Clinical Utility of Molecular Autopsy in Fetal and Pediatric Patients with Suspected Genetic Disorders

Year 2022, Volume: 11 Issue: 1, 82 - 89, 19.03.2022

Ozlem Akgun-dogan , Nihat Buğra Ağaoğlu , Yasemin Alanay

https://doi.org/10.37989/gumussagbil.1078850

Abstract

Molecular autopsy is defined as whole exome/genome sequencing (WES/WGS) performed on DNA samples in the postmortem period to clarify the genetic etiology in patients who demised without a diagnosis. With this study, we aim to present our experience with postmortem WES/WGS analysis, in a group of pediatric patients to increase the knowledge on the clinical utility of molecular autopsy and its effect on genetic counseling.
A retrospective cohort study was conducted on postmortem WES/WGS analysis records performed between 2017-2021 in Acibadem University Department of Pediatric Genetics. Clinical data and analysis results of patients who died in the perinatal/infancy period without a molecular diagnosis were collected from medical records.
A total of 16 cases were included in the study. In 56% of the cases, molecular autopsy revealed a diagnosis. In 10 genes (BBS9, BRAF, SLC12A1, PIEZO1, WDR62, ERCC8, NDUFAF2, RAG1, MOGS, ETFB), 12 variants were detected. Fifty percent of these variants were novel, reported for the first time with this study. Inborn diseases of metabolism (33%) and neurologic disorders (22%) were the most common disease groups.
Our results show that WES/WGS analysis yields a high diagnostic rate in the postmortem period. The diagnosis elucidated by molecular autopsy provides invaluable information for the family who has experienced a loss. The identification of the underlying genetic cause enables the family to plan for future pregnancies. Diagnosing a fetus or an infant who was lost without a specific diagnosis helps identify novel genes and further delineate perinatal lethal phenotypes related to known genes.

Keywords

Molecular autopsy, Pediatric, Genetic diseases, Postmortem, Next Generation Sequencing

Genetik Hastalık Şüphesi Olan Fetal ve Pediatrik Hastalarda Moleküler Otopsinin Klinik Faydası

Abstract

Moleküler otopsi, herhangi bir tanı konulamadan kaybedilen hastalarda genetik etiyolojiyi aydınlatmak üzere postmortem dönemde gerçekleştirilen tüm ekzom/genom dizilemeyi (WES/WGS) kapsamaktadır. Çalışmamızın amacı pediatrik yaş grubunda postmortem WES/WGS tecrübemizi paylaşarak, moleküler otopsinin klinik kullanımdaki yararını ve genetik danışmanlık üzerindeki etkisini sunmaktır.
Çalışmamız retrospektif kohort çalışması olarak planlandı. Acıbadem Üniversitesi Pediatrik Genetik Anabilim Dalı'nda 2017-2021 yılları arasında, perinatal veya infant döneminde moleküler tanı konulamadan kaybedilen ve postmortem WES/WGS yapılan hastaların klinik verileri ve moleküler sonuçları hastalara ait tıbbi kayıtlar incelenerek toplandı.
Çalışmaya toplam 16 vaka dahil edildi. Vakaların %56'sında moleküler otopsi sonrası tanı konuldu. On gende (BBS9, BRAF, SLC12A1, PIEZO1, WDR62, ERCC8, NDUFAF2, RAG1, MOGS, ETFB), toplam 12 varyant tespit edildi. Bu varyantların %50'si daha önce bildirilmeyen, novel varyantlardı. Doğuştan metabolizma hastalıkları (%33) ve nörolojik bozukluklar (%22) en sık görülen hastalık grupları olarak öne çıktı.
Sonuçlarımız, WES/WGS analizinin özellikle ülkemiz gibi akraba evliliği oranının yüksek olduğu bölgelerde ölüm sonrası dönemde yüksek bir tanı oranına sahip olduğunu göstermektedir. Moleküler otopsi ile aydınlatılan tanı, kayıp yaşayan aile için gelecekteki gebeliklerin planlanması ve yönetimi açısından çok değerli bilgiler sağlamaktadır. Ayrıca, spesifik bir tanı olmadan kaybedilen fetüs veya infantların teşhisi, yeni genlerin tanımlanmasına ve bilinen genlerle ilgili perinatal ölümcül fenotiplerin belirlenmesine de olanak tanımaktadır.

Keywords

Moleküler otopsi, Pediatrik, Genetik Hastalıklar, Postmortem, Yeni Nesil Dizileme

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