENTPD1 were set to 21937992
Phenotypes for gene: ENTPD1 were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to Spastic paraplegia 64, autosomal recessive, OMIM:615683
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.
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
ENTPD1 was added to Intellectual disabilitypanel. Sources: Expert Review Red
ENTPD1 was created by ellenmcdonagh