Intellectual disability - microarray and sequencing
Gene: ITPR1The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' 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 mode of inheritance: Should be updated from 'biallelic' to 'both mono- and biallelic' at the next GMS panel update inline with the review by Tracy Lester. Although not observed in all, some patients do exhibit cognitive deficits which may be an early and severe feature. There are sufficient unrelated cases with heterozygous variants and ID (associated with either Gillespie or SCA) to warrant including this MOI on this panel.Created: 17 May 2023, 1:10 p.m. | Last Modified: 17 May 2023, 1:10 p.m.
Panel Version: 5.130
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
PMID:29925855 - All 7 EOA patients with ITPR1 de novo variants (3 from cohort #1; 4 from cohort #2) presented with infantile onset cerebellar ataxia starting before the age of 2 years, including delayed motor milestones (Table 2). Cognitive deficits of variable degree were observed in 3 out of 4 patients where this information was available, reaching from only mild dyscalculia (P2) to severe intellectual disability with a speech vocabulary of only a few words (P7 at age 12 years). In contrast, patient P1 showed normal intelligence with an IQ of 97.
PMID:27108797 - Here, we report that both recessive and dominant ITPR1 mutations cause Gillespie syndrome. ITPR1 is a predominant isoform in the brain among the three types of ITPRs and is strongly expressed in cerebellar Purkinje cells.31 Mice with complete homozygosity for Itpr1 ablation suffer from severe epilepsy and ataxia and die either in utero or before weaning.32 Consistently, ITPR1 mutations have been reported to cause cerebellar diseases including late-onset spinocerebellar ataxia type 15 (SCA15 [MIM: 606658]),33 congenital nonprogressive spinocerebellar ataxia and mild cognitive impairment (SCA29 [MIM: 117360]),34 infantile-onset cerebellar ataxia with mild cognitive deficit,35 and childhood-onset ataxic cerebellar palsy with moderate intellectual disability36 (see ITPR1 schematic diagram in Figure 3A).
Affected individuals had similar iris anomalies and neonatal ataxia with progressive cerebellar atrophy (Figure 2). Moderate to severe intellectual disabilities were noted in the three individuals with recessive mutations (F1:II1, F2:II1, and F3:II1; Table 1). In contrast, the affected individual F4:II1 aged 18 years and harboring the de novo c.7687_7689del mutation was reported to have normal intelligence (Table 1).
As de novo variants are associated with ID/DD the inheritance should be updated to be BOTH AD and AR.Created: 9 May 2023, 12:31 p.m. | Last Modified: 9 May 2023, 12:31 p.m.
Panel Version: 5.107
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
developmental delay; intellectual disability; hypotonia; ataxia; cerebellar malformatons
Publications
Variants in this GENE are reported as part of current diagnostic practice
Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.Created: 29 Sep 2018, 7:37 p.m.
Comment on mode of inheritance: The three cases with ID are those with biallelic variants. Heterozygotes are reported with the ocular features.Created: 13 Nov 2017, 3:13 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
SPINOCEREBELLAR ATAXIA TYPE15
Publications
There is strong evidence that variants in this gene are linked to Gillespie syndrome. However, the prevalence of intellectual disability in patients with Glliespie syndrome is not across the board. Therefore I am not certain of the link between Intellectual Disability and variants in this gene.Created: 31 Oct 2017, 10:36 a.m.
This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_201507;in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf;in_gilissen_2014_known;in_omim_20150205_movement . Main mutation mechanism : Loss of function; All missense/in frameCreated: 27 Jul 2017, 6:55 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; ddg2p_201507; gilissen_2014_known; omim_20150205_movement; GEL_ID_red_20160217; neuro_20160418_strict; Loss of function; All missense/in frame. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation TrustCreated: 19 Jul 2017, 12:41 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
Comment on list classification: Not an ID geneCreated: 7 Feb 2016, 9:13 p.m.
Tag Q2_23_MOI was removed from gene: ITPR1. Tag Q2_23_NHS_review was removed from gene: ITPR1.
Source NHS GMS was added to ITPR1. Mode of inheritance for gene ITPR1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: ITPR1 were changed from Gillespie syndrome 206700 to Gillespie syndrome, OMIM:206700; Spinocerebellar ataxia 15, OMIM:606658; Spinocerebellar ataxia 29, congenital nonprogressive, OMIM:117360
Mode of inheritance for gene: ITPR1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITPR1 were set to 22986007
Tag Q2_23_MOI tag was added to gene: ITPR1. Tag Q2_23_NHS_review tag was added to gene: ITPR1.
Gene: itpr1 has been classified as Green List (High Evidence).
Source Victorian Clinical Genetics Services was added to ITPR1.
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.
Expert Review Green was added to ITPR1. Panel: Intellectual disability Model of inheritance for gene ITPR1 was set to BIALLELIC, autosomal or pseudoautosomal
This gene has been classified as Red List (Low Evidence).
This gene has been classified as Red List (Low Evidence).
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
ITPR1 was created by ellenmcdonagh
ITPR1 was added to Intellectual disabilitypanel. Sources: Expert Review Amber