Abstract
PurposeTo investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). MethodsMultiple 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. ResultsThe 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 software-based 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. ConclusionKMT2D 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.
Highlights
Diverse developmental phenotypes resulting from distinct variants in the same gene are being increasingly recognized, largely due to wider application of next-generation sequencing and multicenter collaborations.[1]
Circular dichroism spectroscopy indicated that these missense variants (MVs) perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition
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 Kabuki syndrome type 1 (KS1)
Summary
Diverse developmental phenotypes resulting from distinct variants in the same gene are being increasingly recognized, largely due to wider application of next-generation sequencing and multicenter collaborations.[1] These discoveries provide unique biological insights into gene and protein functions, and are critical for appropriate medical management, and counseling of patients and families. Defective histone lysine methylation and chromatin remodeling defects underlie several congenital malformation disorders.[2] KMT2D encodes a very large (593 kDa) protein that catalyzes the mono-, di-, and trimethylation of the lysine. KMT2D has a high level of predicted disorder content (55%) with many regions of intrinsic disorder, which are typical features of nuclear proteins that regulate transcription and chromatin organization.[4] Kabuki syndrome type 1 (KS1, MIM 147920) is an autosomal dominant condition caused by loss-of-function KMT2D (MIM 602113) variants.[5] Over 700 KMT2D variants have been reported in the literature in individuals with KS1.
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