Heterozygous RNF13 Truncating Variants Are Associated With Developmental and Epileptic Encephalopathy.
TL;DR
A case series of an additional 13 affected individuals with RNF13 variants (2 missense, 11 truncating) supports and broadens previous reports and helps to define a narrow but critical region of the protein that is intolerant to truncating variation, although the gene is not highly constrained.
Abstract
Developmental and epileptic encephalopathy 73 (DEE73; OMIM 618379) is an autosomal dominant severe neurodevelopmental disorder associated with pathogenic variants in the RING finger protein 13 gene (RNF13; OMIM 609247), which encodes a transmembrane E3 ubiquitin ligase. The phenotype of affected individuals includes microcephaly, seizures, intellectual disability, developmental delay, absent or limited speech, restricted movement, cortical blindness, and skeletal defects (hip dysplasia, club feet, scoliosis). The currently known DEE73 phenotype is based on two reports of four unrelated individuals: three with missense variants in a di-leucine motif that is essential for binding to the Adaptor Protein Complex 3 (AP-3), and one with a truncating variant located in the last exon. This case series of an additional 13 affected individuals with RNF13 variants (2 missense, 11 truncating) supports and broadens previous reports. Importantly, it helps to define a narrow but critical region of the protein that is intolerant to truncating variation, although the gene is not highly constrained.