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Ramos E.M.,Massachusetts General Hospital | Ramos E.M.,University of Porto | Latourelle J.C.,Boston University | Lee J.-H.,Massachusetts General Hospital | And 26 more authors.
Human Genetics | Year: 2012

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and behavioral disturbances, caused by the expansion of a CAG trinucleotide repeat in the HD gene. The CAG allele size is the major determinant of age at onset (AO) of motor symptoms, although the remaining variance in AO is highly heritable. The rs7665116 SNP in PPARGC1A, encoding the mitochondrial regulator PGC-1α, has been reported to be a significant modiWer of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these Wndings in a large collection of (1,727) HD patient DNA samples of European origin. In the entire cohort, rs7665116 showed a significant effect in the dominant model (p value = 0.008) and the additive model (p value = 0.009). However, when examined by origin, cases of Southern European origin had an increased rs7665116 minor allele frequency (MAF), consistent with this being an ancestry-tagging SNP. The Southern European cases, despite similar mean CAG allele size, had a significantly older mean AO (p < 0.001), suggesting population-dependent phenotype stratiWcation. When the generalized estimating equations models were adjusted for ancestry, the effect of the rs7665116 genotype on AO decreased dramatically. Our results do not support rs7665116 as a modiWer of AO of motor symptoms, as we found evidence for a dramatic effect of phenotypic (AO) and genotypic (MAF) stratiWcation among European cohorts that was not considered in previously reported association studies. A significantly older AO in Southern Europe may reXect population diVerences in genetic or environmental factors that warrant further investigation. © The Author(s) 2012. Source

Morrison P.J.,Regional Medical Genetics Center | Morrison P.J.,Queens University of Belfast | Morrison R.J.,Queens University of Belfast | McKinstry C.S.,Royal Victoria Hospital
British Journal of Radiology | Year: 2012

Ossification of the stylohyoid ligament is very common in the Caucasian population. More than 9000 descriptions of apparently isolated case reports on PubMed have been cited over the last 20 years, often associated with an incidental finding on imaging after neck trauma. No cases of familial ossification have been described. We document a family with several affected members, each with an ossified stylohyoid ligament, confirming that ossification may be hereditary in some families and is most likely due to an autosomal dominant gene. © 2012 The British Institute of Radiology. Source

Kronn D.,New York Medical College | Kronn D.,Regional Medical Genetics Center | Mofidi S.,New York Medical College | Braverman N.,McGill University | Harris K.,New York State Department of Health
Genetics in Medicine | Year: 2010

Background: Recent expansion of the newborn screening panels has presented an interesting challenge to specialty care centers, especially the clinical genetics community. Some of the conditions in the core and secondary newborn screening panels have extremely variable clinical presentations; others are so rare that only a handful of newborns have been diagnosed with them to date (Region 4 Collaborative MS/MS project-http://region4genetics.org/msms-data- project/data-project-home.aspx). Definition of some disorders is problematic-does continued abnormality of the screening analyte constitute diagnosis or is further testing necessary? Methods: A work group of the New York Mid-Atlantic Consortium for Genetic and Newborn Screening Services (region 2), one of seven regional collaboratives funded by the Federal Health Resources and Services Administration and administered by the Maternal and Child Health Bureau (U22MC03956), has developed guidelines for the confirmation of diagnosis of the conditions in the newborn screening panels for use by the specialty care centers. Discussion: The diagnostic guidelines are a work in progress and are being reviewed and revised regularly as our understanding of the newborn screened disorders improves. The aim is to make it a relevant guide for specialty care physicians and other healthcare professionals in the diagnostic workup of these patients. © 2010 Lippincott Williams & Wilkins. Source

Ramos E.M.,Massachusetts General Hospital | Ramos E.M.,University of Porto | Latourelle J.C.,Boston University | Gillis T.,Massachusetts General Hospital | And 40 more authors.
Neurogenetics | Year: 2013

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3′ UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations. © 2013 The Author(s). Source

Lee J.-M.,Massachusetts General Hospital | Lee J.-M.,The Broad Institute of MIT and Harvard | Gillis T.,Massachusetts General Hospital | Mysore J.S.,Massachusetts General Hospital | And 36 more authors.
American Journal of Human Genetics | Year: 2012

Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of "synthetic association" with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for ∼50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for ∼83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder. © 2012 The American Society of Human Genetics. Source

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