Kabuki Syndrome via the KDM6A 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).

Kabuki syndrome can be autosomal dominant (caused by mutations in KMT2D, also called MLL2) or X-linked dominant (caused by mutations in KDM6A). The KDM6A protein coded by exons 1 to 29 of the KDM6A gene on Xp11.2 is histone demethylase that specifically demethylates the Lys-27 position of histone H3. In two cohort studies with 303 and 81 clinically diagnosed Kabuki patients, KMT2D mutations were found in 43% -61% of the studied patients, while KDM6A mutations were identified in approximately 1% to 6% of the studied patients (Miyake et al.; Micale et al. 2014).Pathogenic variants in KDM6A cause X-linked dominant Kabuki syndrome, and can affect both males and females. To date, ~20 unique pathogenic variants have been documented and include small deletions, gross deletions and gross insertions. Large deletions/duplications and complex large rearrangements account for 65% of pathogenic variants found in KDM6A (Lindgren et al. 2013; Human Gene Mutation Database).

In two cohort studies with 303 and 81 clinically diagnosed Kabuki patients, KMT2D pathogenic variants were found in 43% -61% of the studied patients, while KDM6A pathogenic variants were identified in approximately 1% to 6% 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 KDM6A gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).