Submission Details

KMT2D was first reported as a causative gene for autosomal dominant Kabuki syndrome in 2010 (PMID: 20711175). This gene encodes the enzyme lysine-specific methyltransferase 2D (KMT2D). KMT2D binds multiple co-factors including the paired box (PAX) transactivation domain interacting protein (PTIP) and is part of the COMPASS (COMplex of Proteins Associated with SET1), which plays a key role in B cell terminal differentiation. Evidence supporting this gene-disease relationship includes case-level and experimental data. There have been many cases reported with a broad spectrum of clinical features including growth delay, long palpebral fissures, frequent infections and others. The resulting syndrome is often referred to as Kabuki Syndrome 1. Kabuki syndrome is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Other findings may include congenital heart defects (CHD), genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. Prevalence of CHD in Kabuki syndrome patients reported in the literature is approximately 70%, with left-sided obstructive lesions and septal defects being the most commonly reported (PMID: 28884922). Functional differences can include increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities (including isolated premature thelarche in females), feeding problems, and hearing loss (PMID: 21882399). Patients with pathogenic variants have been reported globally with a combined predominantly humoral immune deficiency but variable B and T cell lymphocytopenia. Newborn screening has flagged Kabuki patients for low TRECS, and so this is evidence of impaired thymopoesis in some patients before birth (PMID: 31304419). Over 540 variants (insertions, duplications, and missense variations) have been reported in numerous publications. This curation reports seven variants to achieve the minimum required genetic evidence score of 12 points (PMIDs: 24460868, 24739679, 25142838, 26411453, 26194542, 31363182, 31949313). Age of onset in probands ranged between 3 months to 32 years. Patients with Kabuki syndrome have been reported to have some or all of the following features: splenomegaly, impaired B cell maturation, decreased IgM levels, IgA deficiency, and/or impaired vaccine response. The clinical manifestation of immunodeficiency is due to the role of KMT2D in B cell terminal differentiation. KMT2D has been shown to have incomplete penetrance (PMID: 31949313) and variable expressivity. Immunophenotypes observed in patients (IgA deficiency, impaired response to vaccination, impaired B cell maturation, and splenomegaly) are recapitulated in mouse models (PMID: 3186409) and in vitro with primary human cells (impaired B cell maturation) (PMID: 26194542). Cardiac defects observed in patients are also recapitulated in mouse models (PMID: 26932671). KMT2D associated Kabuki syndrome can present prenatally with variable ultrasound findings including cardiac anomalies, polyhydramnios, genitourinary anomalies, single umbilical artery, IUGR, hydrops/pleural effusion/ascites, CNS anomalies, facial anomalies, skeletal findings, increased NT, cystic hygroma, oligohydramnios and gastrointestinal anomalies (PMIDs: 34185329, 33898534, 36436503, 38821912, 33686258, 37594370, 33686258, 32627857, 36658419, 34185329, 38708840). In almost half the cases, multiple prenatal USG findings are noted (PMID: 34185329). In a meta-analysis, KMT2D pathogenic variants were noted as the most common molecular findings for fetuses affected with isolated cardiac defect or cardiac defect with extra-cardiac malformations (PMID: 38708840). Prenatal cardiac findings included a myriad of defects. Among extra-cardiac malformations, renal anomalies were commonly seen (PMID: 34185329). In summary, KMT2D is definitively associated with autosomal dominant Kabuki syndrome 1 with a Predominantly humoral immunodeficiency phenotype. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the SCID-CID GCEP on October 21, 2021. It was reevaluated on April 8, 2025 (SOP v11) by the Intellectual Disability and Autism GCEP and August 14, 2025 (SOP v11) by the ClinGen Congenital Heart Disease GCEP. Although a new mention of intellectual disability as a phenotype was published (PMID: 21882399) and mouse models recapitulating CHD were added (PMID: 26932671), the classification did not change.