Pub Date : 2022-09-01DOI: 10.1136/jnnp-2022-ehdn.47
Caroline S. Binda, Branduff McAllister, G. Menzies, Gareth Edwards, James Davies, L. Jones, Thomas H. Massey
{"title":"C03 FAN1 coding variants identified in individuals with Huntington’s disease implicate its nuclease activity and dna binding in age at onset","authors":"Caroline S. Binda, Branduff McAllister, G. Menzies, Gareth Edwards, James Davies, L. Jones, Thomas H. Massey","doi":"10.1136/jnnp-2022-ehdn.47","DOIUrl":"https://doi.org/10.1136/jnnp-2022-ehdn.47","url":null,"abstract":"","PeriodicalId":447196,"journal":{"name":"C: Genetic modifiers","volume":"48 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122438762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-01DOI: 10.1136/jnnp-2022-ehdn.50
K. Fears, Caroline S. Binda, Elin Miles, Thomas H. Massey, L. Jones
{"title":"C06 The role of FAN1 in HTT cag repeat instability and age at onset in the R6/1 mouse model of Huntington’s disease","authors":"K. Fears, Caroline S. Binda, Elin Miles, Thomas H. Massey, L. Jones","doi":"10.1136/jnnp-2022-ehdn.50","DOIUrl":"https://doi.org/10.1136/jnnp-2022-ehdn.50","url":null,"abstract":"","PeriodicalId":447196,"journal":{"name":"C: Genetic modifiers","volume":"3 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125946579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-01DOI: 10.1136/jnnp-2022-ehdn.52
Joseph Stone, Thomas H. Massey, Nicholas Allen, L. Jones
{"title":"C08 Knockout of mismatch repair genes MLH1 and MSH3 ablates expansion of the CAG repeat in a human iPSC model of Huntington’s disease","authors":"Joseph Stone, Thomas H. Massey, Nicholas Allen, L. Jones","doi":"10.1136/jnnp-2022-ehdn.52","DOIUrl":"https://doi.org/10.1136/jnnp-2022-ehdn.52","url":null,"abstract":"","PeriodicalId":447196,"journal":{"name":"C: Genetic modifiers","volume":"91 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124683509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-01DOI: 10.1136/jnnp-2022-ehdn.54
Sowmya Devatha Venkatesh, M. Varghese, Ravikant Yadav, S. Jain, M. Purushottam
{"title":"C10 Haplotype structure analysis of Indian Huntington’s disease patients at HTT gene locus","authors":"Sowmya Devatha Venkatesh, M. Varghese, Ravikant Yadav, S. Jain, M. Purushottam","doi":"10.1136/jnnp-2022-ehdn.54","DOIUrl":"https://doi.org/10.1136/jnnp-2022-ehdn.54","url":null,"abstract":"","PeriodicalId":447196,"journal":{"name":"C: Genetic modifiers","volume":"6 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127260352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-01DOI: 10.1136/jnnp-2022-ehdn.56
Davina J. Hensman Moss, Anupriya Dalmia, Valentina Galassi Deforie, K. Ibáñez, S. Tabrizi, N. Lahiri, H. Houlden, P. Holmans, L. Jones, A. Tucci
{"title":"C12 HTT repeat instability in family trios in the 100,000 genomes project","authors":"Davina J. Hensman Moss, Anupriya Dalmia, Valentina Galassi Deforie, K. Ibáñez, S. Tabrizi, N. Lahiri, H. Houlden, P. Holmans, L. Jones, A. Tucci","doi":"10.1136/jnnp-2022-ehdn.56","DOIUrl":"https://doi.org/10.1136/jnnp-2022-ehdn.56","url":null,"abstract":"","PeriodicalId":447196,"journal":{"name":"C: Genetic modifiers","volume":"40 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123535615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-01DOI: 10.1136/jnnp-2022-ehdn.55
Alessia Squitieri, Ludovica C Busi, Marco Di Marsico, F. Perrone, T. Mazza, R. Aiese Cigliano, F. Squitieri
{"title":"C11 Identifying loss-of-interruptions (LOI) in huntington disease families of Italian origin","authors":"Alessia Squitieri, Ludovica C Busi, Marco Di Marsico, F. Perrone, T. Mazza, R. Aiese Cigliano, F. Squitieri","doi":"10.1136/jnnp-2022-ehdn.55","DOIUrl":"https://doi.org/10.1136/jnnp-2022-ehdn.55","url":null,"abstract":"","PeriodicalId":447196,"journal":{"name":"C: Genetic modifiers","volume":"16 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129956353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-01DOI: 10.1136/jnnp-2022-ehdn.51
Ross Ferguson, M. Flower, S. Tabrizi
