Exome sequencing identifies compound heterozygous DYNC2H1 variants associated with short-rib polydactyly syndrome type III with involvement of omphalocele in a fetus.

Abstract

Objectives: We present prenatal diagnosis findings and molecular genetic analysis in a fetus with a short-rib thoracic dysplasia-3 (SRTD3) (OMIM 613091) Method: A 34-year-old pregnant woman was referred to maternal-fetal medicine unit for fetal abnormality on scan. This was the second pregnancy of a non-consanguineous Chinese couple who has a healthy son. Her first trimester combined Down syndrome screening showed trisomy 21 risk of 1 in 150. Ultrasound at 13 weeks 4 days showed omphalocele and short long bones. Couple decided for termination of pregnancy at 14 weeks 6 days after counselling in view of early onset and severe skeletal dysplasia and omphalocele. External examination of the abortus showed post-axial polydactyly of both hands and omphalocele. Postmortem examination was declined. Babygram showed abnormally short limbs affecting the proximal and distal long bones which are not curved and no fracture. The 12 pairs of ribs were short. Results: Placental tissue was sent for genetic workup. FGFR3 gene sequencing showed no pathogenic variants, normal chromosomal microarray and karyotype 46,XX. Trio-based whole exome sequencing was performed. A web-based tool, PhenoTips® was used to predict genes associated with the aforementioned fetal anomalies to facilitate result analysis. The fetus was compound heterozygous for a missense variant c.1265T>C p.(Leu422Pro) of maternal origin and a nonsense variant c.1540C>T p.(Arg514Ter) of paternal origin in DYNC2H1 gene which were subsequently confirmed by Sanger sequencing. The genetic finding well correlated with the skeletal phenotype of SRTD3 while omphalocele has not been reported for this condition. Conclusions: WES has successfully identified one novel nonsense pathogenic variant c.1540C>T p.(Arg514Ter) and one rare missense variant c.1265T>C p.(Leu422Pro) in DYNC2H1 associated with fetal short-rib polydactyly syndrome, type III. Open-source tool, if available, may be useful to predict genes to facilitate analysis and reassure result interpretation. To our knowledge, this is the first prenatal report of DYNC2H1 causing SRTD3 with omphalocele.