Further Delineation of the Microcephaly-Micromelia Syndrome Associated with Loss-of-Function Variants in .

The gene encodes the downstream neighbor of SON, a replisome component that stabilizes the replication fork during replication. A severe form of microcephalic dwarfism, microcephaly-micromelia syndrome (MIMIS), has been recently associated with biallelic loss of function. Affected fetuses suffer severe growth restriction, microcephaly, and variable limb malformations which result in intrauterine or perinatal death. All described fetuses carried a homozygous founder mutation (c.1047-9A>G), a splice-altering variant that leads to transcript degradation. We evaluated 2 newborns from a consanguineous Emirati family with severe microcephaly, micromelia, craniofacial dysmorphism, and skeletal abnormalities; both died shortly after birth. Here, we report the second homozygous loss-of-function variant (c.763C>T) in causing MIMIS, and we provide detailed clinical description of this very rare disorder. In addition, we review all MIMIS cases in the literature and summarize the striking features of this phenotype. This manuscript is aimed to increase the clinical understanding of this rare, extremely severe disorder and encourage clinical and molecular geneticists to consider screening for loss-of-function variants in families with recurrent pregnancy loss and/or perinatal deaths.