Abstract

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