AAD10; ALR; CAGL114; KABUK1; KMS; MLL2; MLL4; TNRC21
The KMT2D gene is associated with autosomal dominant Kabuki syndrome (MedGen UID: 162897).
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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, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|