Novel Compound Heterozygous Variants of DYNC2H1 Causing The Short Rib-Polydactyly Syndrome, Type III With Situs Inversus Totalis in a Fetus

Background Short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3) is an autosomal recessive disorder. SRTD3 presents clinically with the narrow thorax, short ribs, shortened tubular bones, and acetabular roof abnormalities. Clinical signs of SRTD3 vary among individuals. Mutations of DYNC2H1 were reported to cause SRTD3. Methods We performed a detailed clinical prenatal sonographic characterization of the fetus with SRTD3. Whole-exome sequencing was used to identify causative variants in the trio family. The identified variants were validated by Sanger sequencing and mass spectrometry in the families. Multiple computational tools were used to predict the harmfulness of the two variants. Results We presented with the prenatal sonographic image of the fetus with SRTD3, including abnormal rib curvature, narrow thorax, bilateral hypoplastic lungs, bilateral polydactyly, syndactyly and fetal visceral situs inversus with mirror-image dextrocardia. We revealed novel compound variants of DYNC2H1 (NM_001080463.1: c.11504T > G (p.Ile3835Arg) and c.2106 + 3A > T). Various statistical methods predicted that the variants would cause harmful effects on genes or gene products. Conclusion It is the first time that fetal SRTD3 with situs inversus totalis in a Chinese family. Our study not only revealed two novel compound heterozygous Dynein Cytoplasmic 2 Heavy Chain 1 (DYNC2H1) variants, expanding the genetic spectrum of SRTD3 but also raising the new phenotype. Our study helps add experience to further our expertise in prenatal counseling for SRTD3.

CRISPR/Cas9 targeting Ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease

Skeletal ciliopathies (e.g. Jeune syndrome, short rib polydactyly syndrome, Sensenbrenner syndrome) are frequently associated with cystic kidney disease and other organ manifestations, but a common molecular mechanism has remained elusive.We established two models for skeletal ciliopathies (ift80 and ift172) in Xenopus tropicalis, which exhibited severe limb deformities, polydactyly, cystic kidneys, and ciliogenesis defects, closely matching the phenotype of affected patients.Employing data-mining and an in silico screen we identified candidate genes with similar molecular properties to genetically validated skeletal ciliopathy genes. Among four genes experimentally validated, CRISPR/Cas9 targeting of ttc30a replicated all aspects of the phenotypes observed in the models of genetically confirmed disease genes, including ciliary defects, limb deformations and cystic kidney disease.Our findings establish three new models for skeletal ciliopathies (ift80, ift172, ttc30a) and identify TTC30A/B as an essential node in the network of ciliary chondrodysplasia and nephronophthisis-like disease proteins implicating post-translational tubulin modifications in its pathogenesis.