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      Genetic Mapping and Exome Sequencing Identify Variants Associated with Five Novel Diseases

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          The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb) that contain many genes (mean = 79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.

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          Most cited references 56

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          Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2.

          Contactin-associated protein-like 2 (CASPR2) is encoded by CNTNAP2 and clusters voltage-gated potassium channels (K(v)1.1) at the nodes of Ranvier. We report a homozygous mutation of CNTNAP2 in Old Order Amish children with cortical dysplasia, focal epilepsy, relative macrocephaly, and diminished deep-tendon reflexes. Intractable focal seizures began in early childhood, after which language regression, hyperactivity, impulsive and aggressive behavior, and mental retardation developed in all children. Resective surgery did not prevent the recurrence of seizures. Temporal-lobe specimens showed evidence of abnormalities of neuronal migration and structure, widespread astrogliosis, and reduced expression of CASPR2. Copyright 2006 Massachusetts Medical Society.
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            Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.

            We sequenced all protein-coding regions of the genome (the "exome") in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby increasing plasma triglyceride and HDL cholesterol levels in rodents. Our finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders. (Funded by the National Human Genome Research Institute and others.).
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              RAIDD is a new 'death' adaptor molecule.

               S.-H. Duan,  V M Dixit (1997)
              The effector arm of the cell-death pathway is composed of cysteine proteases belonging to the ICE/CED-3 family. In metazoan cells these exist as inactive polypeptide precursors (zymogens), each composed of a prodomain, which is cleaved to activate the protease, and a large and small catalytic subunit. The coupling of these 'death' proteases to signalling pathways is probably mediated by adaptor molecules that contain protein-protein interaction motifs such as the death domain. Here we describe such an adaptor molecule, RAIDD, which has an unusual bipartite architecture comprising a carboxy-terminal death domain that binds to the homologous domain in RIP, a serine/threonine kinase component of the death pathway. The amino-terminal domain is surprisingly homologous with the sequence of the prodomain of two ICE/CED-3 family members, human ICH-1 (ref. 5) and Caenorhabditis elegans CED-3 (ref. 6). This similar region mediates the binding of RAIDD to ICH-1 and CED-3, serving as a direct link to the death proteases, indicating that the prodomain may, through homophilic interactions, determine the specificity of binding of ICE/CED-3 zymogens to regulatory adaptor molecules. Finally, alternations in the sequence of the N-terminal domain that are equivalent to inactivating mutations in the C. elegans ced-3 gene prevent homophilic binding, highlighting the potentially primordial nature of this interaction.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                17 January 2012
                20 January 2012
                : 7
                : 1
                [1 ]Clinic for Special Children, Strasburg, Pennsylvania, United States of America
                [2 ]Department of Biology and Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, Pennsylvania, United States of America
                [3 ]The Broad Institute, Boston, Massachusetts, United States of America
                [4 ]Department of Biology, Swarthmore College, Swarthmore, Pennsylvania, United States of America
                [5 ]Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America
                [6 ]College of Medicine, University of Vermont, Burlington, Vermont, United States of America
                [7 ]Lancaster General Hospital, Lancaster, Pennsylvania, United States of America
                Innsbruck Medical University, Austria
                Author notes

                Conceived and designed the experiments: EGP RNJ JTE CF SG DHM KAS. Performed the experiments: EGP RNJ RAW NPA RPC CJF KFH JJL MHM CJM DTN KAP KNW RAS RD EAS JTE CF SR-B. Analyzed the data: EGP RNJ CS KC RAW NPA RPC CJF KFH JJL MHM CJM DTN KAP KNW RAS RD EAS JTE CF SR-B. Contributed reagents/materials/analysis tools: CS KC JTE CF NLR SG DHM KAS. Wrote the paper: EGP RNJ KAS. Delineation of phenotype: NLR DHM KAS. Patient management, collection of samples, and summarization of clinical data: NLR DHM KAS.

                Puffenberger et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 15
                Research Article
                Computational Biology
                Population Genetics
                Evolutionary Biology
                Population Genetics
                Human Genetics
                Population Genetics
                Population Biology
                Population Genetics



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