Novel loss of function variant in SOST from Chinese family results in van Buchem disease

Background SOST encodes a secreted glycoprotein that is similar in sequence to the DAN (differential screening-selected gene aberrative in neuroblastoma) family of bone morphogenetic protein (BMP) antagonists. Loss-of-function variants of SOST result in sclerosteosis, Van Buchem disease (VBD), or craniodiaphyseal dysplasia. SOST -related genetic disorders are highly rare, and only limited studies have reported variants associated with VBCH. Methods Clinical data such as magnetic resonance imaging (MRI), computed tomography (CT), emission computer tomography (ECT), electromyogram (EMG), routine blood tests, and physical examinations were collected from the proband. Trio-whole exome sequencing (Trio-WES) of this family was performed on the family, and all variants with a minor allele frequency (< 0.01) in the exon and canonical splicing sites were selected for further pathogenic evaluation. Candidate pathogenic variants were validated through Sanger sequencing. The wild-type and variant of SOST were cloned into an expression vector, and the RNA and protein expression levels were investigated in the HEK293T cell line. Results In this study, we present a case study of a proband who displays abnormal facial expressions accompanied by numbness. The results of the brain MRI show thicening of the skull and disapearance of the diplopia signal. The temporal bone CT scan indicates diffuse osteosclerosis affecting the bilateral ossicular chains and internal auditory meatus, as well as stenosis of the bilateral internal auditory meatus. Trio-WES sequencing detected a new homozygous variant in the proband on SOST gene [NM_025237.3: c.327C > A, (p.Cys109*)], which was also validated in his sister from the same family. According to the ACMG guidelines, this variant is classified as likely pathogenic (LP). Further in vitro experiments demonstrated that the novel detected variant caused a decrease in SOST expression at the RNA and protein level by producing a truncated protein. Conclusion The report presents new evidence for the clinical diagnosis of SOST -related facial numbness and expands the variant spectrum of SOST.