Compound inheritance of rare and common RET variants in a Chinese family with three unfavorable pregnancies involving Hirschsprung's disease

Objective

Specific alleles of the RET gene (rs2506030, rs7069590 and rs2435357) are associated with an increased risk of Hirschsprung disease (HSCR). This study aimed to investigate the modified effects of these functionally independent enhancer variants on the penetrance of RET-associated HSCR in a Chinese family with three adverse pregnancy outcomes.

Case report

A 31-year-old pregnant woman underwent amniocentesis at 24 weeks of gestation due to two adverse pregnancy outcomes and abnormalities on prenatal ultrasound for the pregnancy, which manifested as fetal echogenic bowel and left renal agenesis. Chromosomal microarray and trio whole-genome sequencing analyses were performed. The fetus was found to carry a novel heterozygous nonsense variant, c.1840G > T p.(Glu614Ter), in the RET allele inherited from the asymptomatic mother and asymptomatic maternal grandfather. Genotype information was obtained for the three RET single-nucleotide polymorphisms. Moreover, co-segregation analysis of the coding and non-coding regions of RET was performed in the selected family members using Sanger sequencing. The high-risk GTT haplotype was identified in the fetus, which was inherited from the father, whereas the low-risk GTC haplotype was identified in the relatives carrying the RET c.1840G > T variant who did not have HSCR. The absence of the high-risk GTT haplotype in cis may explain the normal phenotype of the carriers with this RET variant. Therefore, prenatal intervention and subsequent preimplantation genetic testing were conducted in this family.

Conclusions

Compound inheritance of rare and common RET variants was identified as the likely cause of the three adverse pregnancy outcomes in this family. Our study revealed that prenatal intervention and preimplantation genetic testing are recommended in this family. In addition, we speculated that compound inheritance may influence RET-related renal agenesis.