Germline but not somatic de novo mutations are common in human congenital diaphragmatic hernia.

OBJECTIVES: Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn morbidity and mortality. CDH is considered to be a multifactorial disease, with strong evidence implicating genetic factors. Although recent studies suggest the biological role of deleterious germline de novo variants, the effect of gene variants specific to the diaphragm remains unclear, and few single genes have been definitively implicated in human disease. METHODS: We performed genome sequencing on 16 individuals with CDH and their unaffected parents, including 10 diaphragmatic samples. RESULTS: We did not detect damaging somatic mutations in diaphragms, but identified germline heterozygous de novo functional mutations of 14 genes in nine patients. Although the majority of these genes are not known to be associated with CDH, one patient with CDH and cardiac anomalies harbored a frameshift mutation in NR2F2 (aka COUP-TFII), generating a premature truncation of the protein. This patient also carried a missense variant predicted to be damaging in XIRP2 (aka Myomaxin), a transcriptional target of MEF2A. Both NR2F2 and MEF2A map to chromosome 15q26, where recurring de novo deletions and unbalanced translocations have been observed in CDH. CONCLUSIONS: Somatic variants are not common in CDH. To our knowledge, this is the second case of a germline de novo frameshift mutation in NR2F2 in CDH. Since NR2F2 null mice exhibit a diaphragmatic defect, and XIRP2 is implicated in cardiac development, our data suggest the role of these two variants in the etiology of CDH, and possibly cardiac anomalies.

Epidemiology and Prognosis of Congenital Diaphragmatic Hernia: A Population-Based Cohort Study in Utah.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a relatively frequent and severe malformation. Population-based data on clinical presentation and associated mortality are scarce. We examined a state-wide cohort of infants with a clinically validated diagnosis of CDH to assess their clinical profile, sociodemographic patterns, and infant mortality. METHODS: We identified CDH cases from Utah's statewide population-based surveillance program among the cohort of all pregnancy outcomes (live births, stillbirths, and pregnancy terminations) delivered from 1999 to 2011. Clinical geneticists reviewed all cases and classified them based on etiology (known, unknown), and whether they were isolated, multiple (additional unrelated major malformations or unique minor malformation), or syndromic (genetic, chromosomal). RESULTS: CDH occurred in 1 in 3156 births (227/718,990, or 3.17 per 10,000), with no time trend during the 13 years (p = 0.85). CDH was much more common in males (male to female ratio, 1.72:1; p < 0.01). Clinically, 64% of the cases were isolated, 23% were multiples, and 13% were syndromic. Most cases were live born (90%), with fewer stillbirths (7%) and pregnancy terminations (3%). Overall infant mortality was 32.5%, and varied considerably by underlying etiology (isolated 21%; multiple 44%; syndromic 82%). Prognosis was related to specific clinical findings within each etiologic group (e.g., prematurity, low Apgar score, and intrathoracic liver). CONCLUSION: This information on specific clinical and etiologic factors associated with prognosis can help clinicians and parents in the complex discussions about care planning and management that often occur in a crisis situation, following the diagnosis of CDH, whether prior or after delivery. Birth Defects Research 109:1451-1459, 2017.© 2017 Wiley Periodicals, Inc.