Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. In this retrospective case-control series, 8.5% of cases received a probable molecular diagnosis based on clinical exome sequencing

2. Loss-of-function variants in genes with high natural selection pressure were more likely to be associated with stillbirths

Evidence Rating Level: 3 (Average)

Study Rundown:

Stillbirths are often attributed to genetic aberrations but there is a paucity of data on the genetic contribution. The authors in this study analyzed a series of stillbirths and using exome sequencing, analyzed their pathological genotypes. The results of the study demonstrated that 8.5% of cases had suggestive genetic variants for a probable molecular diagnosis with links to cardiac and multi-system developmental disorders. Through a comparison of the general human population, loss-of-function mutations in genes that are under high natural selection pressure to have less genetic variation were commonly identified in these stillbirth cases. These variants were less likely to have been associated with known human disease. However, caution has to be used for interpretation as the samples did not include parental data which helps provide inheritance information and the yield was lower than other studies given the exclusion of heterozygous variants. The results of this study highlighted that clinical exome sequencing can play a role in identifying new pathological variants that lead to fetal in utero demise and may assist families in counselling.

In-Depth [retrospective cohort]:

This was a retrospective case-control study of 246 stillborn cases and 18,653 genes were evaluated according to intolerance of genetic variation for single-nucleotide variants and small insertions and deletions. 6.1% of cases met the criteria for molecular diagnosis in a known disease gene and an additional 2.4% had a suggestive genotype with a total of 8.5% of cases receiving a probable molecular diagnosis for the stillbirth. 40% of cases had a multisystem developmental disorder, 33% had a cardiac only association and 13% of cases had primarily renal association. There were only one case each, with primarily brain involvement and bone involvement, respectively. For genes that were deemed intolerant to genetic variation (e.g. high natural selection pressure to have minimal variation), there was an enrichment of loss-of-function variants in cases when compared to the general human population (OR 2.15, 95% CI 1.46 to 3.06) which were mainly in genes not known to be associated with human illness (OR 2.2, 95% CI 1.41 to 3.34).

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