Molecular autopsy by proxy in preconception counseling.

Area of Science:

• Genetics
• Reproductive Medicine
• Molecular Diagnostics

Background:

• Monogenic diseases cause significant early pregnancy loss and neonatal death, presenting diagnostic challenges.
• Lack of deceased offspring DNA hinders molecular diagnosis for reproductive planning.
• Molecular autopsy by proxy (MABP) involves genetic testing of relatives to determine the cause of death.

Purpose of the Study:

• To evaluate the utility of MABP in consanguineous couples experiencing recurrent pregnancy loss or neonatal death without available offspring DNA.
• To establish a molecularly informed genetic counseling strategy for such couples.

Main Methods:

• Whole exome sequencing was performed on DNA from 83 consanguineous Saudi couples with a history of child loss.
• Genetic variants in parents were analyzed to identify shared carrier status for pathogenic or likely pathogenic variants.
• Variant reclassification and analysis of secondary findings were conducted.

Main Results:

• A molecular diagnosis was achieved in 52% (43/83) of families.
• Shared carrier status for pathogenic/likely pathogenic variants was identified in 43 families, and variants of uncertain significance in 24 families.
• Secondary findings with potential clinical implications were noted in 10 families.

Conclusions:

• MABP is an effective strategy for molecularly informed genetic counseling in consanguineous couples with unexplained pregnancy loss or neonatal death.
• This approach is particularly valuable in populations with a high prevalence of autosomal recessive disorders.
• MABP facilitates reproductive planning by identifying genetic risks even when offspring DNA is unavailable.