RESUMO
RATIONALE: Bronchopulmonary dysplasia (BPD), a prevalent severe lung disease of premature infants, has a strong genetic component. Large-scale genome-wide association studies for common variants have not revealed its genetic basis. OBJECTIVES: Given the historical high mortality rate of extremely preterm infants who now survive and develop BPD, we hypothesized that risk loci underlying this disease are under severe purifying selection during evolution; thus, rare variants likely explain greater risk of the disease. METHODS: We performed exome sequencing on 50 BPD-affected and unaffected twin pairs using DNA isolated from neonatal blood spots and identified genes affected by extremely rare nonsynonymous mutations. Functional genomic approaches were then used to systematically compare these affected genes. MEASUREMENTS AND MAIN RESULTS: We identified 258 genes with rare nonsynonymous mutations in patients with BPD. These genes were highly enriched for processes involved in pulmonary structure and function including collagen fibril organization, morphogenesis of embryonic epithelium, and regulation of Wnt signaling pathway; displayed significantly elevated expression in fetal and adult lungs; and were substantially up-regulated in a murine model of BPD. Analyses of mouse mutants revealed their phenotypic enrichment for embryonic development and the cyanosis phenotype, a clinical manifestation of BPD. CONCLUSIONS: Our study supports the role of rare variants in BPD, in contrast with the role of common variants targeted by genome-wide association studies. Overall, our study is the first to sequence BPD exomes from newborn blood spot samples and identify with high confidence genes implicated in BPD, thereby providing important insights into its biology and molecular etiology.
Assuntos
Displasia Broncopulmonar/genética , Exoma/genética , Pulmão/embriologia , Morfogênese/genética , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Via de Sinalização Wnt/genética , Animais , Coleta de Amostras Sanguíneas , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Haploinsuficiência , Humanos , Lactente , Lactente Extremamente Prematuro , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Camundongos , Triagem Neonatal , Análise de Sequência de DNARESUMO
Understanding causes of infant mortality shapes public health policy and prioritizes diseases for investments in surveillance, intervention and medical research. Rapid genomic sequencing has created a novel opportunity to decrease infant mortality associated with treatable genetic diseases. Herein, we sought to measure the contribution of genetic diseases to mortality among infants by secondary analysis of babies enrolled in two clinical studies and a systematic literature review. Among 312 infants who had been admitted to an ICU at Rady Children's Hospital between November 2015 and September 2018 and received rapid genomic sequencing, 30 (10%) died in infancy. Ten (33%) of the infants who died were diagnosed with 11 genetic diseases. The San Diego Study of Outcomes in Mothers and Infants platform identified differences between in-hospital and out-of-hospital causes of infant death. Similarly, in six published studies, 195 (21%) of 918 infant deaths were associated with genetic diseases by genomic sequencing. In 195 infant deaths associated with genetic diseases, locus heterogeneity was 70%. Treatment guidelines existed for 70% of the genetic diseases diagnosed, suggesting that rapid genomic sequencing has substantial potential to decrease infant mortality among infants in ICUs. Further studies are needed in larger, comprehensive, unbiased patient sets to determine the generalizability of these findings.