Phenotypic expansion of KMT2D-related disorder: Beyond Kabuki syndrome

Abstract

Pathogenic variants in KMT2D, which encodes lysine specific methyltransferase 2D, cause autosomal dominant Kabuki syndrome, associated with distinctive dysmorphic features including arched eyebrows, long palpebral fissures with eversion of the lower lid, large protuberant ears, and fetal finger pads. Most disease-causing variants identified to date are putative loss-of-function alleles, although 15-20% of cases are attributed to missense variants. We describe here four patients (including one previously published patient) with de novo KMT2D missense variants and with shared but unusual clinical findings not typically seen in Kabuki syndrome, including athelia (absent nipples), choanal atresia, hypoparathyroidism, delayed or absent pubertal development, and extreme short stature. These individuals also lack the typical dysmorphic facial features found in Kabuki syndrome. Two of the four patients had severe interstitial lung disease. All of these variants cluster within a 40-amino-acid region of the protein that is located just N-terminal of an annotated coiled coil domain. These findings significantly expand the phenotypic spectrum of features associated with variants in KMT2D beyond those seen in Kabuki syndrome and suggest a possible new underlying disease mechanism for these patients.

Keywords: KMT2D; Kabuki syndrome; athelia.

Figure 1.. Facial features of three individuals with KMT2D missense variants.

A-C: Patient 1, at age 12 months, 5 years, and 15 years. Arched eyebrows, depressed nasal bridge, small alae nasi, tented upper lip. D-F: Patient 2, at age 5 years, 8 years, and 15 years. Up-swept frontal hair line, widely spaced eyes, downslanting palpebral fissures, flat and wide nasal bridge, narrow and hypoplastic alae nasi, pointed nasal tip with low hanging columella, and a very thin upper lip with downturned corners. G-I: Patient 3, at age 8 months, 10 years, and 13 years. Tall, broad forehead with deep-set eyes, small nose, thin lips, dry, curly, and coarse hair. J: Patient 4, at age 24 years. Broad, depressed nasal tip and right facial nerve palsy. Reproduced, with permission, from Sakata et al., 2017.

Figure 2.. Chest, back, ear, scalp, and lung abnormalities in individuals with KMT2D missense variants.

A-B: Patient 1, athelia at age 12 months and 5 years. C-D: Patient 2, hypoplastic, faintly pigmented nipples at age 5 years and 15 years. E: Patient 1, hypertrichosis at age 5 years. F: Patient 1, at age 12 months. Small ears with unusual superior helical ear tags (blue arrow). G: Patient 2, at age 8 years. Small, protruding, dysplastic, cup-shaped ears. H: Patient 2, at age 8 years. Scalp scars, after resolution of cutis aplasia at birth. I: Patient 1, at age 6 months. Computed tomography of lungs shows diffuse interstitial infiltrates and numerous, small, bilateral cysts. J: Patient 1. 10X hematoxylin and eosin (H&E) stained sections of explanted lung at age 19 months demonstrate an area of alveolar remodeling with enlarged airspaces; such areas were found throughout all lobes, interspersed with areas with smaller airspaces. K. Patient 1. 20X H&E. Areas with smaller airspaces show widened alveolar septa and prominent type II pneumocyte hyperplasia (black arrows). Airspaces contain macrophages (white arrows), degenerating cells, cholesterol clefts (black arrowheads) and dense eosinophilic and proteinaceous material (*). Pulmonary arterioles show mild medial and intimal thickening.

Figure 3.. Teeth, hand, and feet abnormalities in individuals with KMT2D missense variants.

A-B: Patient 2, at age 15 years. Teeth are crowded, yellow, and covered with plaque, with abnormal conical shape of the lower central incisors. C: Patient 1, fingers at age 12 months prior to lung transplant showing clubbing due to lung disease, but absence of fetal fingertip pads. D-E: Patient 2, at age 15 years. Normal fingers with absence of fetal fingertip pads and dysplastic nails of great toes. F-H: Patient 3 at age 13 years, 14 years, and 13 years. Prominent clubbing of digits and absence of fetal fingertip pads.

Figure 4.. Growth curves for individuals with KMT2D missense variants.

A-B: Patient 1. C-D: Patient 2.

Figure 5.. KMT2D missense variants, evolutionary conservation, protein domains, and population variation.

A: Location of patients’ KMT2D missense variants on a highly conserved multi-species alignment of KMT2D protein sequence. ECRs: evolutionarily constrained regions as identified by Aminode (Chang et al., 2018). CC: coiled-coil domain, which extends from residues 3562-3614. B: Schematic of domains of KMT2D protein from InterPro (Mitchell et al., 2019). ZF: zinc-finger. HMG: high mobility group. CC: coiled-coil. FYR: FY-rich. SET: SET methyltransferase domain. C: In green are shown two regions of missense constraint from human population data (Samocha et al., 2017).