Abstract
ABSTRACT
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
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.