The First Known Case Report of a Novel Homozygous Nonsense Variant in the OSBPL9 Gene Associated With Fetal Cerebral Ventriculomegaly, Cerebellar Hypoplasia, and Arthrogryposis Multiplex

Oxysterol-binding protein-like protein 9 (<i>OSBPL9</i>) is a member of a large eukaryotic gene lipid transport protein family that mediates the exchange of sterols and phospholipids between the trans-Golgi network and the endoplasmic reticulum. Denovo missense mutations in the <i>OSBPL9</i> gene have been previously reported to be associated with intellectual disability. Herein, we report for the first time, to the best of our knowledge, a novel homozygous nonsense variant in the <i>OSBPL9</i> gene in a consanguineous family with two fetuses with cerebral ventriculomegaly, cerebellar hypoplasia, and arthrogryposis multiplex. Whole exome sequencing and homozygosity mapping by chromosomal microarray identified one fetus to be homozygous for a novel nonsense variant chr1-51760720C>CAAT or c.615_616insTAA or p.Pro206*. Exome sequencing identified the asymptomatic parents as carriers for the same variant, indicating an autosomal recessive inheritance pattern. A review of medical literature using databases such as PubMed/MEDLINE (Medical Literature Analysis and Retrieval System Online), and Google Scholar did not reveal any case with the <i>OSBPL9</i> variant and fetal malformations such as ventriculomegaly, cerebellar hypoplasia, and arthrogryposis multiplex. A protein network analysis using the STRING (Search Tool for Retrieval of Interacting Genes/Proteins) database showed close interactions between the <i>OSPBPL9, OSBP, PI4K2A, PIP5K1C, PI4KA, CERT1, EXOSC3, RARS2, VRK1, </i>and <i>TSEN54</i> genes but no interactions with the <i>L1CAM, KIDINS220,</i> and <i>KIAA1109</i> genes. These proteins are important for the metabolism of sphingomyelin, sterol, and lipids such as phosphatidylinositol and ceramide in the cell. Mutations in these proteins are known to cause related genetic disorders, which include structural brain abnormalities, fetal arthrogryposis, and intellectual disability as a phenotype. This is the first known report of a homozygous variant in the <i>OSBPL9</i> gene in a recessive inheritance pattern, and the first report of association with a fetal anomaly phenotype. Previously, only two cases with an <i>OSBPL9</i> gene variant have been documented in the literature, showing a sporadic autosomal dominant inheritance pattern. Thus, this case report expands the phenotype of <i>OSBPL9</i> gene-related human disease. This case report will aid clinical diagnosis, genetic counseling, and preventive strategies such as prenatal diagnosis and/or preimplantation genetic diagnosis in families affected with <i>OSBPL9</i> gene variants. The limitation of this study is the lack of RNA, protein, cellular, or animal model studies or functional studies to confirm this association.