{"title":"C07 A CRISPRI platform to assess the role of HD risk modifiers in CAG repeat expansion in iPSC derived striatal neurons","authors":"Ross Ferguson, M. Flower, S. Tabrizi","doi":"10.1136/jnnp-2022-ehdn.51","DOIUrl":"https://doi.org/10.1136/jnnp-2022-ehdn.51","url":null,"abstract":"","PeriodicalId":447196,"journal":{"name":"C: Genetic modifiers","volume":"40 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131594232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-01DOI: 10.1136/jnnp-2022-ehdn.49
Jasmine Donaldson, Joseph Hamilton, Jessica F. Olive, R. Goold, S. Tabrizi
{"title":"C05 The role of FAN1 nuclease activity and mlh1 binding in stabilisation of the cag repeat in HD-IPSC derived models","authors":"Jasmine Donaldson, Joseph Hamilton, Jessica F. Olive, R. Goold, S. Tabrizi","doi":"10.1136/jnnp-2022-ehdn.49","DOIUrl":"https://doi.org/10.1136/jnnp-2022-ehdn.49","url":null,"abstract":"","PeriodicalId":447196,"journal":{"name":"C: Genetic modifiers","volume":"45 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132035913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-05-29DOI: 10.1101/2022.05.28.22275723
S. Gebre-Medhin, K. Dalene Skarping, A. Petersen
Patients with Lynch syndrome (LS) are prone to cancer due to heterozygous germline pathogenic variants in genes encoding DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. LS cancer cells exhibit deficient DNA mismatch repair and microsatellite instability due somatic inactivation of the second copy of the affected gene. To study microsatellite characteristics in non-neoplastic cells in LS we determined CAG repeat size in the huntingtin gene (HTT) microsatellite in lymphocyte DNA from LS patients with germline pathogenic variants in MLH1 (n = 11), MSH2 (n = 9), MSH6 (n = 7) and non-LS controls (n=19). Mean repeat size in LS was 19,55 CAG (MLH1), 19,39 CAG (MSH2), 18.07 CAG (MSH6), respectively compared to 18,42 CAG in controls. Standard deviation for CAG repeat size in LS was 4,183 CAG (MLH1), 5,089 CAG (MSH2), 3,075 CAG (MSH6), respectively, compared to 3,342 CAG in controls. Peak CAG repeat size in LS was 32 CAG (MLH1), 32 CAG (MSH2), 24 CAG (MSH6), respectively compared to 27 CAG in controls. Collectively, our data indicate that HTT CAG repeat size tends to be larger and more variable in individuals with LS caused by pathogenic variants in MLH1 and MSH2.
{"title":"Huntingtin gene CAG repeat size in patients with Lynch syndrome","authors":"S. Gebre-Medhin, K. Dalene Skarping, A. Petersen","doi":"10.1101/2022.05.28.22275723","DOIUrl":"https://doi.org/10.1101/2022.05.28.22275723","url":null,"abstract":"Patients with Lynch syndrome (LS) are prone to cancer due to heterozygous germline pathogenic variants in genes encoding DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. LS cancer cells exhibit deficient DNA mismatch repair and microsatellite instability due somatic inactivation of the second copy of the affected gene. To study microsatellite characteristics in non-neoplastic cells in LS we determined CAG repeat size in the huntingtin gene (HTT) microsatellite in lymphocyte DNA from LS patients with germline pathogenic variants in MLH1 (n = 11), MSH2 (n = 9), MSH6 (n = 7) and non-LS controls (n=19). Mean repeat size in LS was 19,55 CAG (MLH1), 19,39 CAG (MSH2), 18.07 CAG (MSH6), respectively compared to 18,42 CAG in controls. Standard deviation for CAG repeat size in LS was 4,183 CAG (MLH1), 5,089 CAG (MSH2), 3,075 CAG (MSH6), respectively, compared to 3,342 CAG in controls. Peak CAG repeat size in LS was 32 CAG (MLH1), 32 CAG (MSH2), 24 CAG (MSH6), respectively compared to 27 CAG in controls. Collectively, our data indicate that HTT CAG repeat size tends to be larger and more variable in individuals with LS caused by pathogenic variants in MLH1 and MSH2.","PeriodicalId":447196,"journal":{"name":"C: Genetic modifiers","volume":"170 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116418559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-09-01DOI: 10.1136/jnnp-2021-ehdn.28
S. Lobanov, Branduff McAllister, M. McDade-Kumar, Jong-Min Lee, M. MacDonald, J. Gusella, M. Ryten, N. Williams, P. Holmans, Thomas H. Massey, L. Jones
