Center of Medical Genetics, Northwest Women's and Children's Hospital, The Affiliated Northwest Women's and Children's Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Nagoya, 468-8503, Japan.
J Hum Genet. 2024 Jul;69(7):321-327. doi: 10.1038/s10038-024-01248-3. Epub 2024 Apr 2.
Spondylocostal dysostosis (SCDO) encompasses a group of skeletal disorders characterized by multiple segmentation defects in the vertebrae and ribs. SCDO has a complex genetic etiology. This study aimed to analyze and identify pathogenic variants in a fetus with SCDO. Copy number variant sequencing and whole exome sequencing were performed on a Chinese fetus with SCDO, followed by bioinformatics analyses, in vitro functional assays and a systematic review on the reported SCDO cases with LFNG pathogenic variants. Ultrasound examinations in utero exhibited that the fetus had vertebral malformation, scoliosis and tethered cord, but rib malformation was not evident. We found a novel homozygous variant (c.1078 C > T, p.R360C) within the last exon of LFNG. The variant was predicted to cause loss of function of LFNG by in silico prediction tools, which was confirmed by an in vitro assay of LFNG enzyme activity. The systematic review listed a total of 20 variants of LFNG in SCDO. The mutational spectrum spans across all exons of LFNG except the last one. This study reported the first Chinese case of LFNG-related SCDO, revealing the prenatal phenotypes and expanding the mutational spectrum of the disorder.
脊柱肋骨骺发育不良（SCDO）是一组以脊柱和肋骨多发节段性发育缺陷为特征的骨骼疾病。SCDO 具有复杂的遗传病因。本研究旨在分析和鉴定一名 SCDO 胎儿的致病性变异。对一名 SCDO 胎儿进行了拷贝数变异测序和全外显子组测序，随后进行了生物信息学分析、体外功能测定以及对具有 LFNG 致病性变异的报道 SCDO 病例的系统回顾。宫内超声检查显示胎儿存在脊柱畸形、脊柱侧凸和脊髓栓系，但肋骨畸形不明显。我们在 LFNG 的最后一个外显子内发现了一个新的纯合变异（c.1078C>T，p.R360C）。该变异通过计算机预测工具预测会导致 LFNG 功能丧失，体外 LFNG 酶活性测定也证实了这一点。该系统回顾共列出了 20 个与 SCDO 相关的 LFNG 变异。突变谱跨越 LFNG 的所有外显子，但最后一个除外。本研究报道了首例中国 LFNG 相关 SCDO 病例，揭示了产前表型，并扩展了该疾病的突变谱。
