Marie Ryan, Mark A Doherty, Ahmad Al Khleifat, Emmet Costello, Jennifer C Hengeveld, Mark Heverin, Ammar Al-Chalabi, Russell L Mclaughlin, Orla Hardiman
{"title":"<i>C9orf72</i> Repeat Expansion Discordance in 6 Multigenerational Kindreds.","authors":"Marie Ryan, Mark A Doherty, Ahmad Al Khleifat, Emmet Costello, Jennifer C Hengeveld, Mark Heverin, Ammar Al-Chalabi, Russell L Mclaughlin, Orla Hardiman","doi":"10.1212/NXG.0000000000200112","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objectives: </strong>A hexanucleotide repeat expansion in the noncoding region of the <i>C9orf72</i> gene is the most common genetically identifiable cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in populations of European ancestry. Pedigrees associated with this expansion exhibit phenotypic heterogeneity and incomplete disease penetrance, the basis of which is poorly understood. Relatives of those carrying the <i>C9orf72</i> repeat expansion exhibit a characteristic cognitive endophenotype independent of carrier status. To examine whether additional shared genetic or environmental risks within kindreds could compel this observation, we have conducted a detailed cross-sectional study of the inheritance within multigenerational Irish kindreds carrying the <i>C9orf72</i> repeat expansion.</p><p><strong>Methods: </strong>One hundred thirty-one familial ALS pedigrees, 59 of which carried the <i>C9orf72</i> repeat expansion (45.0% [95% CI 36.7-53.5]), were identified through the Irish population-based ALS register. <i>C9orf72</i> genotyping was performed using repeat-primed PCR with amplicon fragment length analysis. Pedigrees were further investigated using SNP, targeted sequencing data, whole-exome sequencing, and whole-genome sequencing.</p><p><strong>Results: </strong>We identified 21 kindreds where at least 1 family member with ALS carried the <i>C9orf72</i> repeat expansion and from whom DNA was available from multiple affected family members. Of these, 6 kindreds (28.6% [95% CI 11.8-48.3]) exhibited discordant segregation. The <i>C9orf72</i> haplotype was studied in 2 families and was found to segregate with the <i>C9orf72</i>-positive affected relative but not the <i>C9orf72</i>-negative affected relative. No other ALS pathogenic variants were identified within these discordant kindreds.</p><p><strong>Discussion: </strong>Family members of kindreds associated with the <i>C9orf72</i> repeat expansion may carry an increased risk of developing ALS independent of their observed carrier status. This has implications for assessment and counseling of asymptomatic individuals regarding their genetic risk.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 1","pages":"e200112"},"PeriodicalIF":3.0000,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10751011/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurology-Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1212/NXG.0000000000200112","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/2/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background and objectives: A hexanucleotide repeat expansion in the noncoding region of the C9orf72 gene is the most common genetically identifiable cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in populations of European ancestry. Pedigrees associated with this expansion exhibit phenotypic heterogeneity and incomplete disease penetrance, the basis of which is poorly understood. Relatives of those carrying the C9orf72 repeat expansion exhibit a characteristic cognitive endophenotype independent of carrier status. To examine whether additional shared genetic or environmental risks within kindreds could compel this observation, we have conducted a detailed cross-sectional study of the inheritance within multigenerational Irish kindreds carrying the C9orf72 repeat expansion.
Methods: One hundred thirty-one familial ALS pedigrees, 59 of which carried the C9orf72 repeat expansion (45.0% [95% CI 36.7-53.5]), were identified through the Irish population-based ALS register. C9orf72 genotyping was performed using repeat-primed PCR with amplicon fragment length analysis. Pedigrees were further investigated using SNP, targeted sequencing data, whole-exome sequencing, and whole-genome sequencing.
Results: We identified 21 kindreds where at least 1 family member with ALS carried the C9orf72 repeat expansion and from whom DNA was available from multiple affected family members. Of these, 6 kindreds (28.6% [95% CI 11.8-48.3]) exhibited discordant segregation. The C9orf72 haplotype was studied in 2 families and was found to segregate with the C9orf72-positive affected relative but not the C9orf72-negative affected relative. No other ALS pathogenic variants were identified within these discordant kindreds.
Discussion: Family members of kindreds associated with the C9orf72 repeat expansion may carry an increased risk of developing ALS independent of their observed carrier status. This has implications for assessment and counseling of asymptomatic individuals regarding their genetic risk.
期刊介绍:
Neurology: Genetics is an online open access journal publishing peer-reviewed reports in the field of neurogenetics. Original articles in all areas of neurogenetics will be published including rare and common genetic variation, genotype-phenotype correlations, outlier phenotypes as a result of mutations in known disease-genes, and genetic variations with a putative link to diseases. This will include studies reporting on genetic disease risk and pharmacogenomics. In addition, Neurology: Genetics will publish results of gene-based clinical trials (viral, ASO, etc.). Genetically engineered model systems are not a primary focus of Neurology: Genetics, but studies using model systems for treatment trials are welcome, including well-powered studies reporting negative results.