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

Abstract

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 16^th 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 1^st cousin unions and only 2 (2.0 %) was born out of wedlock.

Keywords: DFNB31; Hereditary hemochromatosis; Jervell and Lange- Nielsen´s syndrome; Long QT syndrome; Non syndromic hearing loss; TMC1; WHRN; Wilson´s disease.

Fig. 1

Pedigree showing individuals with Long QT Syndrome (LQTS) and hereditary hemochromatosis (HH). LQTS are marked with half filled symbols, hemochromatosis with filled blue symbols. Double horisontal lines mark consanguineous marriages

Fig. 2

Pedigree connecting families with LQTS and HH to a common founder couple b 1614/1605. IV:1 is identical to AJ b 1694 from Fig. 1 and V:3-V4 b 1729 /1727 were her neighbors . Double heterozygotes (LQT/HFE) are marked by lower arrows. XII:12 ,marked by a lower left arrow, had a hearing aid at age 42. Symbols as in Fig. 1

Fig. 3

Pedigree showing individuals with hearing loss marked with filled yellow symbols with a short lower arrow (suspected Jervell & Lange-Nielsen Syndrome). LQTS as in Fig. 1. Admixture from an outside origin is marked with filled red symbols

Fig. 4

Pedigree showing families with LQTS and hearing loss (suspected Jervell and Lange Nielsen syndrome (JLNS). D 9 was deaf-mute and died of stroke at age 9 suggesting JLNS. The pedigree also show connection to a hemochromatosis founder family born 1580 in which three HL families D 87, D 24 and D 86 were available for molecular genetic evaluation. The D 24 parents were 3^rd cousins once removed from a marriage 1788 marked with a vertical arrow. The LQTS founder II family is marked by a left upper arrow. Symbols as in Fig. 2

Fig. 5

Pedigree of the D 24 family presenting the origin and segregation of the p.S660Afs*30 mutation of the WHRN DFNB31gene. Two siblings from a marriage in 1778 (arrow) may have introduced the mutation by co migration with the HFE mutation (in blue). A founder effect of the late 16^th century seems likely. VI:1-2 is equal to II:5-6 of Fig. 3

Fig. 6

Pedigree showing the ancestry of the D 87 family with homozygosity for the TMC1/p.L605P in repeat generations. Both parents of XIII:2 share origin in a generation VIII family with hearing loss. The first HL member observed (on the 23^rd of December 1715 (44) is seen as IV:16. IV:18 is the “Finnkommissioner” of the HFE family marrying into the Finnish founder family. Finnish ancestry is marked with light blue symbols

Fig. 7

A pedigree connecting 68 hearing loss families including the D 87 family with the TMC1/p.L605P mutation to the common founder of Fig. 6. The first documented hearing loss individual (MP b 1655), is marked by an upper arrow and the “Finncommisioner” with a lower arrow