BACKGROUND

The fetal monogenic causes of early pregnancy losses (EPLs) are mainly unknown, with only a few articles on the subject published. In our previous study of EPLs using whole-exome sequencing analysis, we confirmed a genetic diagnosis of -related Joubert syndrome (JS) in three EPLs from two couples and identified a relatively common allele among our population (NM_001384732.1:c.1819delT;c.7817T>A, further after referred as “complex allele”). Pathogenic variants in the gene are reported to cause JS type 17, a primary ciliopathy with various system defects.

AIMS

To examine the hypothesis that the “complex allele,” whether homozygous or compound heterozygous, is a common cause of EPLs in our population.

STUDY DESIGN

Cohort study/case-control study.ontrol study.

METHODS

In this study, we used polymerase chain reaction-based methods to screen for “complex allele” presence among 246 euploid EPLs (< 12 gestational weeks) from families in North Macedonia. We also investigated the impact of this allele in 650 women with EPLs versus 646 women with no history of pregnancy loss and at least one livebirth, matched by ethnic origin.

RESULTS

We found a high incidence of JS in the total study group of EPLs (2.03%), with a considerably higher incidence among Albanian families (6.25%). Although not statistically significant, women with EPLs had a higher allele frequency of the “complex allele” (AF = 1.38%) than the controls (AF = 0.85%; = 0.2). Albanian women had significantly higher frequency of the “complex allele” than the Macedonians (AF = 1.65% and 0.39%, respectively; = 0.003).

CONCLUSION

To the best of our knowledge, this is the highest reported incidence of fetal monogenic disease that might cause EPLs. Targeted screening for the “complex allele” would be warranted in Albanian ethnic couples because it would detect one JS in every 16 euploid EPLs. Our findings have a larger impact on the pathogenesis of pregnancy loss and contribute to a better understanding of the pathogenicity of the variants in the gene.