De novo KMT2D heterozygous frameshift deletion in a newborn with a congenital heart anomaly

Abstract

Kabuki syndrome (KS) is characterized by typical facial features and patients are also affected by multiple congenital anomalies, of which congenital heart anomalies (CHAs) are present in 28.0 to 80.0%. In approximately 75.0% of patients, the genetic causes of KS are caused by mutation in the KMT2D gene. Although KS is a well-characterized syndrome, reaching the diagnosis in neonates is still challenging. Namely, newborns usually display mild facial features; therefore the diagnosis is mainly based on congenital malformations. In our case, a newborn was referred for next generation sequencing (NGS) testing due to the prenatally observed CHA. After birth, a ventricular septal defect (VSD), vesicoureteral reflux, muscular hypotonia, cleft palate, mild microcephaly, and some dysmorphic features, were noted. The NGS analysis was performed on the proband’s genomic DNA using the TruSight One Sequencing Panel, which enriches exons of 4813 genes with clinical relevance to the disease. After variant calling, NGS data analysis was predominantly focused on rare variants in genes involved in VSD, microcephaly, and muscular hypotonia; features observed predominantly in our proband. With the aforementioned protocol, we were able to determine the previously unreported de novo frameshift deletion in the KMT2D gene resulting in translation termination. Although our proband is a typical representative of KS, his diagnosis was reached only after NGS analysis. Our proband thus represents the importance of genotypephenotype driven NGS analysis in diagnosis of patients with congenital anomalies.

Kabuki Syndrome—Clinical Review with Molecular Aspects

“…Good general condition and prognosis was seen, and surgical correction of cardiological abnormalities was performed. This highlights the importance of a case-by-case surgical treatment approach to KS patients as well as genotype-phenotype-driven diagnostics [ 75 ]. Knockdown Xenopus frogs develop hypoplastic hearts with defective chamber development.…”

“…Indications for surgical intervention depend on the general condition and prognosis of the child. No special considerations based on KMT2D variants have been suggested [ 75 ].…”

Sequencing of a Chinese tetralogy of Fallot cohort reveals clustering mutations in myogenic heart progenitors

“…The candidate genes identified in the Chinese cohort belonging to the early-pattern M1 included KMT2D , which encodes a histone modifier associated with CHD in Kabuki syndrome ( 32 ). Additionally, 3 other genes associated with syndromic forms of CHD ( EVC , TEP1 , and CECR2 ) ( 33 – 35 ) were found in the enriched modules with early expression patterns, i.e., M1 and M8.…”

Molecular insights of KMT2D and clinical aspects of Kabuki syndrome type 1

“…The only ongoing recruiting clinical trial (NLM, NCT04722315) utilizes the Atkins ketogenic diet as an intervention that inhibits histone deacetylase activity. The observational patient registration study (NLM, NCT01793168), established by the Coordination of Rare Diseases at Stanford Research, advances research in >7000 rare diseases by connecting individuals, researchers, and advocacy groups in a centralized patient registry site (Stanford Health, 2023). A 2018 trial (NLM, NCT01314534) examined the memory index of children aged 6-16 years old and reported dysregulation among the full-scale intellectual quotient, verbal comprehension index, perceptual reasoning index, processing speed index, and working memory index (Lehman et al, 2017).…”

“…Most KMT2D pathogenic variants are de novo and often result in truncations, splicing errors, and coding frameshifts (Banka et al, 2012, 2013; Guo et al, 2022; Stangler Herodež et al, 2020). However, the entire variant landscape includes missense, nonsense, splice‐site, deletions, insertions, duplications, mosaic, and frameshifts, all of which are associated with KMT2D haploinsufficiency (Baldridge et al, 2020; Bögershausen & Wollnik, 2013; Cocciadiferro, 2018; Dentici et al, 2015; Guo et al, 2022; Hannibal et al, 2011; Montano et al, 2022; Murakami et al, 2020; Paděrová et al, 2016; Sobreira et al, 2017).…”