Genetics of Common Birth Defects in Newborns

Birth defects are among the leading causes of morbidity and mortality in children and are present in 3% to 6% of births. The majority of birth defects are thought to be isolated and nonsyndromic at birth; however, as the child grows and develops, many are appreciated to be associated with other medical problems, difficulty with growth, and/or neurodevelopmental and behavioral issues. The etiologies for most birth defects are unknown and are likely multifactorial. However, as genomic technologies have matured and been used to interrogate large cohorts of individuals with birth defects, a range of genetic causes have been identified, including chromosome disorders, copy number variants, monogenic disorders, epigenetics, and common variants. In some cases, there may be contributions from both the maternal and fetal genomes because the mother’s genotype influences the metabolism of cofactors such as folate that may be critical to certain birth defects including neural tube defects. A limitation to the systematic analysis of the etiology of birth defects has been the limited availability of unbiased prospective data from mothers during pregnancy along with birth and long-term outcomes paired with comprehensive genomic data to assess the contribution of genes, the environment, and their interactions. Advances in genomic tools have now made it possible to genomically assess fetuses and newborns with birth defects to diagnose the 20% to 30% of cases with identifiable genetic etiologies and provide more accurate prognostic information and tailored surveillance as well as intervention to those infants likely to have associated medical and neurodevelopmental issues. In addition to supporting the care of the infant, this genetic information can provide important information to parents to accurately estimate the risk of recurrence and provide families with informed reproductive strategies for future pregnancies.