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

Hereditas, Dec 2017

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 Fjällsjö 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.

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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

Olsson et al. Hereditas 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 K. Sigvard Olsson 0 3 Olof Wålinder 2 Ulf Jansson 1 Maria Wilbe 7 Marie-Louise Bondeson 7 Eva-Lena Stattin 6 Ruma Raha-Chowdhury 5 Roger Williams 4 0 Section of Hematology and Coagulation, Department of Medicine, Sahlgrenska Academy, University of Göteborg , S 413 45 Göteborg , Sweden 1 Department of Clinical Chemistry, Sundsvall Hospital , Sundsvall , Sweden 2 Department of Medicine, Östersund Hospital , Östersund , Sweden 3 Section of Hematology and Coagulation, Department of Medicine, Sahlgrenska Academy, University of Göteborg , S 413 45 Göteborg , Sweden 4 Institute of Hepatology London, Foundation for Liver Research , London , SE5 9NT and Faculty of Life Sciences & Medicine, King ́s College London , London , UK 5 John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge , Cambridge , UK 6 Department of Immunology , Genetics and Pathology , Uppsala University , Uppsala , Sweden 7 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University , Uppsala , Sweden 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 Fjällsjö 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. (Continued on next page) - (Continued from previous page) 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. Background River valley populations of northern Sweden are well suited for research of monogenic diseases because the wilderness between them creates sub-isolates [ 1 ]. This usually mean a good breeding ground for autosomal recessive (AR) diseases like hereditary hemochromatosis (HH), common in the river valleys of Jämtland [ 2, 3 ]. In this disease, homozygous carriers of the HFE/p.C282Y mutation have an increased ability to absorb iron due to reduced levels of hepcidin, the iron regulating hormone of the liver [4].With time, the iron loading can reach toxic amounts affecting multiple organs in particular the liver, but most often the phenotype is mild. The disease was once regarded rare in Scandinavia and England, possibly due to widespread iron deficiencies in these countries [ 5 ]. Paradoxically these and other north European countries today demonst (...truncated)


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K. Sigvard Olsson, Olof Wålinder, Ulf Jansson, Maria Wilbe, Marie-Louise Bondeson, Eva-Lena Stattin, Ruma Raha-Chowdhury, Roger Williams. 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, Hereditas, 2017, pp. 16, Volume 154, Issue 1, DOI: 10.1186/s41065-017-0052-2