Abstract
PurposeThe variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood. MethodsGenetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed. ResultsSixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID. ConclusionWe expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.
Highlights
Kabuki syndrome (KS, MIM 147920 and MIM 300867) is one of the commonest congenital disorders caused by variants in genes encoding histone lysine methylases and demethylases.[1]
Ascertainment We identified 36 new patients (18 males/18 females) with hetero/ hemizygous KDM6A variants (Supplementary Table S1)
We identified 49 patients (19 males and 30 females) with KDM6A variants from 17 peer-reviewed articles (Supplementary Figure S1 and Supplementary Table S1)
Summary
Kabuki syndrome (KS, MIM 147920 and MIM 300867) is one of the commonest congenital disorders caused by variants in genes encoding histone lysine methylases and demethylases.[1] It is characterized by a distinctive facies (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows with the lateral third displaying notching or sparseness; large, prominent, or cupped ears; and short columella with depressed nasal tip), developmental delay and/or intellectual disability (ID), and several structural (e.g., congenital heart defects, genitourinary malformations) and functional anomalies (e.g., increased susceptibility to infections, endocrine disorders, deafness).[2] The majority of patients with KS have loss-of-function (LoF), mostly de novo, variants in KMT2D (formerly known as MLL2 and ALR) (KS1, MIM 147920).[3,4] KMT2D is located on chromosome 12, and encodes lysine (K)-specific methyltransferase 2D, which catalyzes the trimethylation of the lysine 4 on histone 3 (H3K4), promoting the expression of its target genes.[5]. Toward its N-terminus, the protein includes eight tetratricopeptide repeats (TPR) that may contribute indirectly to substrate binding, but their precise function is unknown
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