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Common founder effe...
Common founder effects of hereditary hemochromatosis, Wilson's disease, the long QT syndrome and autosomal recessive deafness caused by two novel mutations in the WHRN and TMC1 genes
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- Olsson, Sigvard (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin,Institute of Medicine,University of Göteborg, Sahlgrenska Academy, Department of Medicine, Section of Hematology and Coagulation
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- Walinder, O. (författare)
- Östersund Hospital, Department of Medicine
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- Jansson, U. (författare)
- Sundsvall Hospital, Department of Clinical Chemistry
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- Wilbe, Maria (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Medicinsk genetik och genomik
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- Bondeson, Marie-Louise, 1960- (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Medicinsk genetik och genomik
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- Stattin, Evalena (författare)
- Uppsala universitet,Medicinsk genetik och genomik
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- Raha-Chowdhury, R. (författare)
- University of Cambridge, Department of Clinical Neurosciences, John van Geest Centre for Brain Repair
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- Williams, R. (författare)
- Foundation for Liver Research, Institute of Hepatology London; King ́s College London, Faculty of Life Sciences & Medicine
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(creator_code:org_t)
- 2017-12-19
- 2017
- Engelska.
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Ingår i: Hereditas. - : Springer Science and Business Media LLC. - 1601-5223 .- 0018-0661. ; 154
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Background: Genealogy and molecular genetic studies of a Swedish river valley population resulted in a large pedigree, showing that the hereditary hemochromatosis (HH) HFE/p.C282Y mutation is inherited with other recessive disorders such as Wilson's disease (WND), a rare recessive disorder of copper overload. The population also contain individuals with the Swedish long QT syndrome (LQTS1) founder mutation (KCNQ1/p.Y111C) which in homozygotes causes the Jervell & Lange Nielsen syndrome (JLNS) and hearing loss (HL). Aims of the study were to test whether the Swedish long QT founder mutation originated in an ancestral HFE family and if carriers had an increased risk for hemochromatosis (HH), a treatable disorder. We also aimed to identify the pathogenic mutation causing the hearing loss disorder segregating in the pedigree. Methods: LQTS patients were asked about their ancestry and possible origin in a HH family. They were also offered a predictive testing for the HFE genotype. Church books were screened for families with hearing loss. One HH family had two members with hearing loss, who underwent molecular genetic analysis of the LQTS founder mutation, connexin 26 and thereafter exome sequencing. Another family with hearing loss in repeat generations was also analyzed for connexin 26 and underwent exome sequencing. Results: Of nine LQTS patients studied, four carried a HFE mutation (two p.C282Y, two p.H63D), none was homozygous. Three LQTS patients confirmed origin in a female founder (b 1694, identical to AJ b 1694, a HFE pedigree member from the Fax river. Her descent of 44 HH families, included also 29 families with hearing loss (HL) suggesting JLNS. Eleven LQTS probands confirmed origin in a second founder couple (b 1614/1605) in which the woman b 1605 was identical to a HFE pedigree member from the Fjallsjo river. In her descent there were not only 64 HH, six WND families, one JLNS, but also 48 hearing loss families. Most hearing loss was non syndromic and caused by founder effects of the late 16th century. One was of Swedish origin carrying the WHRN, c.1977delC, (p.S660Afs*30) mutation, the other was a TMC1(NM_138691), c.1814T>C,(p.L605P) mutation, possibly of Finnish origin. Conclusions: Deep human HFE genealogies show HFE to be associated with other genetic disorders like Wilson's disease, LQTS, JLNS, and autosomal recessive hearing loss. Two new homozygous HL mutations in WHRN/p.S660Afs*30 and TMC1/p.L605P were identified, none of them previously reported from Scandinavia. The rarity of JLNS was possibly caused by miscarriage or intrauterine death. Most hearing loss (81.7%) was seen after 1844 when first cousin marriages were permitted. However, only 10 (10.3%) came from 1st cousin unions and only 2 (2.0 %) was born out of wedlock.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Psykiatri (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Psychiatry (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- NATURVETENSKAP -- Biologi -- Genetik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Genetics (hsv//eng)
Nyckelord
- Hereditary hemochromatosis
- Wilson's disease
- Long QT syndrome
- Jervell and Lange-Nielsen's syndrome
- Non syndromic hearing loss
- WHRN
- DFNB31
- TMC1
- hearing impairment
- northern sweden
- iron-metabolism
- population
- genetics
- family
- prevalence
- phenotype
- interval
- whirlin
- Genetics & Heredity
- braekeleer m
- 1992
- annales de genetique
- v35
- p202
- braekeleer m
- 1993
- annals of human biology
- v20
- p501
- Hereditary hemochromatosis
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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