Novel heterozygous variants in KMT2D associated with holoprosencephaly

Abstract

Lysine methyltransferase 2D (KMT2D; OMIM 602113) encodes a histone methyltransferase involved in transcriptional regulation of the beta‐globin and estrogen receptor as part of a large protein complex known as activating signal cointegrator‐2‐containing complex (ASCOM). Heterozygous germline mutations in the KMT2D gene are known to cause Kabuki syndrome (OMIM 147920), a developmental multisystem disorder. Neither holoprosencephaly nor other defects in human forebrain development have been previously associated with Kabuki syndrome. Here we report two patients diagnosed with alobar holoprosencephaly in their antenatal period with de novo monoallelic KMT2D variants identified by trio‐based exome sequencing. The first patient was found to have a stop‐gain variant c.12565G>T (p.Gly4189*), while the second patient had a missense variant c.5A>G (p.Asp2Gly). Phenotyping of each patient did not reveal any age‐related feature of Kabuki syndrome. These two cases represent the first report on association between KMT2D and holoprosencephaly.

Holoprosencephaly in Kabuki syndrome

“…Recently, alobar holoprosencephaly has been reported in a 5-day-old female infant as well as in a female fetus at 22 weeks of gestation who both carried de novo pathogenic variants in KMT2D (Tekendo-Ngongang, Kruszka, Martinez, & Muenke, 2019). These reported patients lacked age-related features of Kabuki syndrome.…”

“…Several structural brain abnormalities have been reported in individuals with Kabuki syndrome including: cerebellar atrophy, Dandy‐Walker malformation, Arnold‐Chiari malformation, subarachnoid cysts, cortical dysplasia, syringo‐hydromyelia, hippocampal atrophy, and dysgenesis of the corpus callosum (Ben‐Omran & Teebi, ; Boisgontier et al, ; Guo, Liu, & Li, ; Sanchez‐Carpintero, Herranz, Reynoso, & Zubieta, ). Recently, alobar holoprosencephaly has been reported in a 5‐day‐old female infant as well as in a female fetus at 22 weeks of gestation who both carried de novo pathogenic variants in KMT2D (Tekendo‐Ngongang, Kruszka, Martinez, & Muenke, ). These reported patients lacked age‐related features of Kabuki syndrome.…”

“…Holoprosencephaly is defined as incomplete separation of the forebrain during embryonic development and occurs in as many as 1:10,000 live births (Orioli & Castilla, ). Holoprosencephaly may present in isolation or as part of a recognizable genetic syndrome due to pathogenic variants in more than 40 different genes (Tekendo‐Ngongang et al, ). We identified a de novo, pathogenic KMT2D variant using trio whole‐exome sequencing in a 2‐year‐old female with lobar holoprosencephaly, microcephaly, and cranio‐facial features of Kabuki syndrome.…”

Comorbidity of congenital heart defects and holoprosencephaly is likely genetically driven and gene‐specific

“…Several damaging genes variants causal for syndromic or nonsyndromic forms of HPE are known to be associated with CHD in both humans and model organisms (Barratt, Glanville‐Jones, & Arkell, ; Martinez, Kruszka, & Muenke, ). For instance, KMT2D variants were recently associated with HPE (the cases in this study did not have a phenotype consistent with Kabuki syndrome) (Tekendo‐Ngongang, Kruszka, Martinez, & Muenke, ). In a small study of 27 patients with Kabuki syndrome and KMT2D variants, 70% of participants had CHD (Digilio et al, ).…”

“…Exome sequencing was carried out on 111 (25.6%) individuals of the cohort (Table S1). Exome sequencing was performed at the NIH Intramural Sequencing Center (NISC) as per the HiSeq2000 Sequencer protocol (Illumina, San Diego, CA) followed by copy number variations (CNVs) prediction from exome data, carried out using the eXome‐hidden Markov model (XHMM) caller as previously described (Kruszka et al, ; Tekendo‐Ngongang et al, ). CNVs were assessed in two patients using microarray‐based comparative genomic hybridization (aCHG) following standard protocols (Agilent Technologies Inc, Santa Clara, CA).…”