Kabuki Syndrome via the KMT2D Gene

Kabuki syndrome is a multiple congenital disorder characterized by arched and broad eyebrows, long palpebral fissures with the everted lateral third of the lower eye lids, depressed nasal tip, large protruding earlobes, persistence of fetal fingertip pads, skeletal defects, developmental delay and mental retardation. Other features include congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies hearing loss, and widely spaced teeth and hypodontia. Patients may also have frequent infections, seizures, and feeding problems (Miyake et al. 2013; Adam et al. 2013).

KMT2D–related Kabuki syndrome is inherited in autosomal dominant manner. The KMT2D protein coded by exons 1 to 54 of the KMT2D gene on 12q12-q14 is a histone methyltransferase that methylates the Lys-4 position of histone H3. Mutations in KMT2D account for approximately 2/3 of mutations identified in Kabuki patients (Micale et al. 2014). To date, almost 300 unique pathogenic variants in KMT2D have been documented. They are missense: 16%, nonsense: 33%; splicing: 9%, small del/ins: 41%, and ~1% large deletions and duplications. The majority of mutations occur de novo (Micale et al. 2014; Banka et al. 2013; Human Gene Mutation Database).

In two cohort studies with 303 and 81 clinically diagnosed Kabuki patients, KMT2D causative variants were found in 43% and 61% of the studied patients (Miyake et al.; Micale et al. 2014).

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the KMT2D gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.