Background The length of the HTT CAG repeat explains around 60% of the variance in Huntington’s disease (HD) age at onset. Recently, genome-wide association studies (GWAS) of HD age at onset have identified multiple single nucleotide variants (SNVs) that influence onset, including an intronic SNV, rs79727797, in TCERG1 (p=3.76E-10). Aims Since the SNV does not modify the protein or appear to change gene expression, we tested whether the GWAS signal is due to genetic variation not present in the GWAS. Methods/Techniques We developed a novel method for calling perfect and imperfect short tandem repeats from whole exome sequencing (WES) data, and applied it to 610 WES samples from HD individuals with age at onset or cognitive test data discrepant from those predicted by their HTT CAG length. We identified an exonic (CAGGCC)n short tandem repeat in TCERG1 previously reported to be associated with altered HD age at onset. The reference allele is (CAGGCC)6. We identified 5 length alleles with 3 to 8 hexamer repeats. Results/Outcome Reduced repeat length is significantly associated with later HD age-at-onset (sum of repeat from both TCERG1 repeat alleles: p=6.51E-9). The (CAGGCC)3 allele (frequency 4.1%) is in linkage disequilibrium (r2=0.98) with the minor allele at rs79727797, associated with later onset in the GWAS. Conditioning the association of rs79727797 on TCERG1 (CAGGCC)n length reduces its significance from p=2.4E-6 to p=0.96, while STR length is still significantly associated with HD age at onset after conditioning on rs79727797 (p=3.9E-4). This indicates that the repeat, rather than rs79727797, is responsible for the association at this locus. Conclusion The GWAS signal in TCERG1 is attributable to a short tandem repeat, rather than SNVs. Further biological study of the mechanism by which it alters HD age at onset is warranted.
{"title":"C04 Protein coding tandem repeat in TCERG1 modifies huntington’s disease onset","authors":"S. Lobanov, Branduff McAllister, M. McDade-Kumar, Jong-Min Lee, M. MacDonald, J. Gusella, M. Ryten, N. Williams, P. Holmans, Thomas H. Massey, L. Jones","doi":"10.1136/jnnp-2021-ehdn.28","DOIUrl":"https://doi.org/10.1136/jnnp-2021-ehdn.28","url":null,"abstract":"Background The length of the HTT CAG repeat explains around 60% of the variance in Huntington’s disease (HD) age at onset. Recently, genome-wide association studies (GWAS) of HD age at onset have identified multiple single nucleotide variants (SNVs) that influence onset, including an intronic SNV, rs79727797, in TCERG1 (p=3.76E-10). Aims Since the SNV does not modify the protein or appear to change gene expression, we tested whether the GWAS signal is due to genetic variation not present in the GWAS. Methods/Techniques We developed a novel method for calling perfect and imperfect short tandem repeats from whole exome sequencing (WES) data, and applied it to 610 WES samples from HD individuals with age at onset or cognitive test data discrepant from those predicted by their HTT CAG length. We identified an exonic (CAGGCC)n short tandem repeat in TCERG1 previously reported to be associated with altered HD age at onset. The reference allele is (CAGGCC)6. We identified 5 length alleles with 3 to 8 hexamer repeats. Results/Outcome Reduced repeat length is significantly associated with later HD age-at-onset (sum of repeat from both TCERG1 repeat alleles: p=6.51E-9). The (CAGGCC)3 allele (frequency 4.1%) is in linkage disequilibrium (r2=0.98) with the minor allele at rs79727797, associated with later onset in the GWAS. Conditioning the association of rs79727797 on TCERG1 (CAGGCC)n length reduces its significance from p=2.4E-6 to p=0.96, while STR length is still significantly associated with HD age at onset after conditioning on rs79727797 (p=3.9E-4). This indicates that the repeat, rather than rs79727797, is responsible for the association at this locus. Conclusion The GWAS signal in TCERG1 is attributable to a short tandem repeat, rather than SNVs. Further biological study of the mechanism by which it alters HD age at onset is warranted.","PeriodicalId":447196,"journal":{"name":"C: Genetic modifiers","volume":"23 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127068320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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