Abstract：
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.
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.
摘要：
伴有或不伴有多指的短肋骨胸部发育不良3（SRTD3，OMIM：613091）是一种常染色体隐性遗传疾病。SRTD3在临床上表现为胸部狭窄，短肋骨,缩短的管状骨，髋臼屋顶异常。SRTD3的临床体征因个体而异。据报道,DYNC2H1(OMIM:603297)的致病变体导致SRTD3。
我们对SRTD3胎儿进行了详细的临床产前超声检查。三联全外显子组测序用于鉴定家族中的致病变体。通过Sanger测序和质谱验证家族中鉴定的变体。使用多种计算工具来预测两种变体的危害性。进行小基因剪接测定以评估剪接位点变体的影响。
我们评估了SRTD3胎儿的产前超声图像，包括异常的肋骨弯曲，狭窄的胸部，双侧肺发育不全,双侧多指，齐体,胎儿内脏位置倒置伴镜像右位心。我们揭示了DYNC2H1的新化合物变体（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将对基因或基因产物造成有害影响。小基因测定结果表明，c.21063A>T引起外显子14的跳跃，在蛋白质中产生外显子14丢失。
这项研究确定了一个中国家庭中SRTD3的胎儿，其全位倒置并具有镜像右位心，揭示了两个新的复合杂合动力蛋白细胞质2重链1（DYNC2H1）变体，扩大SRTD3的表型谱。预测c.21063A>T的小基因研究会导致外显子14的框内排斥，该外显子被预测具有重要的分子功能。我们的发现强烈支持WES在产前诊断中的使用，并有助于了解DYNC2H1基因型和表型的相关性。具体的超声检查结果和分子诊断有助于增加我们在SRTD3产前咨询方面的专业知识。
我们对SRTD3胎儿进行了详细的临床产前超声检查。三联全外显子组测序用于鉴定家族中的致病变体。通过Sanger测序和质谱验证家族中鉴定的变体。使用多种计算工具来预测两种变体的危害性。进行小基因剪接测定以评估剪接位点变体的影响。
我们评估了SRTD3胎儿的产前超声图像，包括异常的肋骨弯曲，狭窄的胸部，双侧肺发育不全,双侧多指，齐体,胎儿内脏位置倒置伴镜像右位心。我们揭示了DYNC2H1的新化合物变体（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将对基因或基因产物造成有害影响。小基因测定结果表明，c.21063A>T引起外显子14的跳跃，在蛋白质中产生外显子14丢失。
这项研究确定了一个中国家庭中SRTD3的胎儿，其全位倒置并具有镜像右位心，揭示了两个新的复合杂合动力蛋白细胞质2重链1（DYNC2H1）变体，扩大SRTD3的表型谱。预测c.21063A>T的小基因研究会导致外显子14的框内排斥，该外显子被预测具有重要的分子功能。我们的发现强烈支持WES在产前诊断中的使用，并有助于了解DYNC2H1基因型和表型的相关性。具体的超声检查结果和分子诊断有助于增加我们在SRTD3产前咨询方面的专业知识。
