De novo variants in SUPT16H cause neurodevelopmental disorders associated with corpus callosum abnormalities

Abstract

IntroductionWhole-exome sequencing (WES) has identified de novo variants in chromatin remodelling genes in patients with neurodevelopmental disorders (NDD). We report on a novel genetic discovery in chromatin remodelling in patients with NDD who also have corpus callosum (CC) anomalies.ObjectiveTo discover novel genes linked to both CC anomalies and NDD.MethodsClinical WES was performed for evaluation of NDD, identifying five patients with de novo variants in SUPT16H, a subunit of the FACT (facilitates chromatin transcription) complex. The clinical phenotypes, genetic results and brain MRIs were obtained and systematically reviewed. In silico protein function predictions were assessed and allele frequencies in control populations were compared.ResultsWe identified four patients with de novo missense variants in SUPT16H and one patient with a de novo deletion including SUPT16H. These variants were not reported in the updated Genome Aggregation Database. When assayable, all protein products were predicted to be damaging. Symptoms included intellectual disability, autistic features, minor dysmorphic features and seizures. Anomalies of the CC were seen in all three patients with available brain imaging.ConclusionOur findings implicate the gene SUPT16H in a novel disorder characterised by neurodevelopmental deficits and CC anomalies.

Dominant effects of the histone mutant H3-L61R on Spt16-gene interactions in budding yeast

“…In the present study, we carried out further analyses of the H3-L61R mutant and found that whereas it allows for cell viability when wild-type histone H3 is co-expressed in cells, it also confers strong dominant defects on Spt16-gene interactions. Our findings, combined with another recent study implicating mutant versions of the human Spt16 protein in neurodevelopmental disorders [ 21 ], point to a possible molecular mechanism driving disease state in individuals expressing H3.3 L61R.…”

Clinical evaluation of rare copy number variations identified by chromosomal microarray in a Hungarian neurodevelopmental disorder patient cohort

“…CHD8 is currently thought to be one of the most common genetic drivers of ASD, and is often additionally associated with macrocephaly, overgrowth, facial minor anomalies and gastrointestinal problems [21][22][23][24]. SUPT16H was recently linked to a NDD consisting of DD/ID, ASD, seizures, precocious puberty, craniofacial minor anomalies, and corpus callosum abnormalities, but not macrocephaly [25]. Notably, neither of our three patients had increased head circumference; on the contrary, SEG2_49 had microcephaly (with generalized somatic underdevelopment).…”

Clinical evaluation of rare copy number variations identified by chromosomal microarray in a Hungarian neurodevelopmental disorder patient cohort

“…CHD8 is currently thought to be one of the most common genetic drivers of ASD, and is often additionally associated with macrocephaly, overgrowth, facial minor anomalies and GI problems (15)(16)(17)(18). SUPT16H was recently linked to a neurodevelopmental disorder consisting of DD/ID, ASD, seizures, precocious puberty, craniofacial minor anomalies, and corpus callosum abnormalities, but not macrocephaly (19).…”