Department of Fetal Medicine Unit and Prenatal Diagnosis Center, Shanghai First Maternity and Infant Hospital of Tongji University, Shanghai, China.
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas.
Birth Defects Res. 2018 Mar 1;110(4):364-371. doi: 10.1002/bdr2.1146. Epub 2018 Jan 23.
Genetic skeletal disorders (GSDs) are clinically and genetically heterogeneous with more than 350 genes accounting for the diversity of disease phenotypes. Prenatal diagnosis of these disorders has been challenging because of the limited but variable prenatal phenotypes, highlighting the need of a novel genetic approach. Short-rib polydactyly syndrome (SRPS) Type III is an autosomal recessive GSD characterized by extreme narrowness of the thorax, severely shortened tubular bones, polydactyly and multiple malformations.
Cytogenetic and molecular analyses using GTG-banding, single nucleotide polymorphism array and a novel GSDs targeted gene panel sequencing were performed in a 24 weeks fetus with increased biparietal diameter (BPD), short limbs, narrow thorax and polyhydramnios.
No chromosomal abnormalities and pathogenic copy number variations (CNVs) were detected in the fetus. Two novel compound heterozygous mutations c.2992C > T and c.12836G > C in the DYNC2H1 gene were identified by targeted genes panel sequencing. A literature review was performed to delineate the prenatal phenotype of SRPS Type III.
This is the first report of prenatal diagnosis of DYNC2H1 mutations causing SRPS Type III in a fetus with increased BPD associated with polyhydramnios in China. Our findings expand the mutation spectrum of DYNC2H1 in this rare disease and demonstrate that targeted gene panel capture followed by next-generation sequencing (NGS) is an efficient and cost-effective method to perform a molecular prenatal diagnosis of a rare genetic skeletal disorder.
遗传性骨骼疾病（GSDs）在临床上和遗传上具有异质性，超过 350 个基因导致疾病表型的多样性。由于产前表型有限且多变，这些疾病的产前诊断一直具有挑战性，这凸显了需要一种新的遗传方法。短肋多指畸形综合征（SRPS）III 型是一种常染色体隐性遗传 GSD，其特征为胸廓极度狭窄、管状骨严重缩短、多指畸形和多种畸形。
对一名 24 周胎儿进行了 GTG 带、单核苷酸多态性微阵列和一种新的 GSD 靶向基因panel 测序的细胞遗传学和分子分析，该胎儿存在双顶径增加、四肢短小、胸廓狭窄和羊水过多。
在胎儿中未检测到染色体异常和致病性拷贝数变异（CNVs）。通过靶向基因panel 测序鉴定出 DYNC2H1 基因中的两个新的复合杂合突变 c.2992C>T 和 c.12836G>C。进行了文献复习以描绘 III 型 SRPS 的产前表型。
这是首例在中国报告的与羊水过多相关的双顶径增加的胎儿中 DYNC2H1 突变导致 III 型 SRPS 的产前诊断。我们的发现扩展了该罕见疾病中 DYNC2H1 的突变谱，并证明靶向基因 panel 捕获后进行下一代测序（NGS）是一种对罕见遗传性骨骼疾病进行分子产前诊断的有效且具有成本效益的方法。
