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  • Genetic loading in familial migraine with aura.

    24 October 2018

    Migraine with aura (MA) arises from a combination of genetic and environmental factors. The sibling risk, age at onset, and aura type were compared in 54 MA probands categorised by family history of MA. Three family types were ascertained each having an MA proband and: (1) an MA parent and MA offspring (three generation; n=15), (2) either an MA parent or an MA offspring (two generation; n=20), and (3) neither an MA parent nor an MA offspring (one generation; n=19). The crude recurrence risk to siblings of probands was 2.7-fold higher in three generation compared with two generation MA families (chi(2)=6.24, p=0.0125) and 4.8-fold higher in three generation compared with one generation MA families (chi(2)=9.95, p<0.002). The mean age at onset decreased with an increase in genetic load. The MA probands from three generation families were significantly younger than probands from the one generation families (F=5.14, p=0.030). MA probands from three generation families were more likely to report more than one type of aura than MA probands from two generation families (chi(2)=4.44, p=0.035). The significant difference in genetic loading and the earlier age at onset in the three generation families add further evidence for a genetic basis for MA and the difference in sibling risks demonstrates that the MA population is heterogeneous.

  • Follow-up investigation of 12 proposed linkage regions in multiple sclerosis.

    24 October 2018

    Multiple sclerosis (MS) is an autoimmune disease with overwhelming evidence for genetic determination, and for which a maternal parent-of-origin effect has been reported. As with many complex diseases, multiple suggestive linkage signals have been observed. However, the only unambiguous association and linkage identified to date is with alleles of the human lymphocyte antigen (HLA) class II region. We have now carried out high-density microsatellite genotyping for 12 of the most promising regions (1p, 1q, 2q, 4q, 5p, 9q, 10p, 11p, 12q, 17q, 18p, 19p) from a whole-genome scan in 552 affected sibling pairs. This has been carried out in 194 families containing avuncular pairs. These permit examination of parent-of-origin effects in non-colineal pairs when divided into likely maternal and paternal trait transmission. The results do not confirm any non-major histocompatibility complex linkage in the overall subset nor in the maternal, paternal or HLA-DRB1*1501 subsets. We were able to establish exclusion for a locus with lambda(AV) > or = 1.3 for all the previously suggested regions. These results again raise the possibility that the paradigm of multiple genes of small individual effect used to justify genome searches in MS is incorrect.

  • A multigenerational family with multiple sclerosis.

    24 October 2018

    We report a family with 15 individuals affected with multiple sclerosis present in three and possibly four generations. The segregation of multiple sclerosis within this pedigree is consistent with an autosomal dominant mode of inheritance with reduced penetrance. The clinical characteristics of the affected individuals are indistinguishable from those seen in sporadic multiple sclerosis with respect to sex ratio, age at onset, onset symptom, MRI and clinical course. Eleven of 14 cases (78.6%) were positive for the known multiple sclerosis-associated major histocompatibility complex (MHC) Class II HLA DRB1*15 allele. Parametric linkage analysis gave a non-significant LOD score of 0.31 (theta; = 0.33) for the DRB1 gene. However, among 11 affected children with at least one DRB1*15 bearing parent, all 11 out of 11 received at least one copy of this known susceptibility allele. A transmission disequilibrium test analysis was significant for the DRB1*15 allele within this single family; P = 0.0054. The inheritance pattern in this family suggests the presence of a single major locus responsible for multiple sclerosis susceptibility, with DRB1 acting as an important modifier. This family could be an important resource for the identification of a multiple sclerosis susceptibility gene.

  • A genome scan in a single pedigree with a high prevalence of multiple sclerosis.

    24 October 2018

    BACKGROUND: Multiple sclerosis (MS) is a disease that is widely believed to be autoimmune in nature. Genetic-epidemiological studies implicate susceptibility genes in the pathogenesis of MS, although non-MHC susceptibility linkages have been difficult to confirm. Insight into pathways that are intrinsic to other complex diseases has come from the genetic analysis of large, autosomal-dominant kindreds. Here, we present a genetic study of a large and unique kindred in which MS appears to follow an autosomal-dominant pattern of inheritance, with consistent penetrance in four generations. METHODS: Eighty-two individuals of this 370-member family were genotyped with 681 microsatellite markers spanning the genome, with an average spacing of 5.3 cM. RESULTS: Parametric linkage analysis was performed and no significant LOD score (LOD >3.3) was observed. For a rare dominant disease model with reduced penetrance, 99.6% of the genome was excluded at a LOD score <-1 and 96% at a LOD score <-2. The HLA-DRB1 candidate gene was also genotyped by allele-specific methods. In each instance where at least one parent was positive for HLA-DRB1*15, one or more HLA-DRB1*15 alleles were transmitted to the affected offspring (11/11). HLA-DRB1*15 was transmitted equally from both the familial and the married-in parents and therefore this locus does not appear to be an autosomal-dominant acting gene in this family but an important modifier of risk. CONCLUSIONS: These results further stress the importance of the HLA-DRB1*15-bearing haplotype in determining MS susceptibility. Furthermore, this study highlights the complexity of MS genetics, even in the presence of a single family, seemingly segregating MS as an autosomal-dominant trait.

