Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families.

TitleMolecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families.
Publication TypeJournal Article
Year of Publication2020
AuthorsIssa, MY, Chechlacz, Z, Stanley, V, George, RD, McEvoy-Venneri, J, Belandres, D, Elbendary, HM, Gaber, KR, Nabil, A, Abdel-Hamid, MS, Zaki, MAHS, Gleeson, JG
JournalBMC Med Genomics
Date Published2020 05 13
KeywordsChild, Preschool, Female, Genes, Recessive, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genotype, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Male, Mutation, Nervous System Diseases, Pedigree, Pregnancy, Prenatal Diagnosis, Recurrence, Retrospective Studies

BACKGROUND: The causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following the molecular diagnosis in older children in a family, parents could use this information to opt for fetal genotyping in subsequent pregnancies, which could inform decisions about elective termination of pregnancy. The use of NGS diagnostic sequencing in families has not been demonstrated to yield benefit in subsequent pregnancies to reduce recurrence. Here we evaluated whether genetic diagnosis in older children in families supports reduction in recurrence of recessive neurogenetic disease.

METHODS: Retrospective study involving families with a child with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis. Prenatal molecular testing was offered to couples in which a molecular diagnosis was made, to help couples seeking to prevent recurrence. With this information, families made decisions about elective termination. Pregnancies that were carried to term were assessed for the health of child and mother, and compared with historic recurrence risk of recessive disease.

RESULTS: Between 2010 and 2016, 1172 families presented with a child a likely rPBD, 526 families received a molecular diagnosis, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Sixty tested negative for recurrence for the biallelic mutation in the fetus, and all, except for one spontaneous abortion, carried to term, and were unaffected at follow-up. Of 24 that genotyped positive for the biallelic mutation, 16 were electively terminated, and 8 were carried to term and showed features of disease similar to that of the older affected sibling(s). Among the 101 pregnancies, disease recurrence in living offspring deviated from the expected 25% to the observed 12% ([95% CI 0·04 to 0·20], p = 0·011).

CONCLUSIONS: Molecular diagnosis in an older child, coupled with prenatal fetal genotyping in subsequent pregnancies and genetic counselling, allows families to make informed decisions to reduce recessive neurogenetic disease recurrence.

Alternate JournalBMC Med Genomics
PubMed ID32404165
PubMed Central IDPMC7218834
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
/ HH / Howard Hughes Medical Institute / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
UL1 TR001442 / TR / NCATS NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
R01 NS052455 / NS / NINDS NIH HHS / United States