Family-Based Whole Genome Sequence Analysis Uncovers Age Onset Modifiers of Huntington's Disease
Julia KayeLeandro de Araújo LimaAlexander R. PicoStephanie LamMichela TragliaMinnie DengSid MahajanMin‐Gyoung ShinReuben ThomasAaron DaubIan H. KratterHengameh ZahedMariah DunlapHanna MayLisa JoLise BarbéElaine RobyAlexandra NelsonAlisha K. HollowayTammy GillisMarcy E. MacDonaldJacqueline Gray JacksonHong LiGustavo GlusmanJared C. RoachChristopher A. RossTatiana ForoudStacia K. WymanSteven Finkbeiner
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Abstract:
Huntington’s disease (HD) is a monogenic disorder that is caused by a CAG repeat expansion in the HTT gene. However, beyond the CAG repeat size other genes also contribute to variations in neurodegeneration of the cortex and striatum as well as the timing of disease onset1,2. The standard method to find genetic modifiers of HD has been the use of genome-wide association studies (GWAS) of large numbers of unrelated patients1,3-5. Previous efforts in this vein have identified single nucleotide variants (SNVs) significantly associated with pathways involved in DNA damage and handling that modify HD age of onset (AO)1,3-8. However, many of these associations have small effect sizes, and typically it is not known whether the SNVs identified with GWAS are the basis for the modifying effect. Here, to augment modifier GWAS, we set out to identify variants that may modify AO in HD by performing family-based studies. We performed whole genome sequencing in families with HD in which individuals with similar CAG expansions showed variation in AO (ranging from a 3- to 20-year difference). We examined the segregation of every variant in the genome and associated the occurrence of those variants with AO. Focusing on rare and uncommon variants, we used a priori knowledge to examine the proximity of our top variants to previously reported GWAS loci. Further, we developed an HD impact scoring system to rank each variant and highlight those most likely to be impactful in the context of influencing the pathology associated with the CAG repeat expansion mutation. Pathway enrichment analysis of these genes revealed numerous pathways previously implicated in HD, as well as novel pathways that may be important in disease onset. Finally, we showed that a putative AO modifier in the ovarian-tumor-domain-containing deubiquitinase 3 (OTUD3) gene correlated with an altered rate of degeneration in patient-derived neurons, and that knockdown of OTUD3 accelerated degeneration in a human cell model of HD, validating our approach. This family-based strategy creates a novel resource for the HD community and establishes a framework that could be applied to study genetic modifiers of many other rare familial diseases.Keywords:
Sequence (biology)
Huntington’s Disease is a progressive, adult onset, neurodegenerative disease. It is inherited in an autosomal dominant fashion and is caused by a trinucleotide repeat expansion in huntingtin, which encodes the protein huntingtin. The length of the expanded trinucleotide repeats accounts for some, but not all of the age of onset of the condition. Despite the monogenic basis of Huntington’s disease, the clinical features display marked variability within families and between those who carry the same length expansion. The variability in age of onset and in clinical features is likely to be due to a number of environmental and other genetic factors. Identification of these factors may lead to novel therapeutic approaches. A number of potential disease modifying agents have been elucidated and are approaching clinical trials. Robust ‘biomarkers’ of disease onset and progression are essential for developing a framework for future clinical trials that have the ability to judge the efficacy of any therapeutic intervention. In this thesis I will present work arising from TRACK-HD, an international observational biomarker study of Huntington’s Disease which has identified a panel of biomarkers for use in future clinical trials. A number of subs-studies arising from TRACK-HD are also presented here. Firstly, a study investigating the use of Positron Emission Tomography and peripheral immune markers as biomarkers of disease progression followed by a candidate genetic modifier study focusing on immune pathways as genetic modifiers of age of onset in Huntington’s Disease.
Huntingtin Protein
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In a recent publication Brackenridge and Teltscher (1975) concluded that the age of onset of Huntington9s disease was in part a function of the age of the transmitting parent at the time of birth of a subsequently affected child. Their analysis suggested that the younger the parent was at the time of birth of the subsequently affected child, the later in life symptoms of disease would appear in the child. The data of Brackenridge and Teltscher have been statistically reevaluated here, and this analysis fails to support their conclusion. Consequently it would be irresponsible to counsel persons at risk for Huntington9s disease to plan families early in life.
