Integrated Molecular Autopsy in a Highly Consanguineous Perinatal Cohort With Severe Malformations and Strong Genetic Susceptibility.

This retrospective study covers 28 perinatal cases (22 fetuses, 6 neonates) with severe anomalies detected prenatally, normal first-tier genetic testing and high consanguinity (42.9%). Deep post-mortem phenotyping (radiography, macroscopy, histopathology) guided singleton exome sequencing (n = 28), supplemented by genome sequencing (n = 14) for exome-negative rescue or technical validation, with trio Sanger confirmation. Integrated molecular autopsy established a molecular diagnosis in 19 of 28 cases (67.9%), with yields of 100% in skeletal dysplasias (5/5), 62.5% in central nervous system defects (5/8) and 60% in cardiovascular malformations (3/5). Autosomal recessive inheritance accounted for 52.6% of solved cases, agreement between morphological hypotheses and molecular diagnoses was substantial (Cohen's kappa 0.81), six cases (21.4%) were phenotypic expansions and 32.1% remained unexplained.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The 67.9% yield applies to a 28-case, highly selected and heavily consanguineous cohort: it does not transfer to a non-consanguineous population, as the authors acknowledge. The transferable lesson is the value of post-mortem phenotyping to guide variant prioritisation in exome/genome, not the figure itself. The benefit for counselling about a subsequent pregnancy is direct in solved cases.

Analysis by Dr Thibaut Benquey