Molecular autopsy for fetal structural anomaly: diagnostic and clinical utility of multidisciplinary team approach

• Published in: Ultrasound in obstetrics & gynecology 2024-09, Vol.64 (3), p.381-387
• Main Authors: Wall, E., Petley, E., Mone, F., Doyle, S., Hartles‐Spencer, L., Allen, S. K., Castleman, J., Marton, T., Williams, D.
• Format: Article
• Language: English
• Subjects: Adult; Autopsies; Autopsy; Autopsy - statistics & numerical data; Congenital Abnormalities - diagnosis; Congenital Abnormalities - diagnostic imaging; Congenital Abnormalities - genetics; Death; Diagnosis; Diagnostic systems; Evaluation; Exome Sequencing; Female; Fetus - abnormalities; Fetus - pathology; Fetuses; Gene sequencing; Genetic analysis; Genetic screening; Genetic testing; Genetic Testing - methods; Genetic Testing - statistics & numerical data; Genetics; Genomes; Genomic analysis; Genotypes; Gynecology; Humans; Impact analysis; Infant, Newborn; Medical diagnosis; molecular postmortem; Mortality; Multidisciplinary teams; Obstetrics; Patient Care Team; Perinatal Death; perinatal postmortem; Phenotypes; Pregnancy; Prenatal Diagnosis - methods; prenatal exome sequencing; Retrospective Studies; service evaluation; Whole genome sequencing
• ISSN: 0960-7692; 1469-0705; 1469-0705
• DOI: 10.1002/uog.27647

ABSTRACT Objective In the West Midlands regional genetics service, cases of perinatal death with a possible genetic diagnosis are evaluated by the perinatal pathology genetic multidisciplinary team (MDT). The MDT assesses autopsy findings and suggests appropriate genomic assessment. The objective of this retrospective service evaluation was to determine the clinical utility of the MDT in assessing perinatal deaths associated with structural anomaly. This is the first evaluation since the introduction of whole‐genome and whole‐exome sequencing in routine clinical care. Methods This was a retrospective service evaluation including all cases of perinatal death with an associated structural anomaly and suspected genetic etiology that underwent perinatal MDT assessment between January and December 2021. All cases received a full or partial postmortem examination and at least a chromosomal microarray analysis. Demographic characteristics, phenotype, genotype, MDT recommendations, diagnoses, outcomes and impact of postmortem analysis and genetic testing data were collected from patient case notes. Results Overall, 123 cases were discussed at the MDT meetings in 2021. Genetic evaluation was recommended in 84 cases and accepted in 64 cases. A range of genetic tests were requested according to indication and availability. Thirty diagnoses were made in 29 cases from 26 unrelated families. The diagnostic yield was 24% (29/123) in all cases or 45% (29/64) in cases with a suspected genetic diagnosis who underwent genetic testing. Postmortem examination provided clinically actionable phenotypic data in 79% of cases. A genetic diagnosis enabled accurate recurrence risk counseling and provision of appropriate follow‐up, including prenatal testing and preimplantation diagnosis for patients with inherited conditions. Conclusions Genomic testing was a clinically useful addition to (but not a substitute for) postmortem examination in cases of perinatal death associated with structural anomaly. The MDT approach helped assess cases and plan appropriate follow‐up. Expedited whole‐genome sequencing or panel‐agnostic analysis were most appropriate for heterogeneous presentations. This broad approach can also expand knowledge of prenatal phenotypes and detect novel disease genes, and should be a priority in future research. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.