Intellectual disability - microarray and sequencing
Gene: KMT2BComment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. Inclusion on this panel would also ensure this gene is included on the Paediatric disorders super panel which is appropriate for the phenotype.Created: 5 Dec 2023, 5:07 p.m. | Last Modified: 5 Dec 2023, 5:07 p.m.
Panel Version: 5.345
PMID: 33150406 - describes a cohort of 53 patients with either KMT2B intragenic variants or chromosomal microdeletions. Clinical presentation most commonly comprises early-onset dystonia, but there were also reports of atypical patterns of dystonia evolution and a subgroup of patients with a neurodevelopmental disorder in the absence of dystonia. Developmental delay preceding the onset of dystonia was reported in 14 children (34.1%). Subsequent cognitive difficulties were noted in 47.6%, ranging from mild to severe intellectual disability. Of the 9 patients who had a non-dystonic disorder, all presented with neurodevelopmental delay, which progressed to intellectual disability.Created: 5 Dec 2023, 4:55 p.m. | Last Modified: 5 Dec 2023, 4:55 p.m.
Panel Version: 5.342
Publications
More recorded cases of KMT2B have been reported PMID: 31216378 and Konstantinos Varvagiannis has reviewed this gene based on PMID: 29697234 which is a review on the disorder. Although more literature, maintaining Amber rating as dystonia is the main phenotype and limited information is reported that ID or DD precedes the onset of this.Created: 25 Jul 2019, 4:50 p.m. | Last Modified: 25 Jul 2019, 4:50 p.m.
Panel Version: 2.982
PMID: 29697234 is a recent review on the disorder. According to the authors, intellectual disability or developmental delay are commonly reported. Developmental delay preceding the onset of dystonia was a feature in 16/39 of the individuals reviewed while mild cognitive impairment was present in 21/39. Developmental delay is a feature also in some patients with 19q13.12 deletion spanning KMT2B (5/10).
Reduced penetrance and variability within the same family have been reported (according to the article, in approx. 16% the pathogenic variant is inherited, 6% from an unaffected parent).
All types of variants have been reported. Haploinsufficiency is likely the underlying mechanism.
This gene is included in panels for intellectual disability offered by several diagnostic laboratories.
As a result, KMT2B can be considered for upgrade to green (ID is a feature in several individuals) or remain amber (mild cognitive impairment) depending on the criteria used.Created: 30 Nov 2018, 7:57 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
Variants in this GENE are reported as part of current diagnostic practice
Comment when marking as ready: Only one case to date presenting as ID without dystonia (the predominant phenotype). Unclear as to the clinical utility on the ID panel based upon current evidence. Considered amber and watchlist.Created: 5 Mar 2018, 1:27 p.m.
Added watchlist tag. Building evidence for cases with moderate to severe ID (PMID: 29276005; 25405613)Created: 27 Feb 2018, 1:15 p.m.
Comment on publications: PMID: 29289525 is a reviewCreated: 27 Feb 2018, 10:54 a.m.
Comment on list classification: Zech et al 2016 (PubMed:27839873) Four individuals from different families with loss-of-function variants in KMT2B and Early Onset Generalized Dystonia. Three are de novo variants. Two individuals have mild impairment of cognition and intellect. The father and grandfather of one of these two individuals also have the same KMT2B variant and show Early-onset non-generalized dystonia with mild impairment of cognition and intellect. Also found significantly decreased total mRNA levels of KMT2B in mutant fibroblasts suggesting haploinsufficiency.
Meyer et al 2016 (PMID:27992417) 27 patients with KMT2B variants. Some with several genes deleted, others with single base pair deletions or changes. Of those with only changes in KMT2B six have v. mild to moderate intellectual disability.
Fuandes et al 2018 (PMID: 29276005) report cases from Zech and Meyer plus one new patient with a de novo heterozygous variant in KMT2B and severe developmental delay/intellectual disability.
Agha et al 2014 (PMID:25405613) report a homozygous variant in KMT2B in a consanguineous family. Proband has severe intellectual disability, parents unaffected.Created: 21 Feb 2018, 5:32 p.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_2_4_2017 . Main mutation mechanism : Loss of functionCreated: 27 Jul 2017, 7:09 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : gilissen_2014_candidate; Nijmegen_ID_candidates; neuro_20160418_strict; Loss of function. 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, 12:45 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
Comment on publications: added publications from Eleanor Williams (Genomics England Curator), 21 Feb 2018Created: 14 Mar 2018, 11:29 a.m.
Comment on list classification: This gene is from an expert list and needs further assessment by the Genomics England curation team to assess inclusion and pertinence to this panel.Created: 20 Jul 2017, 12:11 p.m.
Tag Q3_23_promote_green was removed from gene: KMT2B. Tag Q4_23_promote_green tag was added to gene: KMT2B.
Gene: kmt2b has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: KMT2B were changed from Dystonia 28, childhood-onset, 617284 to Dystonia 28, childhood-onset, OMIM:617284; Intellectual developmental disorder, autosomal dominant 68, OMIM:619934
Publications for gene: KMT2B were set to 25529582; 27839873; 27992417; 29276005; 25405613; 29289525; 29697234; 31216378
Tag watchlist was removed from gene: KMT2B. Tag Q3_23_promote_green tag was added to gene: KMT2B.
Publications for gene: KMT2B were set to 25529582; 27839873; 27992417; 29276005; 25405613; 29289525; 31216378
Publications for gene: KMT2B were set to 25529582; 27839873; 27992417; 29276005; 25405613; 29289525
Phenotypes for KMT2B were set to Dystonia 28, childhood-onset, 617284
Publications for KMT2B were set to 25529582; 27839873; 27992417; 29276005; 25405613; 29289525
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.
This gene has been classified as Amber List (Moderate Evidence).
KMT2B was added to Intellectual disabilitypanel. Sources: BRIDGE study SPEED NEURO Tier1 Gene
KMT2B was created by BRIDGE