Phenylalanine hydroxylase deficiency exhibits mutation heterogeneity in two large old order Amish settlements

Das Deutsch Center (DDC) Clinic for Special Needs Children, Middlefield, Ohio 44062, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 08/2007; 143A(16):1938-40. DOI: 10.1002/ajmg.a.31852
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    • "One of the known pitfalls of homozygosity mapping is allelic heterogeneity, meaning that there are multiple deleterious variants of the same gene in the population and hence affected individuals may be compound heterozygotes for two mutations (Miano et al. 2000). Indeed, allelic heterogeneity has been documented for at least two disorders prevalent in the OOA: phenylalanine hydroxylase deficiency (Wang et al. 2007) and Cohen syndrome (Taban et al. 2007); in the case of Cohen syndrome, there are affected OOA individuals who are compound heterozygotes for two mutations of the causative gene, VPS13B (Taban et al. 2007). If one wants to avoid the allelic heterogeneity pitfall, one can use Ped- Hunter (Agarwala et al. 1998; Lee et al. 2010) to automatically and systematically extract from AGDB (Agarwala et al. 2003) pedigrees that connect all the obligate carriers and affected individuals. "
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    ABSTRACT: Genome mapping in animals is now one of the leading disciplines in animal sciences. It is employed for all facets in genome analysis in animals and their improvement for benefit of human beings. Mapping of genomes in farm animals, companion animals, laboratory animals, aquatic animals, insects, and primates, including humans have generated stupendous data bases to elucidate origin, evolution, phylogenetic relationship; position of genes; function, expression, regulation and sequence of genes. This information has tremendous applied value in agriculture, medicine, and environmental sciences. Paradoxically the information is mainly scattered only on the pages of journals, review papers and project/institutional reports. It is imperative now to have a comprehensive compilation of all these research findings in a single series for easy access to all levels of end users. The series Genome Mapping in Animals will fill this gap. It will provide comprehensive and up to date reviews on a large variety of selected animals systems contributed by teams of leading scientists from around the world.
    Volume 5 edited by R. Duggirala, L. Almasy, S. Williams-Blangero, S.F.D. Paul, C. Kole, 01/2015; Springer-Verlag GmbH Berlin Heidelberg., ISBN: Genome Mapping and Genomics in Animals ISBN 978-3-662-46305-5 ISBN 978-3-662-46306-2 (eBook)
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    ABSTRACT: Hypertrophic cardiomyopathy is one of the most common inherited cardiac disorders, with a prevalence of 1:500 in the general population. We have recently reported a severe neonatal hypertrophic cardiomyopathy caused by a novel homozygous splice site c.3330 + 2 T > G mutation in the MYBPC3 gene in an Amish community. The affected children typically presented with signs and symptoms of congestive heart failure during the first three weeks of life, and most of them died before one year of age unless they received a heart transplant. Since the condition is inherited in an autosomal dominant pattern with incomplete penetrance, further studies to understand the clinical course in the heterozygous carrier of c.3330 + 2 T > G mutation were performed when we provided the service of carrier testing in the community. The preliminary results indicated a relatively low incidence of the phenotypic expression of hypertrophic cardiomyopathy, although the disease was identified in a few heterozygous carriers before they reached to their adolescence. Significant variation of the phenotypic expression suggests the complexity of the disease development. The Amish community is often composed of genetically and geographically isolated, large, multigenerational families with similar environmental influences, and potentially harbors a reduced number of risk factors compared to a more heterogeneous population. Therefore, our further study will not only benefit the Amish population but also will help us to understand the hypertrophic cardiomyopathy as a whole, for the disease development, diagnosis, treatment, and prognosis. Partnering with the community to establish solid, trustful relationships with the affected families and to provide much needed services to them has been the key to success in the past and will remain essential for our future study.
    Progress in Pediatric Cardiology 05/2011; 31(2):129-134. DOI:10.1016/j.ppedcard.2011.02.011

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