Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births1, but the incidence of CHD is up to ten fold higher in human fetuses2,3. A genetic contribution is strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk4. Here we report findings from a recessive forward genetic screen in fetal mice, showing the cilium and cilia transduced cell signaling play important roles in the pathogenesis of CHD. The cilium is an evolutionarily conserved organelle projecting from the cell surface with essential roles in diverse cellular processes. Using echocardiography, we ultrasound scanned 87,355 chemically mutagenized C57BL/6J fetal mice and recovered 218 CHD mouse models. Whole exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia transduced cell signaling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signaling. Surprisingly, many CHD genes encoded interacting proteins, suggesting an interactome protein network may provide a larger genomic context for CHD pathogenesis. These findings provide novel insights into the potential Mendelian genetic contribution to CHD in the fetal population, a segment of the human population not well studied. We note pathways identified show overlap with CHD candidate genes recovered in CHD patients5, suggesting they may have relevance to the more complex genetics of CHD overall. These CHD mouse models and >8,000 incidental mutations are sperm archived, creating a rich public resource for human disease modeling.

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SUMMARY The morphology of the atrial appendages was examined in 1842 specimen hearts from patients with congenital lesions. The extemal and internal features that permitted the identification of the right and left appendages were studied in detail in one tenth of the hearts. These results were compared with a similar analysis of 25 normal hearts. This study showed that criteria for identification of right and left appendages were reliable. Application of these criteria to the overall collection identified the usual arrangement in 1776 (97%) hearts, a mirror image arrangement in eight (0O4o/o); left atrial isomerism in 22 (1-2%); and right atrial isomerism in 36 (1-9%). Fourteen (081 %) had juxtaposed atrial appendages (13 with usual arrangement and one with left isomerism). This did not interfere with identification of the left and right atria on the basis of appendage morphology. In only two cases did the determination by atrial morphology produce a result that was inconsistent with the arrangement of the other thoracoabdominal organs. Further examination of the atria in these showed a mistake had been made in the initial assessment. The atrial arrangement can be accurately determined by the morphology of the atrial appendages.

Computed-tomography scanning and magnetic-resonance imaging (MRI) have been used to quantify intraabdominal and subcutaneous fat depots. In this study MRI was used to define fat-distribution patterns in 24 obese females with non-insulin-dependent diabetes (NIDDM) and 12 females with simple obesity. Subjects had anthropometric measurements and single-slice abdominal scans performed at the umbilicus. In addition, in 10 of the nondiabetic females, measurements were repeated after 10 wk of a very-low-calorie diet. Nondiabetic females had significantly less intraabdominal fat (P less than 0.01) than did the diabetics but had equivalent subcutaneous fat. There was no significant relationship between waist-to-hip ratio and intraabdominal fat, subcutaneous fat, or their ratio. After a weight loss of 10.6 +/- 3.8 kg there were significant decreases in both intraabdominal and subcutaneous fat (P less than 0.01). Weight loss is associated with decreases in fat in both depots.