Molecular autopsy by proxy: relevance for genetic counseling in rare genetic disorders.

Background: Rare genetic disorders may result in death before a definitive clinical diagnosis is established. Aim: This study aims to outline the processes and challenges in managing, from a genetic perspective, couples who lost children affected by rare genetic disorders. Results: Six couples who experienced child loss due to rare genetic disorders, seen by the primary author at genetic evaluation and counseling sessions, were retrospectively analyzed. Four out of 6 couples reported consanguinity. Exome and genome sequencing were performed for the parents. Carrier status of two rare lethal metabolic disorders was confirmed in one consanguineous couple. Three couples were carriers of 3 other rare diseases. Variants of LYST, MPV17, HEXB, ITGB4, CD3E, ASPM, TK2, COL11A2, and LAMB3 genes were identified. Six out of 10 were pathogenic variants, out of which 4 correlated with the demised children's phenotypes. One couple was negative for pathogenic variants. The last couple did not undergo genetic testing since they were beyond the fertile window. Conclusion: Appropriate parental genetic evaluation and counseling are mandatory for selecting the right genetic test to certify the diagnosis postmortem, by virtue of molecular autopsy by proxy. Clarifying a rare disorder diagnosis can help couples to avoid recurrence and plan early for their next pregnancies.

Molecular autopsy by proxy in preconception counseling.

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.