The greatest opportunity for lifelong impact of genomic sequencing is during the newborn period. The “BabySeq Project” is a randomized trial that explores the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. Families of newborns are enrolled from Boston Children’s Hospital and Brigham and Women’s Hospital nurseries, and half are randomized to receive genomic sequencing and a report that includes monogenic disease variants, recessive carrier variants for childhood onset or actionable disorders, and pharmacogenomic variants. All families participate in a disclosure session, which includes the return of results for those in the sequencing arm. Outcomes are collected through review of medical records and surveys of parents and health care providers and include the rationale for choice of genes and variants to report; what genomic data adds to the medical management of sick and healthy babies; and the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. The BabySeq Project will provide empirical data about the risks, benefits and costs of newborn genomic sequencing and will inform policy decisions related to universal genomic screening of newborns. The study is registered in ClinicalTrials.gov Identifier: NCT02422511 . Registration date: 10 April 2015.

Genomic sequencing (GS) for newborns may enable detection of conditions for which early knowledge can improve health outcomes. One of the major challenges hindering its broader application is the time it takes to assess the clinical relevance of detected variants and the genes they impact so that disease risk is reported appropriately. To facilitate rapid interpretation of GS results in newborns, we curated a catalog of genes with putative pediatric relevance for their validity based on the ClinGen clinical validity classification framework criteria, age of onset, penetrance, and mode of inheritance through systematic evaluation of published evidence. Based on these attributes, we classified genes to guide the return of results in the BabySeq Project, a randomized, controlled trial exploring the use of newborn GS (nGS), and used our curated list for the first 15 newborns sequenced in this project. Here, we present our curated list for 1,514 gene–disease associations. Overall, 954 genes met our criteria for return in nGS. This reference list eliminated manual assessment for 41% of rare variants identified in 15 newborns. Our list provides a resource that can assist in guiding the interpretive scope of clinical GS for newborns and potentially other populations. Genet Med advance online publication 12 January 2017

Cofilin-2, a small actin-binding protein and member of the AC protein family that includes cofilin-1 and destrin, is predominantly expressed at sarcomeres in skeletal and cardiac muscles. The role of cofilin-2 in muscle development and function is unclear. In humans, recessive cofilin-2 mutations have been associated with nemaline myopathy with minicores. To investigate the functional role of cofilin-2 in vivo, we generated constitutive and muscle-specific cofilin-2-deficient mice using a cre–loxP strategy. Cofilin-2-deficient mice were similar to their wild-type (WT) littermates at birth, but died by day 8. They were significantly smaller, severely weak and had very little milk in their stomachs. The sarcomeric structure was intact at birth, but by Day 7, skeletal muscles showed severe sarcomeric disruptions starting at the Z-line, along with filamentous actin accumulations consistent with a lack of actin depolymerization activity. Cofilin-2-deficient muscles contained elevated numbers of slow fibers and exhibited upregulation of slow fiber-specific genes. Increased amounts of other sarcomeric proteins including α-actinin-2, α-sarcomeric actin and tropomyosin were also present. While destrin was not expressed in either WT or cofilin-2-deficient muscles, cofilin-1 was similarly expressed in developing myofibers of both genotypes. There was no evidence for compensatory changes in expression of either family member in cofilin-2-deficient tissues. The onset of pathology and weakness in cofilin-2-deficient muscles correlated with normal developmental loss of cofilin-1 expression within myofibers, suggesting that cofilin-1 serves as an early developmental sarcomeric isoform. Overall, cofilin-2, although not critical for muscle development, is essential for muscle maintenance.