Growth failure in early childhood
Gene: KDM6AAfter NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains AMBER. The additional comments from GLH's is "Previously agreed that Kabuki Syndrome not in scope and the other Kabuki gene (KMT2D) is not recommended to be green rated"Created: 31 Jan 2023, 5:28 p.m. | Last Modified: 31 Jan 2023, 5:28 p.m.
Panel Version: 2.33
There is sufficient evidence linking variants in this gene with Kabuki syndrome (MIM# 300867) which can include postnatal dwarfism. However, the Endocrine Specialist Group previously determined (2019) that the phenotype was not within the scope of this panel and therefore the decision was made to classify it as Red. Given this gene has recently been proposed for this panel by an expert, I am recommending that the Test Evaluation Working Group review and define the panel scope, and reach consensus as to whether this gene is appropriate for inclusion.
IUGR is a frequent prenatal finding and males with pathogenic KDM6A variants appear to have significantly smaller birth lengths but growth retardation is mostly of postnatal origin. Microcephaly can be observed (exclusion criterion for this clinical indication) but only in a subset of cases.Created: 6 Jan 2023, 11:16 a.m. | Last Modified: 6 Jan 2023, 11:16 a.m.
Panel Version: 2.28
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes
Kabuki syndrome 2, OMIM:300867
Publications
Review submitted on behalf of Helen Storr. Mode of inheritance: KMT2D AD; KDM6A X-linked. Most cases are de novo. Phenotypes: Kabuki syndrome. Can be confused with SRS due to overlapping features also an important cause of growth failure. Phenotype is of pre- and post-natal growth failure. Characteristic facial appearance; skeletal abnormalities; short stature; heart defects; and intellectual disability. Other signs and symptoms may include seizures, microcephaly, weak muscle tone (hypotonia), eye problems, cleft palate, and dental problems. Publications: Kabuki syndrome overlaps with SRS so it is important to include these genes in this panel. Important to identifiy and screen for the other defects of this disorder. Mechansim: TheKMT2DandKDM6Agenes belong to a family of genes calledchromatin-modifyingenzymes. These genes encode ahistone methyltransferase(KMT2D) and ahistone demethylase(KDM6A), and regulategene expression. These enzymes transfer methyl groups on and off histones to regulate genes viaepigeneticpathways. When the genes that encode these enzymes are mutated, epigenetic activation of certain developmental genes is impaired and developmental abnormalities occur, leading to the characteristics of Kabuki syndrome. The specific developmental genes that are affected by the impaired epigenetic mechanisms in Kabuki syndrome are currently unclear. Penetrance: Full penetrance.Created: 22 Dec 2022, 11:07 a.m. | Last Modified: 22 Dec 2022, 11:07 a.m.
Panel Version: 2.5
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Following discussion with members of the Endocrine Specialist Group at the Webex call on 23.05.19, it was agreed that this gene was outside the scope of this clinical indication. Therefore demoted gene from Green to Red.Created: 30 May 2019, 9:49 a.m.
Tag Q1_23_promote_green was removed from gene: KDM6A. Tag Q1_23_expert_review was removed from gene: KDM6A.
Publications for gene: KDM6A were set to
Tag Q1_23_promote_green tag was added to gene: KDM6A. Tag Q1_23_expert_review tag was added to gene: KDM6A.
Phenotypes for gene: KDM6A were changed from Kabuki to Kabuki syndrome 2, OMIM:300867
Source Expert Review Red was added to KDM6A. Rating Changed from Green List (high evidence) to Red List (low evidence)
gene: KDM6A was added gene: KDM6A was added to Growth failure in early childhood. Sources: Expert Review Green Mode of inheritance for gene: KDM6A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Phenotypes for gene: KDM6A were set to Kabuki