A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct fromKabuki syndrome

Abstract

To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. Results: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective softwarebased facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition. Conclusion: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.

Phenotypic expansion of KMT2D‐related disorder: Beyond Kabuki syndrome

“…Finally, while this manuscript was under review, we became aware of a study which describes the same genotype–phenotype relationship that we report here, but in a separate cohort of 10 affected individuals (Cuvertino et al, ). We note that two of these patients share the same de novo missense variant as in our Patient 2 (p.(Leu3528Val)), and another patient's variant (p.(Leu3542Pro)) is only one amino acid away from our Patient 3's variant (p.(Ala3541Pro)).…”

Clinical delineation, sex differences, and genotype–phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2

“…These results should facilitate interpretation of KDM6A variants in clinics. In the future, functional analysis using DNA methylation signatures [22][23][24][25] or epigenetic reporter assays 26 might be useful to determine the significance of some PAVs. In future, systematic comparison of KDM6A germline and somatic missense variants, as recently performed for KMT2D, might also be possible.…”

Kabuki Syndrome—Clinical Review with Molecular Aspects

“…Missense KMT2D variant s likely cause reduced histone methylation due to impaired WRAD protein complex formation [ 18 ]. They may result in a novel multiple-malformation syndrome [ 19 ]. Notable clinical differences may be observed: no patient with such variant s presented with intellectual disability, clefting, renal abnormalities or seizures, while six patients presented with hypothyroidism.…”