Department of Ultrasonography, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, China.
College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
BMC Med Genomics. 2022 Mar 12;15(1):55. doi: 10.1186/s12920-022-01205-z.
Short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3, OMIM: 613091) is an autosomal recessive disorder. SRTD3 presents clinically with a narrow thorax, short ribs, shortened tubular bones, and acetabular roof abnormalities. Clinical signs of SRTD3 vary among individuals. Pathogenic variants of DYNC2H1 (OMIM: 603297) have been reported to cause SRTD3.
We performed a detailed clinical prenatal sonographic characterization of a foetus with SRTD3. Trio whole-exome sequencing was used to identify causative variants in the family. The identified variants in the families were validated by Sanger sequencing and mass spectrometry. Multiple computational tools were used to predict the harmfulness of the two variants. A minigene splicing assay was carried out to evaluate the impact of the splice-site variant.
We evaluated prenatal sonographic images of the foetus with SRTD3, including abnormal rib curvature, narrow thorax, bilateral hypoplastic lungs, bilateral polydactyly, syndactyly, and foetal visceral situs inversus with mirror-image dextrocardia. We revealed novel compound variants of DYNC2H1 (NM_001377.3:c.11483T > G (p.Ile3828Arg) and c.2106 + 3A > T). Various statistical methods predicted that the variants would cause harmful effects on genes or gene products. The minigene assay findings suggested that c.2106 + 3A > T caused the skipping over exon 14, producing an exon 14 loss in the protein.
This study identified a foetus with SRTD3 with situs inversus totalis with mirror-image dextrocardia in a Chinese family, revealing two novel compound heterozygous dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) variants, expanding the phenotypic spectrum of SRTD3. The minigene study of c.2106 + 3A > T was predicted to cause an inframe exclusion of exon 14, which was predicted to have important molecular functions. Our findings strongly supported the use of WES in prenatal diagnosis and helped to understand the correlation of genotype and phenotypes of DYNC2H1. The specific sonographic findings and the molecular diagnosis helped add experience to further our expertise in prenatal counselling for SRTD3.
短肋-多指（趾）畸形 3 型伴或不伴并指（趾）（SRTD3，OMIM：613091）是一种常染色体隐性疾病。SRTD3 临床上表现为胸廓狭窄、肋骨短小、管状骨缩短和髋臼顶异常。SRTD3 个体之间的临床表现存在差异。已经报道 DYNC2H1（OMIM：603297）的致病性变异可导致 SRTD3。
我们对一名患有 SRTD3 的胎儿进行了详细的产前超声特征描述。对家系进行了三代全外显子组测序，以鉴定家系中的致病变异。对家系中的变异进行了 Sanger 测序和质谱验证。使用多种计算工具预测了两种变异的危害性。进行了 minigene 剪接分析以评估剪接变异体的影响。
我们评估了患有 SRTD3 的胎儿的产前超声图像，包括肋骨曲率异常、胸廓狭窄、双侧肺发育不全、双侧多指（趾）、并指（趾）和胎儿内脏位反转伴镜像右位心。我们揭示了 DYNC2H1 的新复合变异（NM_001377.3：c.11483T>G（p.Ile3828Arg）和 c.2106+3A>T）。各种统计方法预测这些变异会对基因或基因产物造成有害影响。minigene 分析结果表明，c.2106+3A>T 导致外显子 14 跳过，从而导致蛋白质中外显子 14 的缺失。
本研究在中国一个家系中发现了一例伴有镜像右位心的完全内脏位反转的 SRTD3 胎儿，揭示了两种新的复合杂合 DYNC2H1 变异，扩展了 SRTD3 的表型谱。对 c.2106+3A>T 的 minigene 研究预测会导致外显子 14 的框内缺失，这可能具有重要的分子功能。我们的研究结果强烈支持在产前诊断中使用 WES，并有助于理解 DYNC2H1 的基因型和表型相关性。具体的超声表现和分子诊断为进一步增加我们在 SRTD3 产前咨询方面的专业知识提供了经验。
