De novo SETD5 missense variants in individuals with MRD23 cluster within the protein’s SET domain

SETD5 heterozygous loss-of-function (LoF) variants and 3p25.3 deletions containing the SETD5 gene cause intellectual developmental disorder, autosomal dominant 23 (MRD23). We report five patients with an MRD23 phenotype caused by SETD5 missense variants. We studied patients with de novo SETD5 missense variants. A comprehensive literature search was conducted to reveal additional reports of SETD5 missense and LoF variants. Phenotypes and protein localization of missense variants were reviewed and compared to those reported for SETD5 LoF variants and 3p25.3 deletions. Computational analysis of the potential effect of SETD5 missense variants was performed. Six patients with de novo SETD5 missense variants were identified across five centers, gathered through the Deciphering Developmental Disorders (DDD) study database; four additional individuals with missense variants were reported in the DDD database. A comprehensive literature search revealed 12 unique individuals with missense variants, and 104 individuals with LoF variants or 3p25.3 deletions. One of the variants, p.Arg348Gln, recurred independently in three unrelated individuals. All patients with likely pathogenic missense variants shared dysmorphic features, GDD and autism, consistent with MRD23, but no major congenital anomalies, apart from hydrocephalus, which was a novel feature observed. Heart defects were reported only in the LoF group. Unlike LoF variants, which are scattered throughout the entire SETD5 coding region, pathogenic missense variants were confined to the protein's SET domain. We show that disease-causing missense variants in SETD5 cluster at the protein’s SET domain. This expands the mutation spectrum of the SETD5 -related neurodevelopmental phenotype, providing a framework for improving both postnatal and prenatal genetic diagnostics.