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Primary immunodeficiency

Gene: KMT2D

Amber List (moderate evidence)

KMT2D (lysine methyltransferase 2D)
EnsemblGeneIds (GRCh38): ENSG00000167548
EnsemblGeneIds (GRCh37): ENSG00000167548
OMIM: 602113, Gene2Phenotype
KMT2D is in 21 panels

5 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: Immunopathological manifestations are seen in ~50% of cases with KMT2D-related Kabuki syndrome. There is sufficient evidence to support this gene-disease association and therefore this gene should be promoted to Green status at the next GMS panel update.
Created: 14 Sep 2021, 12:46 p.m. | Last Modified: 14 Sep 2021, 12:46 p.m.
Panel Version: 2.464

Dmitrijs Rots (RadboudUMC)

Green List (high evidence)

Immunodeficiency is a well-known and common feature of KS. Recent study shows:
"Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively"
Created: 12 Sep 2021, 11:06 a.m. | Last Modified: 12 Sep 2021, 11:06 a.m.
Panel Version: 2.458

Phenotypes
Hypogammaglobulinemia; intellectual disability; short stature

Publications

Eleanor Williams (Genomics England Curator)

The following PubMed IDs were added to gene KMT2D (OMIM gene MIM#602113): 23913813;21671394;21607748. These publications have been associated with the gene by the immunodeficiencies subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.
Created: 13 Oct 2020, 9:36 a.m. | Last Modified: 13 Oct 2020, 9:36 a.m.
Panel Version: 2.208

Publications

Louise Daugherty (Genomics England Curator)

Comment on publications: Comment on publications: Added publications to support immunodeficiency phenotype and KS. Stagi S et al. (2016) PMID: 26411453 noted that most KS patients show increased susceptibility to infections and have reduced serum immunoglobulin levels, while some suffer also from autoimmune manifestations, such as idiopathic thrombocytopenic purpura, hemolytic anemia, autoimmune thyroiditis, and vitiligo. They reviewed the immunological aspects of KS and proposed a novel model to account for the immune dysfunction observed in this condition.
Created: 6 Jul 2018, 2:38 p.m.
Comment on publications: Comment on publications: Immunological abnormalities and KS were systematically analyzed for the first time in 2005, Hoffman JD et al. (2005) PMID:15887282. Although it was noted that no studies have analyzed in detail the functional consequences of KMT2D and KDM6A mutations on the immune system of patients with KS, and no mechanistic models accounting for such abnormalities have been proposed. Low serum immunoglobulin levels and reduced memory T and B lymphocytes have been reported Lin JL et al. (2015) PMID:25142838. Also increased occurrence of autoimmune manifestations, such as idiopathic thrombocytopenic purpura (ITP), hemolytic anemia, autoimmune thyroiditis, and vitiligo has been reported by Ming JE et al. (2005) PMID:15523604, suggests that both KMT2D and KDM6A genes may play a relevant, still undisclosed, role in the immune homeostasis.
Created: 6 Jul 2018, 2:37 p.m.
OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): KMT2D (MLL2) .PanelApp HGNC gene symbol check: KMT2D . IUIS Disease: Kabuki Syndrome 1 due to KMT2D deficiency . IUIS Inheritance: AD .T cells: Nl number, defective migration, proliferaton, .B cells: Normal, .IUIS Other affected cells: N/A. IUIS Associated features: Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present. IUIS Major category: Combined immunodeficiencies with associated or syndromic features. IUIS Subcategory: Other Combined immunodeficiencies with associated or syndromic features
Created: 6 Jul 2018, 12:29 p.m.

Sophie Hambleton (Newcastle University)

Red List (low evidence)

Immunodeficiency not a prominent feature
Created: 29 Jun 2018, 9:39 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Kabuki syndrome 1

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • Other
  • IUIS Classification December 2019
  • IUIS Classification February 2018
Phenotypes
  • Kabuki syndrome 1, OMIM:147920
  • Hypogammaglobulinemia
  • Recurrent infections (otitis media, pneumonia)
  • Autoimmunity
Tags
Q3_21_rating
OMIM
602113
Clinvar variants
Variants in KMT2D
Penetrance
None
Publications
Panels with this gene

History Filter Activity

14 Sep 2021, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_21_rating tag was added to gene: KMT2D.

14 Sep 2021, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: KMT2D were set to 25142838; 15523604; 21671394; 32048120; 15887282; 21607748; 32086639; 23913813; 26411453

14 Sep 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: kmt2d has been classified as Amber List (Moderate Evidence).

14 Sep 2021, Gel status: 1

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: KMT2D were changed from Kabuki syndrome 1, 147920; Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present; Combined immunodeficiencies with associated or syndromic features to Kabuki syndrome 1, OMIM:147920; Hypogammaglobulinemia; Recurrent infections (otitis media, pneumonia); Autoimmunity

13 Oct 2020, Gel status: 1

Added New Source, Set publications

Eleanor Williams (Genomics England Curator)

Source Other was added to KMT2D. Publications for gene KMT2D were updated from 25142838; 32048120; 15887282; 15523604; 26411453; 32086639 to 25142838; 15523604; 21671394; 32048120; 15887282; 21607748; 32086639; 23913813; 26411453

28 Feb 2020, Gel status: 1

Added New Source, Set Phenotypes, Set publications

Louise Daugherty (Genomics England Curator)

Source IUIS Classification December 2019 was added to KMT2D. Added phenotypes Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present; Combined immunodeficiencies with associated or syndromic features for gene: KMT2D Publications for gene KMT2D were updated from 15887282; 25142838; 15523604; 26411453 to 25142838; 32048120; 15887282; 15523604; 26411453; 32086639

12 Jul 2018, Gel status: 1

Panel promoted to version 1.0

Louise Daugherty (Genomics England Curator)

2018-07-12 Louise Daugherty (Genomics England Curator) promoted panel to v1.0. Reviews were assessed, and panel was revised according to expert reviews and further in-house curation based on PanelApp guidelines. Previous panels (A- or hypo-gammaglobulinaemia, Congenital neutropaenia, Agranulocytosis, Combined B and T cell defect, Inherited complement deficiency and SCID panels) that were merged with this panel, were checked again for any changes/new reviews prior to versioning of this panel, these merged panels are now retired/made internal.

6 Jul 2018, Gel status: 1

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: kmt2d has been classified as Red List (Low Evidence).

6 Jul 2018, Gel status: 1

Set mode of inheritance

Louise Daugherty (Genomics England Curator)

Mode of inheritance for gene: KMT2D was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

6 Jul 2018, Gel status: 1

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: KMT2D were set to Kabuki syndrome 1, 147920; Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present; Combined immunodeficiencies with associated or syndromic features

6 Jul 2018, Gel status: 1

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: KMT2D were set to 15887282; 25142838; 15523604; 26411453

6 Jul 2018, Gel status: 1

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: KMT2D were set to 15887282; 25142838; 15523604

1 Jul 2018, Gel status: 1

Set penetrance

Louise Daugherty (Genomics England Curator)

Phenotypes for gene KMT2D were set to Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present, Combined immunodeficiencies with associated or syndromic features

26 Jun 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

KMT2D was added to Primary immunodeficiency disorders panel. Sources: IUIS Classification February 2018

26 Jun 2018, Gel status: 1

Created

Louise Daugherty (Genomics England Curator)

KMT2D was created by Louise Daugherty