KMT2D p.Gln3575His segregating in a family with autosomal dominant choanal atresia strengthens the Kabuki/CHARGE connection

Abstract

Choanal atresia is rarely reported in Kabuki syndrome, but is a common feature of CHARGE syndrome. Otherwise, the two conditions have a number of overlapping features, and the molecular links between them have recently been elucidated. Here, we report a case of a mother and her two children who presented with congenital choanal atresia. We performed whole exome sequencing on DNA from the mother and her two unaffected parents, and identified a de novo, novel variant in KMT2D. KMT2D p.Gln3575His segregated with disease status in the family, and is associated with a unique and conserved phenotype in the affected family members, with features overlapping with Kabuki and CHARGE syndromes. Our findings further support the potential etiological link between these two classically distinct conditions. © 2016 Wiley Periodicals, Inc.

Phenotypic expansion of KMT2D‐related disorder: Beyond Kabuki syndrome

“…In 2016, Badalato et al reported a mother, and her son and daughter with choanal atresia, hearing loss, and dental abnormalities, and who all harbor a missense variant (c.10725G>C p.(Gln3575His)) in KMT2D , which was de novo in the mother (Badalato et al, ). While their facial appearances were not typical for Kabuki syndrome, all three did have fetal fingertip pads, and the authors characterized these individuals as cases of “atypical Kabuki syndrome.” As noted by Sakata et al (), this variant is only eleven amino acids away from the variant found in Patient 4.…”

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

“…30 Molecularly, KMT2D and CHD7 both interact with members of the WAR complex 31 and clinical overlap between KMT2D variants and CHARGE syndrome has been previously postulated. 29,31 Two of these previous reports described individuals with clinical features that match those of the Ex38/39 KMT2D MVs cohort and that carry KMT2D missense variants, one with p. Gln3575His and another with p.Leu3564Val, that lie within the central conserved KMT2D region we describe. 29,32 We propose that these previously published individuals have neither KS1 nor CHARGE syndrome, and fit better with the condition that we describe in this study.…”

“…To experimentally test the functional impact of KMT2D missense variants, we generated FLAG-tagged versions of six KMT2D missense alleles: p.Leu3528Val, p.Leu3542Pro, p. Gly3553Val, p.Gln3575His, 29 p.Arg3582Trp, and p.Arg3582Gln. Fluorescence data revealed no changes in trimethylation H3K4 levels between all the missense variants tested in this assay compared with KMT2D normal control activity (Fig.…”

Espectro fenotípico de Síndrome de CHARGE neonatal

“…Otros diagnósticos diferenciales del síndrome de CHARGE son el síndrome de Kabuki, síndrome renalcoloboma, síndrome de Cat-Eye, síndrome de Joubert, síndrome Branquio-Oto-Renal, embriopatía secundaria a exposición a ácido retinoico y asociación VAC-TERL 10,11,17,18 .…”

“…Considerando la prevalencia descrita, (en Chile debiéramos tener 20 casos al año), creemos que hay una alta tasa de subdiagnóstico debido a la sobreposición de síntomas con otros síndromes y la alta morbimortalidad en periodo neonatal. Entre los diagnósticos diferenciales está el síndrome de microdeleción 22q11.2, síndrome de Kallman, síndrome de Kabuki, Treacher Collins, Mowat Wilson y síndrome 3M 10,11 .…”