Exome Sequencing Links the SUMO Protease SENP7 with Fatal Arthrogryposis Multiplex Congenita, Early Respiratory Failure, and Neutropenia

SUMOylation involves the attachment of Small Ubiquitin-like Modifier (SUMO) proteins to specific lysine residues on thousands of substrates with various effects on protein function. Sentrin-specific proteases (SENPs) are proteins involved in the maturation and de-conjugation of SUMO. Specifically, SENP7 is responsible for processing polySUMO chains on targeted substrates including the heterochromatin protein HP1α. Here, we describe a large family with four affected subjects presenting with a spectrum of findings including congenital arthrogryposis, profound developmental delay, and neutropenia with recurrent infections. Exome sequencing identified a homozygous stop gain variant in SENP7 c.1474C>T; p.(Gln492*) as the probable etiology. Protein expression studies in patient fibroblasts showed significant protein dysregulation in total cell lysates and in the chromatin fraction.