Integrated Molecular Autopsy in a Highly Consanguineous Perinatal Cohort With Severe Malformations and Strong Genetic
Sihem Darouich1,2, Samia Darouich3, Ahmed Khemiri4
1Faculté de Médecine de Tunis, Université de Tunis El Manar, Tunis, Tunisia.
Objective:
To evaluate the diagnostic yield of integrated molecular autopsy (IMA) by combining deep post-mortem phenotyping with exome (ES) and targeted genome sequencing (GS) for prenatally detected anomalies.
Method:
This retrospective study evaluated 28 perinatal cases (22 fetuses, six neonates) with severe anomalies, normal first-tier genetics, and high consanguinity (42.9%). Deep phenotyping (radiography, macroscopy, histopathology) guided singleton ES (n = 28), supplemented by GS (n = 14) for exome-negative rescue or technical validation, and trio Sanger confirmation. The inter-method agreement between morphological hypotheses and molecular diagnoses was assessed using Cohen's Kappa.
Results:
The IMA established a molecular diagnosis in 19 of 28 cases (67.9% yield), with system-specific 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% (10/19) of solved cases. The inter-method agreement was substantial (Cohen's Kappa = 0.81, p < 0.001). Phenotypic expansions occurred in six cases (21.4%), while nine cases (32.1%) remained unexplained.
Conclusion:
The IMA framework achieved a high diagnostic yield of 67.9% within a highly selected, consanguineous cohort. Although clinical yield and concordance are influenced by selection biases, comprehensive post-mortem phenotyping remains essential to resolve atypical presentations, guide variant prioritization, and optimize reproductive counseling.
