Objective: To explore the genetic basis for a couple with recurrent conceptions of fetus with abnormal longbones, and another couple with a history of omphalocele.
Methods: Genomic DNA was extracted from the peripheral blood samples from both couples. All exons and flanking regions were analyzed with next generation sequencing. Candidate variants were verified by Sanger sequencing.
Results: Couple one was found to be heterozygous for, a c.997+1G>T splice-site variant and a missence c.871G>A(p.Glu291Lys) variant of the ALPL gene. Both variants were predicted to be pathogenic and may result in reduced function or loss of alkaline phosphatase. For couple two, the wife was found to harbor a novel c.637_652 delins CCC variant of the CDKN1C gene. This deletion-insertion variant resulted in frame-shift and loss of function (p.Ala213Profs*55) of the CDKN1C protein. Maternally inherited CDKN1C LOF variant has been found to underlie Beckwith-Wiedemann syndrome (BWS), which may manifest as omphalocele.
Conclusion: Dispite the lack the direct proof from the lost fetuses, the variants of ALPL and CDKN1C genes can explain the recurrence of fetal malformations for both couples.