Kabuki Syndrome Panel

Kabuki syndrome (KS) 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. PubMed ID: 23913813; Adam et al. 2019 PubMed ID: 21882399).

Kabuki syndrome can be autosomal dominant (caused by pathogenic variants in KMT2D/MLL2) or X-linked dominant (caused by pathogenic variants in KDM6A). 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. The KDM6A protein coded by exons 1 to 29 of the KDM6A gene on Xp11.2 is a histone demethylase that specifically demethylates the Lys-27 position of histone H3. Pathogenic variants in KMT2D and KDM6A account for approximately 2/3 and 1/3 of pathogenic variants identified in Kabuki patients, respectively (Micale et al. 2014. PubMed ID: 24633898).

To date, more than 400 unique pathogenic variants in KMT2D have been documented. They are missense (20%), nonsense (30%), splicing (8%), small del/ins (40%), and ~2% large deletions and duplications. The majority of pathogenic variants occur de novo (Micale et al. 2014. PubMed ID: 24633898; Banka et al. 2013. PubMed ID: 22901312; Human Gene Mutation Database).

Pathogenic variants in KDM6A cause X-linked dominant Kabuki syndrome. To date, more than 30 unique pathogenic variants have been documented and include missense (6%), nonsense (17%), splicing (11%), small deletions (20%), large deletions/duplications and complex large rearrangements (46% ) (Lindgren et al. 2013. PubMed ID: 23354975; Micale et al. 2014. PubMed ID: 24633898; Banka et al. 2013. PubMed ID: 22901312; Human Gene Mutation Database).

Recently, an apparently homozygous undocumented missense RAP1A variant (c.488G>C, p.Arg163Thr) was found in one KS patient due to paternal uniparental isodisomy, and a de novo undocumented missense RAP1B variant (c.451A>G, p.Lys151Glu) was found in one KS patient (Bögershausen et al. 2015. PubMed ID: 26280580). RAP1A and RAP1B are members of the Ras family of small GTPases that function in early tissue/organ development.

Pathogenic variants in ANKRD11, KDM1A, BCO1, HNRNPK , and OTUD6B have been reported in a few cases with Kabuki-like syndrome or patients with mild intellectual disability associated with seizures and dysmorphic features (Tunovic et al. 2014. PubMed ID: 24838796; Gambin et al. 2017. PubMed ID: 27980096; Kernohan et al. 2018. PubMed ID: 30160830; Santiago-Sim et al. 2017. PubMed ID: 28343629).

In two cohort studies with 303 and 81 clinically diagnosed Kabuki patients, KMT2D pathogenic variants were found in 43% and 61% of the studied patients, while KDM6A pathogenic variants were identified in 1% and 6% of the studied patients (Miyake et al. 2013. PubMed ID: 23913813; Micale et al. 2014. PubMed ID: 24633898). RAP1A and RAP1B pathogenic variants account for only rare cases (Bögershausen et al. 2015. PubMed ID: 26280580).

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

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define 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).