  • An autosomal dominant disorder with episodic ataxia, vertigo, and tinnitus.

    24 October 2018

    The authors report an autosomal dominant episodic ataxia that is clinically distinct from the other episodic ataxias. Vestibular ataxia, vertigo, tinnitus, and interictal myokymia are prominent; attacks are diminished by acetazolamide. Linkage analyses of markers flanking the EA1 and EA2 loci demonstrate genetic exclusion from the other autosomal dominant episodic ataxias. The authors suggest EA3 for periodic vestibulocerebellar ataxia and EA4 for the disorder described here.

  • Complex interactions among MHC haplotypes in multiple sclerosis: susceptibility and resistance.

    24 October 2018

    Mechanisms for observed associations within the major histocompatibility complex (MHC) and autoimmune diseases including multiple sclerosis (MS) remain uncertain. Genotyping of the HLA Class II DRB1 locus in 4347 individuals from 873 multiplex families with MS highlights the genetic complexity of this locus. Excess allele sharing in sibling pair families lacking DRB1*15 and DRB1*17 (58.5% sharing; P=0.012) was comparable to that seen where parents were DRB1*15 positive (62%, P=0.0006). DRB1*17 (P=0.00027) was clearly established as an MS susceptibility allele in addition to DRB1*15 (P<10(-14)). DRB1*14 showed striking under-transmission (P=0.000032) to affected offspring newly establishing this allele as a broadly acting resistance factor. Trans interactions were seen in both DRB1*15 and non-DRB1*15 bearing genotype combinations. DRB1*08 was transmitted preferentially with DRB1*15 (P=0.0114) and, in the presence of DRB1*08, the transmission of DRB1*15 was almost invariable (37 transmissions to one non-transmission). DRB1*01 was under-transmitted to offspring in the presence of DRB1*15 (P=0.019). Both DRB1*01 and DRB1*14 haplotypes carry DQA1*01-DQB1*05 alleles, suggesting a common DQ-related mechanism for the protection mediated by these haplotypes. These studies demonstrate that it is the Class II genotype that determines susceptibility and resistance to MS. By analogy with celiac disease and type I diabetes, the pattern of susceptibility strongly supports an autoimmune aetiology.

  • An extended genome scan in 442 Canadian multiple sclerosis-affected sibships: a report from the Canadian Collaborative Study Group.

    24 October 2018

    Multiple sclerosis (MS) is a complex trait with a sibling relative risk (lambda(sibs)) between 18 and 36. We report a multistage genome scan of 552 sibling pairs from 442 families, the largest MS family sample assessed for linkage. The first stage consisted of a genome scan for linkage with 498 microsatellite markers at an average spacing of 7 cM in 219 sibling pairs. The second stage involved further genotyping of markers from positive regions in an independent sample of 333 affected sibling pairs. The global distribution of allele sharing for all markers showed a shift towards greater sharing within the affected sibling pair group but not in the discordant sibling pair group. This shift indicates that the number of contributing genetic factors is likely to be moderate to large. Only markers at chromosome 6p showed significant evidence for linkage (MLOD=4.40), while other regions were only suggestive (1p, 2q, 5p, 9q, 11p, 12q, 18p, 18q and 21q) with MLODs greater than 1.0. The replication analysis involving all 552 affected sibling pairs confirmed suggestive evidence for five locations, namely, 2q27 (MLOD=2.27), 5p15 (MLOD=2.09), 18p11 (MLOD=1.68), 9q21 (MLOD=1.58) and 1p31 (MLOD=1.33). Suggestive linkage evidence for a previously reported location on chromosome 17q (MLOD=1.67) and a prior association with marker D17S789 was replicated. We showed that the overall excess allele sharing we observed for the entire sample was due to increased allele sharing within the DRB1*15 negative subgroup alone. This observation is most consistent with a model of genetic heterogeneity between HLA and other genetic loci. These findings offer guidance for future genetic studies including dense SNP linkage disequilibrium analysis.

  • A genome-wide screen and linkage mapping for a large pedigree with episodic ataxia.

    24 October 2018

    Episodic ataxias are ion channel disorders characterized by attacks of incoordination. The authors performed a genome-wide screen in a large pedigree segregating a novel episodic ataxia and found significant linkage on 1q42 with a multipoint lod score of 3.65. Haplotype analysis and fine mapping yielded a peak 2-point lod score of 4.14 and indicated a 4-cM region on 1q42 that is likely to harbor an episodic ataxia gene.

  • Migraine with aura is not linked to the FHM gene CACNA1A or the chromosomal region, 19p13.

    24 October 2018

    Two microsatellite markers, tightly linked to CACNA1A, were genotyped in migraine with aura (MA) families to determine if this gene, which underlies the 19p13 linked forms of familial hemiplegic migraine, is also linked to MA. Two-point parametric lod and nonparametric linkage scores did not support linkage. Transmission disequilibrium testing provided no evidence for linkage of MA to CACNA1A. In a large dataset of 64 Canadian MA families, the authors did not find evidence to support an MA susceptibility gene in the region of 19p13.