A genome-wide scan in affected sibling pairs with idiopathic recurrent miscarriage suggests genetic linkage

Abstract

Previously, siblings of patients with idiopathic recurrent miscarriage (IRM) have been shown to have a higher risk of miscarriage. This study comprises two parts: (i) an epidemiological part, in which we introduce data on the frequency of miscarriage among 268 siblings of 244 patients with IRM and (ii) a genetic part presenting data from a genome-wide linkage study of 38 affected sibling pairs with IRM. All IRM patients (probands) had experienced three or more miscarriages and affected siblings two or more miscarriages. The sibling pairs were genotyped by the Affymetrix GeneChip 50K XbaI platform and non-parametric linkage analysis was performed via the software package Merlin. We find that siblings of IRM patients exhibit a higher frequency of miscarriage than population controls regardless of age at the time of pregnancy. We identify chromosomal regions with LOD scores between 2.5 and 3.0 in subgroups of affected sibling pairs. Maximum LOD scores were identified in four occurrences: for rs10514716 (3p14.2) when analyzing sister-pairs only; for rs10511668 (9p22.1) and rs341048 (11q13.4) when only analyzing families where the probands have had four or more miscarriages; and for rs10485275 (6q16.3) when analyzing one sibling pair from each family only. We identify no founder mutations. Concluding, our results imply that IRM patients and their siblings share factors which increase the risk of miscarriage. In this first genome-wide linkage study of affected sibling pairs with IRM, we identify regions on chromosomes 3, 6, 9 and 11 which warrant further investigation in order to elucidate their putative roles in the genesis of IRM.

Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans

“…This has restricted their efficient use in clinical studies. Genome-wide scan-based studies have been reported, although they have not reached the classical accepted statistical threshold for significance and have apparently failed to identify specific genes [12,13]. Such failure to identify RSA aetiological genes might be explained by the fact that reproduction's inherent complexity theoretically implies that mutations in hundreds of candidate genes may be responsible for the phenotype [10,14].…”

Association of functional genetic variants of CTLA4 with reduced serum CTLA4 protein levels and increased risk of idiopathic recurrent miscarriages

“…Genomewide scans in affected sibling pairs with IRM have suggested a genetic linkage (11). The underlying genetic causes of IRM are complex, and it is currently unclear which genes are involved or how individual genetic variants contribute to IRM.…”

Clinical characteristics and laboratory findings of 252 Chinese patients with anti-phospholipid syndrome: comparison with Euro-Phospholipid cohort

“…At the genetic level, results from two GWAS had been published [27,28]. The Li study was a pilot study in 44 Han Chinese patients with idiopathic recurrent miscarriage (IRM) and 44 matched healthy controls and identified three regions (6q27, 9q33.1, and Xp22.1) that were significantly associated with IRM.…”