Exome sequencing identifies a recessive PIGN splice site mutation as a cause of syndromic congenital diaphragmatic hernia.

Using exome sequencing we identify a homozygous splice site mutation in the PIGN gene in a foetus with multiple congenital anomalies including bilateral diaphragmatic hernia, cardiovascular anomalies, segmental renal dysplasia, facial dysmorphism, cleft palate, and oligodactyly. This finding expands the phenotypic spectrum associated with homozygous loss of function mutations in PIGN, and adds further support for defective GPI anchor biosynthesis as a cause of developmental abnormalities. We demonstrate that exome sequencing is a valuable approach for the identification of a genetic cause in sporadic cases of multiple congenital anomalies (MCA) due to inherited mutations.

Identification of dosage-sensitive genes in fetuses referred with severe isolated congenital diaphragmatic hernia.

OBJECTIVE: Congenital diaphragmatic hernia (CDH) is a fetal abnormality affecting diaphragm and lung development with a high mortality rate despite advances in fetal and neonatal therapy. CDH may occur either as an isolated defect or in syndromic form for which the prognosis is worse. Although conventional karyotyping and, more recently, chromosomal microarrays support a substantial role for genetic factors, causal genes responsible for isolated CDH remain elusive. We propose that chromosomal microarray analysis will identify copy number variations (CNVs) associated with isolated CDH. METHODS: We perform a prospective genome-wide screen for CNVs using chromosomal microarrays on 75 fetuses referred with apparently isolated CDH, six of which were later reclassified as non-isolated CDH. RESULTS: The results pinpoint haploinsufficiency of NR2F2 as a cause of CDH and cardiovascular malformations. In addition, the 15q25.2 and 16p11.2 recurrent microdeletions are associated with isolated CDH. By using gene prioritisation and network analysis, we provide strong evidence for several novel dosage-sensitive candidate genes associated with CDH. CONCLUSIONS: Chromosomal microarray analysis detects submicroscopic CNVs associated with isolated CDH or CDH with cardiovascular malformations.

Polychlorinated biphenyls in clams and oysters from New Bedford Harbor, Massachusetts, March 1978.

Polychlorinated biphenyl (PCB) concentrations in clams (Mercenaria mercenaria) and oysters (Crassostrea virginica) from 17 stations of the western and New Bedford Harbor areas of Buzzards Bay, Massachusetts, clearly show that the New Bedford Harbor area is severely polluted. Up to 5 ppm PCBs (dry weight) were found in shellfish tissue. The most likely sources of the PCBs are chronic releases from two electrical component manufacturers in New Bedford. Close proximity of the shellfish to the source of input is indicated by a high relative abundance of the di-, tri-, and tetrachlorobiphenyls. The data suggest that the New Bedford Harbor area should be considered, along with the Hudson River and Chesapeake Bay, one of the major sources of PCB inputs to the northeastern United States coastal area.