Prenatal Testing Combined with Familial Genetic Diagnosis Reduces Disease Recurrence

Background: The causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following molecular diagnosis in a child, families could use this information to make informed decisions in planning future pregnancies. However, there are no population-level studies to measure the effect of applying this knowledge on recurrence risk. Methods: In a retrospective study involving 1172 families with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis, prenatal diagnosis was offered to families seeking to prevent recurrence through fetal genotyping. Pregnancies that were carried to term were assessed for the health of child and mother. Findings: Between 2010 and 2016, 526 families received a molecular diagnosis following NGS, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Of 59 fetuses that genotyped negative and were carried to term, all were unaffected at follow-up. Of 24 that genotyped positive, 16 were terminated, reducing the disease recurrence from the expected 25% to the observed 12% ([95% CI 0·04 to 0·20], p=0·011). The remaining 8 pregnancies were carried to term, and all demonstrated disease concordant with their affected sibling(s). Interpretation: Identification of causes through NGS, coupled with prenatal fetal genotyping in subsequent pregnancies, can empower families to make informed decisions and reduce recessive disease recurrence. Funding Statement: NIH R01NS048453, R01NS052455, UL1TR001442 of CTSA and HHMI. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: This study was approved at the host institutions of the respective study sites. The University of California San Diego IRB approved recruitment of subjects for NGS and return of research results to the referring physician and family. The National Research Centre in Cairo approved the study for confirmation of research results, fetal genotyping and genetic counseling for families. Amniocentesis and eTOP utilized standard procedural consent according to local practice.