title: Global genetic analysis in mice unveils central role for cilia in congenital heart disease.
abstract: Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births; the incidence of CHD is up to tenfold higher in human fetuses. A genetic contribution is strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk. Here we report findings from a recessive forward genetic screen in fetal mice, showing that cilia and cilia-transduced cell signalling have 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 signalling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signalling. Surprisingly, many CHD genes encoded interacting proteins, suggesting that 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 that the pathways identified show overlap with CHD candidate genes recovered in CHD patients, suggesting that they may have relevance to the more complex genetics of CHD overall. These CHD mouse models and >8,000 incidental mutations have been sperm archived, creating a rich public resource for human disease modelling.
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: You
authors: Y
authors: Li
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Nikolai T
authors: NT
authors: Klena
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: George C
authors: GC
authors: Gabriel
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Xiaoqin
authors: X
authors: Liu
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Andrew J
authors: AJ
authors: Kim
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Kristi
authors: K
authors: Lemke
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Yu
authors: Y
authors: Chen
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Bishwanath
authors: B
authors: Chatterjee
authors: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors: William
authors: W
authors: Devine
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Rama Rao
authors: RR
authors: Damerla
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Chienfu
authors: C
authors: Chang
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Hisato
authors: H
authors: Yagi
authors: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors: Jovenal T
authors: JT
authors: San Agustin
authors: 1] Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15206, USA [2] Intelligent Systems Program, School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 16260, USA.
authors: Mohamed
authors: M
authors: Thahir
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Shane
authors: S
authors: Anderton
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Caroline
authors: C
authors: Lawhead
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Anita
authors: A
authors: Vescovi
authors: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors: Herbert
authors: H
authors: Pratt
authors: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors: Judy
authors: J
authors: Morgan
authors: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors: Leslie
authors: L
authors: Haynes
authors: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors: Cynthia L
authors: CL
authors: Smith
authors: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors: Janan T
authors: JT
authors: Eppig
authors: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors: Laura
authors: L
authors: Reinholdt
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Richard
authors: R
authors: Francis
authors: The Heart Center, Children's National Medical Center, Washington DC 20010, USA.
authors: Linda
authors: L
authors: Leatherbury
authors: 1] Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15206, USA [2] Intelligent Systems Program, School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 16260, USA.
authors: Madhavi K
authors: MK
authors: Ganapathiraju
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Kimimasa
authors: K
authors: Tobita
authors: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors: Gregory J
authors: GJ
authors: Pazour
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.
authors: Cecilia W
authors: CW
authors: Lo
mesh_terms: D000818:Animals; D002923:Cilia / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology* / Q000502:physiology; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D059472:Exome / Q000235:genetics; D005808:Genes, Recessive; D005820:Genetic Testing; D006330:Heart Defects, Congenital / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction; D014463:Ultrasonography