Monogenic short stature

Gene: KMT2D

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains RED

Created: 31 Jan 2023, 5:28 p.m. | Last Modified: 31 Jan 2023, 5:28 p.m.

Panel Version: 2.33

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains RED

Created: 31 Jan 2023, 5:28 p.m. | Last Modified: 31 Jan 2023, 5:28 p.m.

Panel Version: 2.33

This gene was recently reviewed by the Endocrine Specialist Group (Sept 2022) and it was decided that the phenotype is not relevant to this panel and therefore should remain Red. Cases expected to be picked up via other routes (e.g. ID, skeletal dysplasia, eye panels)

Created: 6 Jan 2023, 11:20 a.m. | Last Modified: 6 Jan 2023, 11:22 a.m.

Panel Version: 2.29

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
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Green List (high evidence)

Perhaps I don't fully understand the scope of this panel but:

Association with Kabuki syndrome: failure to thrive in infancy and short stature are key features.

Note new association between missense variants located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from Kabuki syndrome, through a dominant negative mechanism. ~10 unrelated families with choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. Extreme short stature reported.

Created: 16 Aug 2021, 8:32 a.m. | Last Modified: 16 Aug 2021, 8:32 a.m.

Panel Version: 1.71

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Kabuki syndrome 1, MIM# 147920; KMT2D-associated neurodevelopmental syndrome

Publications

• 31949313
• 32083401
• 21882399

I don't know

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.