May 2026 Research Update

This month, the biggest step forward was a more accurate lab-based way to support a Kabuki syndrome diagnosis when genetics are uncertain. A study built an updated DNA methylation pattern (a chemical "fingerprint" on DNA) for Kabuki syndrome type 1 (KS1) and found it could separate KS1 from people without KS with very high accuracy. It also appeared to recognize some Kabuki syndrome type 2 (KS2) cases, suggesting this approach may help across more than one genetic cause of Kabuki syndrome. [1]

In this work, researchers used samples from 110 people with KMT2D variants and 854 controls to train and test a computer classifier. In validation testing, the episignature approach reached 97% sensitivity and 100% specificity, and it performed better than common computer-based variant prediction tools. The study also reported that the methylation pattern could help sort some KMT2D variants by where they fall in the gene, which may be useful when a variant is hard to interpret. [1]

For families, this study mainly adds a stronger tool for situations where a genetic change is found but its meaning is unclear, or when the clinical picture is complicated. It does not change treatment, but it could matter for getting to a clearer answer about whether a KMT2D change is truly related to Kabuki syndrome, and it may also help with some KDM6A-related (KS2) cases. What remains uncertain is how widely available this testing is in routine care and how it performs across very diverse real-world patients and lab settings beyond the reported validation. [1]

This month also reinforced that changes in Kabuki-related genes can show up with a wide range of features, and sometimes the diagnosis is not straightforward. A small Kabuki syndrome series expanded the list of reported KMT2D variants, while a separate single-family report described a child with a complex left-sided heart obstruction pattern and a KMT2D variant but without meeting Kabuki syndrome criteria. Taken together, these studies add examples of how genetic findings and symptoms do not always match in a simple one-to-one way. [2] [3]

In a Turkish multicenter series of 8 people suspected of having Kabuki syndrome, 7 had pathogenic KMT2D variants, including 3 variants the authors reported as previously unreported. The report also noted one person with a novel KMT2D variant who had recurrent bone fractures, adding to the set of skeletal issues described in Kabuki syndrome. Because the series was small, it mainly contributes additional real-world examples rather than precise estimates of how common any feature is. [2]

In a separate case report, a 4-year-old girl had a Shone syndrome phenotype (multiple left-sided heart obstructions) and a maternally inherited KMT2D missense variant, but she did not meet Kabuki syndrome clinical criteria, and relatives with the same variant did not have heart symptoms. The authors described successful surgical repair and stable follow-up, but they cautioned that a single family cannot prove the KMT2D variant caused the heart condition. This highlights why additional evidence beyond a single genetic result is often needed when a variant is found in an affected child and unaffected relatives. [3]

For patients and caregivers, these reports mainly help set expectations about uncertainty and variability in genetic results. One adds to the growing catalog of KMT2D changes seen in Kabuki syndrome; the other, in a child who did not meet Kabuki syndrome criteria, is a reminder that some gene variants can be found in family members with few or no symptoms, which can complicate interpretation. This does not establish new standard screening or treatment steps, but it may matter when families are trying to understand what a genetic test result does or does not explain, especially for heart findings or bone concerns. What remains uncertain is whether the KMT2D variant in the heart case is truly related to the child's condition, and how often similar patterns occur in larger groups. [2] [3]