What if some KMT2D changes don’t just cause Kabuki syndrome—but a different disorder that only partly overlaps with it?
In classic Kabuki syndrome, variants in KMT2D—a gene encoding an enzyme that modifies histones (proteins around which DNA is wrapped, influencing gene activity)—lead to a recognizable set of features including distinctive facial traits, developmental delays, and growth issues. But this study asked whether certain missense variants (single amino-acid changes in the protein) in KMT2D might produce a strikingly different set of symptoms beyond typical Kabuki signs.
What the Study Did
In a 2020 study, Researchers analyzed four unrelated patients who each had a de novo (new in the individual, not inherited) missense variant in KMT2D. A missense variant changes one amino acid in the protein’s sequence, which can subtly alter protein function.
Instead of focusing on cell models or sequencing technologies like iPSCs or scRNA-seq, this was a clinical genetics study: it correlated patient symptoms with specific locations of variants in the KMT2D protein. All four variants clustered within a narrow 40-amino-acid region near a structural part of the enzyme, hinting at a localized functional role for this segment.
Key Findings
The patients shared several features that are not typical for classic Kabuki syndrome:
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Absent nipples (athelia) and choanal atresia (a blockage of the nasal passage)—rare findings outside Kabuki.
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Hypoparathyroidism (underactive parathyroid glands) and delayed/absent puberty, unusual endocrine features.
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Extreme short stature without the characteristic facial features of Kabuki.
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Severe lung disease in half of the cases—again, not characteristic of standard Kabuki.
These shared traits suggest this cluster of KMT2D missense variants leads to a distinct clinical picture, expanding the range of what KMT2D mutations can do beyond the canonical Kabuki symptom constellation.
What This Means for Kabuki
This paper doesn’t change what causes Kabuki syndrome, but it highlights that not all KMT2D variants behave the same way. Kabuki has historically been associated mainly with loss-of-function mutations (variants that truncate or destroy the protein). In contrast, these particular missense changes seem to produce a different syndrome with overlapping but distinct features.
For clinicians and families, this emphasizes that a genetic diagnosis involving KMT2D might not always map neatly onto “classic Kabuki.” Instead, variant type and location matter, and some missense variants may warrant a separate or refined diagnosis. This helps explain cases where individuals lack the hallmark Kabuki facial features yet have significant multisystem problems tied to KMT2D.
What the Study Doesn’t Resolve
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We still don’t know the exact molecular mechanism by which these clustered missense changes lead to their unique symptoms.
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The study involved only four patients, so the full clinical spectrum of this variant class remains undefined.
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There’s no functional assay yet (e.g., biochemical or cellular tests) linking these variants to specific disruption in enzyme activity.