Molecular autopsy by proxy in preconception counseling
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Authors
Alghamdi, Malak Ali
Alrasheedi, Ameinah
Alghamdi, Esra
Adly, Nouran
AlAali, Wajeih Y.
Alhashem, Amal
Alshahrani, Abdulaziz
Shamseldin, Hanan
Alkuraya, Fowzan S.
Alfadhel, Majid
Issue Date
2021-08-30
Type
Article
Language
en_US
Keywords
Consanguinity , Molecular Autopsy By Proxy , Neonatal Deaths , Recurrent Pregnancy Loss , Whole Exome Sequencing
Alternative Title
Abstract
Monogenic diseases that result in early pregnancy loss or neonatal death are genetically and phenotypically highly variable. This often poses significant challenges in arriving at a molecular diagnosis for reproductive planning. Molecular autopsy by proxy (MABP) refers to the genetic testing of relatives of deceased individuals to deduce the cause of death. Here, we specifically tested couples who lost one or more children/pregnancies with no available DNA. We developed our testing strategy using whole exome sequencing data from 83 consanguineous Saudi couples. We detected the shared carrier state of 50 pathogenic variants/likely pathogenic variants in 43 families and of 28 variants of uncertain significance in 24 families. Negative results were seen in 16 couples after variant reclassification. In 10 families, the risk of more than one genetic disease was documented. Secondary findings were seen in 10 families: either genetic variants with potential clinical consequences for the tested individual or a female carrier for X‐linked conditions. This couple‐based approach has enabled molecularly informed genetic counseling for 52% (43/83 families). Given the predominance of autosomal recessive causes of pregnancy and child death in consanguineous populations, MABP can be a helpful approach to consanguineous couples who seek counseling but lack molecular data on their deceased offspring.
Description
Citation
Ali Alghamdi, M., Alrasheedi, A., Alghamdi, E., Adly, N., AlAali, W. Y., Alhashem, A., Alshahrani, A., Shamseldin, H., Alkuraya, F. S., & Alfadhel, M. (2021). Molecular autopsy by proxy in preconception counseling. Clinical genetics, 100(6), 678–691. https://doi.org/10.1111/cge.14049
Publisher
Clinical Genetics