• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The KMT2D gene is associated with autosomal dominant Kabuki syndrome (MedGen UID: 162897).

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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).

OMIM: 602113

Clinical condition
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).

Gene information
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:

  • Hypotonia/feeding issues: Evaluation by gastroenterologist and feeding specialists. All infants have some degree of hypotonia. Some affected infants require gastrostomy tube. Later issues of diarrhea and constipation need to be addressed
  • Neonatal hypoglycemia: Increased frequency, but hypoglycemia may also be present in older children.
  • Visceral malformations: Ultrasound to rule out renal malformations. Increased frequency of diaphragmatic hernia, ano-rectal malformation and biliary atresia.
  • Cardiac defects: 40-50% of affected Kabuki syndrome individuals have cardiac defects, most often left-sided obstructive lesions and aortic coarctation. ASD and VSD are the most common defects. All patients need evaluation by cardiology.
  • Clefting: One third of Kabuki syndrome patients have clefting. Lip pits are seen in a small proportion of Kabuki syndrome patients.
  • Orthopedic problems: All Kabuki syndrome patients have joint laxity which can lead to hip dislocation. Scoliosis can develop secondarily to hypotonia. Flat feet are common in Kabuki syndrome patients. Patellar dislocation is common in adolescence and obesity may contribute.
  • Seizures: 15-25% of Kabuki syndrome patients have seizures and need referral to neurologist for treatment. Hypoglycemia as cause of seizures needs to be ruled out.
  • Immunity: Kabuki syndrome patients need check of T cells, T cell subsets and immunoglobulins. If abnormal, referral to pediatric immunology.
  • Developmental delay: Range of capabilities in Kabuki syndrome patients. Need evaluation, especially in speech and language.
  • Behavior: Kabuki syndrome patients may exhibit behavior problems and shortened attention span which needs intervention.
  • Autism: Some Kabuki syndrome patients exhibit autistic features and need appropriate treatment.
  • Hearing loss: 40-50% of Kabuki syndrome patients have hearing loss, need hearing assessment and appropriate treatment. Some have recurrent otitis media.
  • Ophthalmic problems: Increased frequency of structural anomalies, such as coloboma. Strabismus occurs in 20-50%. All Kabuki syndrome patients should have an ophthalmologic evaluation.
  • Dental: Dental anomalies are common in Kabuki syndrome and need referral to pediatric dentist.
  • Growth: Growth hormone deficiency has been noted.
  • Hirsutism: One fifth of Kabuki syndrome patients have excessive hair growth.
  • Obesity: Increased frequency at time of puberty.
  • Puberty: Early menstruation in some Kabuki syndrome females.
  • Anesthesia: Special precautions should be taken for any Kabuki syndrome patient undergoing surgical procedures due to hypotonia, joint laxity and ruling out cardiac defect.
  • Autoimmune: Increased risk of autoimmune disease, in particular, idiopathic thrombycytopenic purpura (ITP). Need complete blood count and thyroid function every 2-3 years.

Differential diagnoses (PMID: 21882399):

  • CHARGE syndrome: Cleft palate, congenital heart defects and growth retardation, facial characteristics distinguishable from Kabuki syndrome. Invitae offers testing for CHD7, the gene associated with CHARGE syndrome.
  • 22q11 deletion syndrome: Cleft palate, congenital heart defects and urinary tract anomalies, facial characteristics distinguishable from Kabuki syndrome.
  • IRF-6 related disorders: Van der Woude and popliteal pterygium syndromes. Cleft lip and lip pits, no intellectual deficits as found in Kabuki syndrome. Invitae offers testing for IRF6 and GRHL3, genes associated with Van der Woude and popliteal pterygium syndromes.
  • Branchiootorenal BOR syndrome: Ear pits, cupped ears, hearing loss and renal hypoplasia and renal agenesis. Branchial cleft cysts seen in BOR are not reported in Kabuki syndrome. Invitae offers testing for EYA1 and SIX1, genes associated with branchiootorenal BOR syndrome.

Review date: October 2016

Assay and technical information

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
KMT2D NM_003482.3