Rare Disease Genes—Lessons and Challenges

Peltonen, Leena; Uusitalo, Arja

doi:10.1101/gr.7.8.765

Cited by 18 publications

(11 citation statements)

References 16 publications

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“…Thus, the size of the conserved haplotype might be explained in part by the overrepresentation of male transmission in our families. Also, strong haplotype conservation has been reported for families with FAMMM syndrome from the same geographical area (Gruis et al 1995), as well as for other founder populations (Peltonen and Uusitalo 1997), and therefore might not be uncommon. Nevertheless, because of the finding that genomic imprinting may interfere with sex-specific recombination rates (Paldi et al 1995;Robinson and Lalande 1995), it is tempting to speculate that the PGL1 mutation that is responsible for HN-paragangliomas also affects recombination rates in this region of chromosome 11.…”

Section: Figurementioning

confidence: 88%

Founder Effect at PGL1 in Hereditary Head and Neck Paraganglioma Families from The Netherlands

Schothorst

Jansen

Grooters

et al. 1998

The American Journal of Human Genetics

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PGL1, a gene responsible for hereditary paragangliomas of the head and neck, recently was mapped to a 2-cM interval on chromosome 11q22-q23, by linkage and haplotype-sharing analysis of a large multibranch Dutch family. We determined the disease-linked haplotype, as defined by 13 markers encompassing a large interval on 11q21-q23, in 10 additional families ascertained from the same geographical locale. Alleles were identical for six contiguous markers, spanning a genetic distance of 6 cM and containing PGL1. Despite this strong indication of a common ancestor, no kinships between the families could be demonstrated through genealogical surveys going back to 1800 a.d. We conclude that a single ancestral mutation is responsible for most, if not all, hereditary paragangliomas, in this region of The Netherlands, and that strong founder effects may exist at the PGL1 locus.

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Section: Figurementioning

confidence: 88%

Founder Effect at PGL1 in Hereditary Head and Neck Paraganglioma Families from The Netherlands

Schothorst

Jansen

Grooters

et al. 1998

The American Journal of Human Genetics

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“…We further utilized the characteristics of the isolated Finnish population by analyzing the ancient haplotypes surrounding the CLD locus. Previous molecular genetic studies of the Finnish diseases have shown that, characteristically, one major haplotype or allele has been enriched in disease chromosomes, reflecting one founder mutation (Peltonen and Uusitalo 1997). In CLD, core haplotype 2-2, formed by the closest markers to the CLD locus, D2S314 and D2S2385, was present in 82% of the affected chromosomes and in none of the unaffected chromosomes.…”

Section: Figurementioning

confidence: 95%

Assignment of the Locus for Congenital Lactase Deficiency to 2q21, in the Vicinity of but Separate from the Lactase-Phlorizin Hydrolase Gene

Järvelä

Enattah

Kokkonen

et al. 1998

The American Journal of Human Genetics

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Congenital lactase deficiency (CLD) is an autosomal recessive, gastrointestinal disorder characterized by watery diarrhea starting during the first 1-10 d of life, in infants fed lactose-containing milks. Since 1966, 42 patients have been diagnosed in Finland. CLD is the most severe form of lactase deficiency, with an almost total lack of lactase-phlorizin hydrolase (LPH) activity on jejunal biopsy. In adult-type hypolactasia, the most common genetic enzyme deficiency in humans, this enzyme activity is reduced to 5%-10%. Although the activity of intestinal LPH has been found to be greatly reduced in both forms, the molecular pathogenesis of lactase deficiencies is unknown. On the basis of the initial candidate-gene approach, we assigned the CLD locus to an 8-cM interval on chromosome 2q21 in 19 Finnish families. At the closest marker locus, a specific allele 2 was present in 92% of disease alleles. On the basis of a genealogical study, the CLD mutation was found to be enriched in sparsely populated eastern and northern Finland, because of a founder effect. The results of both the genealogical study and the haplotype analysis indicate that one major mutation in a novel gene causes CLD in the Finnish population. Consequently, the critical region could be restricted further, to an approximately 350-kb interval, by ancient-haplotype and linkage-disequilibrium analyses. Surprisingly, the LPH gene was shown to lie outside the critical CLD region, excluding it as a causative gene for CLD. The LPH locus was found to reside >2 Mb from the critical CLD region.

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“…mini‐ and microsatellites) have not confirmed these findings (52, 55, 61). In particular, with reference to the uneven distribution of recessive disorders, the population structure observed in the Finnish population is compatible with the existence of subpopulations or ‘internal isolates’ (55, 57, 62, 63). The concept of Finnish disease heritage was coined because of the high prevalence of recessive disorders (> 30) (64, 65).…”

Section: Population Genetics Of Selected Isolatesmentioning

confidence: 99%

Genetics of population isolates

2002

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Genetic isolates, as shown empirically by the Finnish, Old Order Amish, Hutterites, Sardinian and Jewish communities among others, represent a most important and powerful tool in genetically mapping inherited disorders. The main features associated with that genetic power are the existence of multigenerational pedigrees which are mostly descended from a small number of founders a short number of generations ago, environmental and phenotypic homogeneity, restricted geographical distribution, the presence of exhaustive and detailed records correlating individuals in very well ascertained pedigrees, and inbreeding as a norm. On the other hand, the presence of a multifounder effect or admixture among divergent populations in the founder time (e.g. the Finnish and the Paisa community from Colombia) will theoretically result in increased linkage disequilibrium among adjacent loci. The present review evaluates the historical context and features of some genetic isolates with emphasis on the basic population genetic concepts of inbreeding and genetic drift, and also the state-of-the-art in mapping traits, both Mendelian and complex, on genetic isolates.

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Rare Disease Genes—Lessons and Challenges

Cited by 18 publications

References 16 publications

Founder Effect at PGL1 in Hereditary Head and Neck Paraganglioma Families from The Netherlands

Founder Effect at PGL1 in Hereditary Head and Neck Paraganglioma Families from The Netherlands

Assignment of the Locus for Congenital Lactase Deficiency to 2q21, in the Vicinity of but Separate from the Lactase-Phlorizin Hydrolase Gene

Genetics of population isolates

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