# Novel Loss of Function Variant in SOST From Chinese Family Results in Sclerosteosis 1

## TL;DR

A new genetic variant in the SOST gene is linked to sclerosteosis, causing bone thickening and facial numbness in a Chinese family.

## Contribution

A novel homozygous loss-of-function SOST variant is identified and experimentally validated as likely pathogenic in causing sclerosteosis.

## Key findings

- A novel SOST variant (c.327C>A) was found in a proband and his sister, classified as likely pathogenic.
- The variant reduced SOST expression at RNA and protein levels and produced a truncated protein.
- Clinical imaging showed skull thickening and osteosclerosis consistent with sclerosteosis.

## Abstract

SOST encodes a secreted glycoprotein that is similar in sequence to the differential screening‐selected gene aberrative in neuroblastoma (DAN) family of bone morphogenetic protein (BMP) antagonists. Pathogenic variants in the SOST gene result in sclerosteosis, van Buchem disease (VBD), or craniodiaphyseal dysplasia. SOST‐related genetic disorders are very rare, and limited studies have reported variants associated with sclerosteosis.

Clinical tests such as magnetic resonance imaging (MRI), computed tomography (CT), emission computed tomography (ECT), electromyogram (EMG), routine blood tests, and physical examinations were conducted for the proband. Trio‐whole exome sequencing (Trio‐WES) was performed, and the rare variants (allele frequency < 0.01) in the exon and splicing regions were selected for further pathogenic evaluation. Candidate pathogenic variants were validated through Sanger sequencing. The wild and mutant SOST sequences were cloned into the pcDNA3.1 expression vector, and the RNA and protein expression levels were investigated in the HEK293T cell line.

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 thickening of the skull and disappearance 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 novel homozygous variant in the proband: NM_025237.3(SOST): c.327C>A (p.Cys109*), which was also validated in his sister from the same family. According to the ACMG guidelines, the variant is classified as “likely pathogenic.” The in vitro experiments demonstrated that the variant caused a decrease in SOST expression at RNA and protein level and produced a truncated protein.

The report presents new evidence for the clinical diagnosis of SOST‐related facial numbness and expands the variant spectrum of SOST.

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 thickening of the skull and disappearance 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 novel homozygous variant in the proband: NM_025237.3(SOST): c.327C>A (p.Cys109*), which was also validated in his sister from the same family. According to the ACMG guidelines, the variant is classified as “likely pathogenic.” The in vitro experiments demonstrated that the variant caused a decrease in SOST expression at the RNA and protein level and produced a truncated protein.