When 25% Feels Like 100%: Confronting Recurrent Cystic Fibrosis Risk Across Consecutive Pregnancies

Cystic fibrosis (CF) is the most common autosomal recessive lethal disorder worldwide caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which represents conditions with variable expressivity and penetrance. CF is not uncommon in India, but with a more genetically heterogeneous mutation spectrum. We present a case where a couple came for preconception counselling after they lost their baby at seven months of age because of CF. Initial targeted exome sequencing of the baby suggested a homozygous pathogenic variant of F508del. The father was a carrier of the F508 variant, while the mother tested negative for this variant. Because of this discrepancy, subsequent testing, multiple ligation-dependent probe amplification (MLPA) was performed, which revealed the mother carried a heterozygous multi-exon deletion (exons 4-11). Re-analysis of preserved tissue of the baby using MLPA diagnosed compound heterozygosity for F508del and the exon 4-11 deletion. This case underscores the importance of combining sequence variant detection with copy number variation (CNV) analysis in CFTR testing to avoid misinterpretation of zygosity. None of the parents had any stigmata of CF-related disease, including congenital bilateral absence of the vas deferens (CBAVD). After discussion, the couple decided on preimplantation genetic testing for monogenic conditions (PGT-M), which yielded a single embryo harboring a compound heterozygous mutation (F508del and exons 4-11). Subsequently, the mother conceived naturally, but prenatal diagnosis by chorionic villus sampling (CVS) found the presence of the same compound heterozygous mutations in the fetus, for which the pregnancy was terminated. Fortunately, in the subsequent spontaneous conception, CVS revealed that the fetus was only heterozygous for exons 4-11, establishing its carrier status. Pregnancy eventually ended in the live birth of the baby, who is now doing well at 20 months of age. Parents, in this case, had a long journey, where the risk of 25% in every pregnancy seemed to be difficult for them to carry on because it recurred three consecutive times in the fetus/embryo(s). This illustrates how statistical probabilities, though clinically accurate, can feel meaningless to those enduring repeated loss, and underscores the profound psychological toll of autosomal recessive disorders. Psychological support, genetic counselling, and ensuring informed decision-making are crucial for parents coping with the psychological impact of having a child with a rare disease. In this case, it is the perseverance of the couple that finally led to a successful outcome. Complexity of genetic analysis and counselling, recurrence three consecutive times, absence of CBAVD in the man despite carrying the CFTR mutation, and finally a successful outcome prompted us to report this case.