AAD10; ALR; CAGL114; KABUK1; KMS; MLL2; MLL4; TNRC21
The KMT2D gene is associated with autosomal dominant Kabuki syndrome (MedGen UID: 162897).
Order this gene as a single gene test.
Invitae tests that include this gene:
DNA in cells is organized into chromatin to allow for efficient and tightly regulated gene expression. Chromatin consists of DNA wrapped around structural / regulatory proteins called histones. The KMT2D gene encodes a histone methyltransferase, which transfers chemical groups (methyl) to the lysine-4 (K4) residue in histone H3, resulting in transcriptional activation (PMID: 23200123).
Kabuki syndrome is a rare developmental disorder that is characterized by distinct facial features that are reminiscent of the facial appearance of Kabuki theater actors. Hallmarks of the facial appearance are: abnormally long palpebral fissures, everted lower eyelids, broad nose with flattened tip and large, cupped shaped ears. Affected children also exhibit skeletal abnormalities, including scoliosis, prominence of fetal finger pads, mild to moderate intellectual disability, and postnatal growth deficiency. Hypotonia and feeding difficulties are often early manifestations of the disorder. Other anomalies include congenital heart defects, cleft lip or cleft palate, seizures, and hearing loss. Abnormalities of the gastrointestinal, genitourinary, ophthalmologic, immunologic, and endocrine systems are also observed. Ear pits and lip pits are sometimes seen in patients with Kabuki syndrome. Recently, cases have been reported with prenatal hydrops which may lead to a broadened phenotype (PMID: 27568880).
The majority of Kabuki patients have pathogenic changes in the KMT2D gene and a small proportion of patients have changes in KDM6A. KMT2D produces a histone methyltransferase protein and KDM6A encodes a histone demethylase. They interact in a large complex with other proteins and influence gene activity through epigenetic modification. These genes have a broad spectrum of pathogenic mutations described, including missense, nonsense, and splice site changes as well as whole exon deletions. The Invitae Kabuki Syndrome Panel includes testing for both sequence and copy number changes.
KMT2D is inherited in an autosomal dominant manner. Most cases are de novo but familial occurrence has been reported (PMID: 23131014). KDM6A is inherited in an X-linked manner (PMID: 24664873).
Management of patients with Kabuki syndrome is complex as multiple organ systems are affected and manifestations are variable. Some highlights of symptoms and implications for management are listed below:
Differential diagnoses (PMID: 21882399):
Review date: October 2016
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|