Paternal age
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Medical genetics is currently enjoying a time of exploration and discovery. Huntington disease has long been of interest in adult medicine. The onset of clinical signs and symptoms is usually delayed until midadulthood. It may seem strange in this context to focus on Huntington disease, but advances in molecular genetics have brought Huntington disease into the purview of pediatrics.These advances in molecular genetics make it possible to detect Huntington disease in a preclinical stage at or even before birth. The molecular approach does not replace prior approaches to Huntington disease but is synergistic and provides a model of the new genetics.Huntington disease is synonymous with Huntington chorea. It is named after George Huntington who, like his father and grandfather before him, studied the disease in families on Long Island, NY.Huntington disease is a more common hereditary disorder than phenylketonuria, which occurs in one of about 10,000 newborns in the United States. By contrast, about one in 2,000 persons is at risk for Huntington disease.Although most cases start clinically in midadulthood, usually between 35 and 42 years of age, there is great variability in age of onset. About 3% of cases are diagnosed as juvenile Huntington disease before the age of 15 years. Late onset is well known after 50 years of age.
Medical genetics
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Medical genetics is currently enjoying a time of exploration and discovery. Huntington disease has long been of interest in adult medicine. The onset of clinical signs and symptoms is usually delayed until midadulthood. It may seem strange in this context to focus on Huntington disease, but advances in molecular genetics have brought Huntington disease into the purview of pediatrics. These advances in molecular genetics make it possible to detect Huntington disease in a preclinical stage at or even before birth. The molecular approach does not replace prior approaches to Huntington disease but is synergistic and provides a model of the new genetics. Huntington disease is synonymous with Huntington chorea. It is named after George Huntington who, like his father and grandfather before him, studied the disease in families on Long Island, NY. Huntington disease is a more common hereditary disorder than phenylketonuria, which occurs in one of about 10,000 newborns in the United States. By contrast, about one in 2,000 persons is at risk for Huntington disease. Although most cases start clinically in midadulthood, usually between 35 and 42 years of age, there is great variability in age of onset. About 3% of cases are diagnosed as juvenile Huntington disease before the age of 15 years. Late onset is well known after 50 years of age.
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ABSTRACT The sequence of the genome of “ Candidatus Tremblaya princeps” strain PCVAL, the primary endosymbiont of the citrus mealybug Planococcus citri , has been determined. “ Ca . Tremblaya princeps” presents an unusual nested endosymbiosis and harbors a gammaproteobacterial symbiont within its cytoplasm in all analyzed mealybugs. The genome sequence reveals that “ Ca . Tremblaya princeps” cannot be considered an independent organism but that the consortium with its gammaproteobacterial symbiotic associate represents a new composite living being.
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Abstract Huntington disease is still under‐diagnosed by neurologists and psychiatrists –particularly in the elderly population. Dr Teodorczuk explores the reasons for under‐diagnosis and misdiagnosis and provides an update on the features of Huntington disease with an emphasis on late‐onset disease. Copyright © 2007 Wiley Interface Ltd
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A set of male monozygotic twins concordant for Huntington's disease is described. The monozygosity of the twins and the diagnosis of Huntington's disease are well established. The twins are now age 30, and although the severity of their chorea differs, they have a similar degree of mental deficit. This family is of additional interest because the daughter of one of the twins has childhood Huntington's disease, and the mother of the twins had the adult-onset rigid variant of the disease. Such unusual families afford some insight into the variability of the clinical manifestations of this hereditary disease.
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Huntington disease (HD) is a severe neurodegenerative disorder for which there is a critical need of disease modifying drugs. Clinical onset typically occurs between the age of 30 and 50, and the disease evolves over 15 to 20 years with worsening psychiatric, motor, and cognitive symptoms (Novak and Tabrizi, 2010).
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Background/Aim
Huntington’s disease (HD) is a severe late-onset autosomal dominant neurodegenerative disorder. The goal of our research was the investigation of the features of the reproductive behaviour in HD patients.Methods
Fertility in 78 patients with HD (mean age 52 years; range = 27–80) and 85 healthy sibs (mean age 51 years; range = 25–80) that were under observation over the period between 1970 and 2000 was analysed.Results
Conjugality among the patients with HD constituted 89.7%, among their healthy sibs – 84.7% (p = 0.5). The early onset of the disease limited marrying and patients’ fertility in marriage. Mean age of the disease manifestation of the patients that were childless (29.5 ± 10.8 years) or the patients that had only one child (31.8 ± 9.8 years) differed from the age of the disease manifestation of the patients that had two or more children (40.4 ± 8.9 years; p < 0.05). The average number of live-birth infants in the families of the HD patients and their healthy sibs was not significantly different from each other (2.9 vs. 2.7; p = 0.2). The infant mortality rate in the families of the HD patients constituted 7.5% (in the families of the healthy sibs the infant mortality was not registered). The rate of childless marriages significantly exceeded among the families of the healthy sibs in comparison with the families of the HD patients (9.7% vs. 2.8%, p < 0.05).Conclusion
The disease did not impact significantly on the reproductive behaviour of patients in case of late-onset manifestation.Cite
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