Abstract
FAM20B encodes glycosaminoglycan xylosylkinase, a key enzyme in proteoglycan biosynthesis. Biallelic pathogenic variants have only recently been linked to skeletal dysplasia. We report two pregnancies from one couple, resulting in three fetuses (twin sibs and younger sib) with severe skeletal anomalies. Prenatal findings included enlarged nuchal translucency, short bowed and dislocated limbs, intrauterine growth restriction, and multiple malformations. Intra-uterine fetal death occurred in Probands 1 and 2, and neonatal death of Proband 3. Postnatally, all three probands showed limb shortening with joint (sub)luxations and contractures, and craniofacial dysmorphisms. SNP-array and exome analysis revealed compound heterozygosity for two novel FAM20B variants: a paternal ~8 kb deletion encompassing the terminal exon and a maternal missense variant (p.Arg290Cys) at an evolutionary conserved position. The same amino acid residue was previously affected in a child with a milder phenotype. In silico modeling supports a destabilizing effect of the missense change on protein structure, especially due to the loss of a salt bridge essential for catalytic function. This report describes the prenatal phenotype of FAM20B-related dysplasia and can help establish the phenotypic spectrum of the disorder. It further supports the essential role of FAM20B in early skeletal development.