Intellectual disability - microarray and sequencing
Gene: KIRREL3
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.Created: 5 Feb 2024, 4:46 p.m. | Last Modified: 5 Feb 2024, 4:46 p.m.
Panel Version: 5.441
At least 12 missense KIRREL3 variants have been reported in 12 unrelated cases with a neurodevelopmental disorder, that includes intellectual disability ranging from mild to severe (PMID: 29271092; 33853164; 33853164). Table 1 in PMID: 37605258, reviews KIRREL3 variants and demonstrates that the variants maybe either de novo (4/11) or inherited from one of the parents (7/11)(mode of inheritance was unknown for one of the variants). The KIRREL3 variants are either absent from controls or are present at a very low frequency. However, the three variants reported in PMID: 19012874, were shown to be present in publicly databases at a high frequency (see KIRREL3 OMIM entry).Created: 5 Feb 2024, 4:44 p.m. | Last Modified: 5 Feb 2024, 5:07 p.m.
Panel Version: 5.441
Publications
21 reported case with mostly de novo, missense variants in PMID: 37605258. Enough evidence for the green rating!Created: 16 Jan 2024, 12:30 p.m. | Last Modified: 16 Jan 2024, 12:30 p.m.
Panel Version: 5.401
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
NDD
Publications
Comment on publications: New publication added (PMID:33853164)Created: 11 Oct 2021, 1:22 p.m. | Last Modified: 11 Oct 2021, 1:22 p.m.
Panel Version: 3.1349
A de novo missense variant in KIRREL3 gene has been reported in a patient with NDD and cerebellar hypoplasia (p.Ser255Leu, PMID: 33853164). However, the same variant is also reported in one gnomAD case and the region is flagged as problematic in gnomAD, thus the classification remains questionable.Created: 28 Sep 2021, 10:26 a.m. | Last Modified: 28 Sep 2021, 10:26 a.m.
Panel Version: 3.1306
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications
Comment on publications: New publication added - PMID:25902260. This paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques
Provides review of cases in literature and functional studies demonstrating brain expressed proteins that interact with the KIRREL3 using yeast two-hybrid screening supporting a link to neurological and cognitive disorders. They also show KIRREL3 localisation to the Golgi complex and synaptic secretary vesicles.Created: 1 Mar 2024, 2:46 p.m. | Last Modified: 1 Mar 2024, 2:46 p.m.
Panel Version: 5.479
Following discussion with the clinical team, this gene has been demoted from Amber to Red, in accordance with the external review by Zornitza StarkCreated: 17 Aug 2020, 10:09 a.m. | Last Modified: 17 Aug 2020, 10:09 a.m.
Panel Version: 3.253
Variants associated with ID have now been re-classified based on population frequency.Created: 8 Feb 2020, 10:06 a.m. | Last Modified: 8 Feb 2020, 10:06 a.m.
Panel Version: 3.0
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Intellectual disability
Publications
Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber 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, 9:34 p.m.
Amber - There are two human cases in the literature linking deletions of or variants in this gene to Intellectual disability. One paper describes a small interstitial deletion of 2.899Mb which encompasses this gene as a candidate. The patient presented with developmental delay and autistic features (PMID: 22965935). The other paper desricbes a patient with profound intellectual disability with a truncation of two genes - KIRREL3 and CDH15 - as a result of a translocation (19012874). Not able to distinguish whether or not this may be a digenic affect or solely due to transloaction of KIRREL3.Created: 13 Dec 2017, 10:16 p.m.
Mode of inheritance
Unknown
Publications
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 4 (MRD4)
Publications
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_20141118_conf;in_ddg2p_20141118_conf;in_ddg2p_2_4_2017;in_gilissen_2014_known . Main mutation mechanism : UncertainCreated: 27 Jul 2017, 7:07 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; ddg2p_20141118_conf; find_uk10k; gilissen_2014_known; Nijmegen_ID_diagnostic; Nijmegen_ID_candidates; GEL_ID_red_20160217; neuro_20160418_strict; Uncertain. 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, 12:44 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 37605258; 33853164
Tag Q1_24_promote_green tag was added to gene: KIRREL3.
Phenotypes for gene: KIRREL3 were changed from Mental retardation, autosomal dominant 4, 612581; MENTAL RETARDATION AUTOSOMAL DOMINANT TYPE 4 (MRD4) to Intellectual developmental disorder, autosomal dominant 4, OMIM:612581; intellectual disability, autosomal dominant 4, MONDO:0012947
Gene: kirrel3 has been classified as Amber List (Moderate Evidence).
Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 29271092; 37605258
Publications for gene: KIRREL3 were set to 22965935; 19012874; 29271092; 29271092:37605258
Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164; 37605258
Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164; 33853164; 37605258
Publications for gene: KIRREL3 were set to 22965935; 19012874; 33853164
Mode of inheritance for gene: KIRREL3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIRREL3 were set to 22965935; 19012874
Source Expert Review Red was added to KIRREL3. Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Gene: kirrel3 has been classified as Amber List (Moderate Evidence).
Source Victorian Clinical Genetics Services was added to KIRREL3.
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 Amber was added to KIRREL3. Panel: Intellectual disability Model of inheritance for gene KIRREL3 was set to Unknown Publications for gene KIRREL3 was set to ['22965935', ' 19012874']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
KIRREL3 was added to Intellectual disabilitypanel. Source: Expert Review Red Model of inheritance for gene KIRREL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
KIRREL3 was added to Intellectual disabilitypanel. Sources: Radboud University Medical Center, Nijmegen