Heterozygous gain of function variants in a critical region of RNF13 cause congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive

Abstract Missense variants in the RNF13 gene have been previously known to cause congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive through a gain‐of‐function disease mechanism. Here, we identify a nonsense variant, expected to result in protein truncation, in a similarly affected patient. We show that this nonsense variant, residing in the terminal exon, is likely to escape nonsense‐mediated decay while removing a critical region for protein function, thus resulting in a gain‐of‐function effect. We review the literature and disease databases and identify several other affected individuals with overlapping phenotypes carrying distinct truncating variants in the terminal exon upstream of the putative critical region. Furthermore, we analyze truncating variants from the general population, namely, the Genome Aggregation Database (gnomAD), and provide additional evidence supporting our hypothesis, and ruling out haploinsufficiency as an alternative disease mechanism. In summary, our case report, literature review, and analysis of disease and population databases strongly support the hypothesis that heterozygous gain‐of‐function variants in a critical region of RNF13 cause congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive.