title: Combined linkage analysis and exome sequencing identifies novel genes for familial goiter.
abstract: Familial goiter is a genetic disease showing heterogeneous expression. To identify causative genes, we investigated three multigenerational goiter families with an autosomal dominant inheritance pattern. We performed genome-wide linkage analysis on all the families, combined with whole-exome sequencing in two affected individuals from each family. For linkage analysis, we considered loci with logarithm of odds (LOD) scores >1.5 as candidate regions for identification of rare variants. In one of the families, we found two rare heterozygous missense variants, p.V56M in RGS12 and p.G37D in GRPEL1, which segregate with goiter and are both located within the same haplotype on 4p16. This haplotype was not observed in 150 controls. In the other two families, we identified two additional rare missense variants segregating with goiter, p.A551T in CLIC6 on 21q22.12 and p.V412A in WFS1 on 4p16. In controls, the minor allele frequency (MAF) of p.V412A in WFS1 was 0.017 while p.A551T in CLIC6 was not detected. All identified genes (RGS12, GRPEL1, CLIC6 and WFS1) show expression in the human thyroid gland, suggesting that they may play a role in thyroid gland function. Moreover, these four genes are novel with regard to their involvement in familial goiter, supporting genetic heterogeneity of this disease.
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Junxia
authors.initials: J
authors.lastname: Yan
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takahashi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ohura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Adachi
authors.forename: Ikuko
authors.initials: I
authors.lastname: Takahashi
authors.forename: Eishin
authors.initials: E
authors.lastname: Ogawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Okuda
authors.forename: Hatasu
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hitomi
authors.forename: Wanyang
authors.initials: W
authors.lastname: Liu
authors.forename: Kouji H
authors.initials: KH
authors.lastname: Harada
authors.forename: Akio
authors.initials: A
authors.lastname: Koizumi
mesh_terms: D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D003001:Cloning, Molecular; D003409:Congenital Hypothyroidism / Q000235:genetics; D030541:Databases, Genetic; D059472:Exome; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006042:Goiter / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007564:Japan; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA / Q000379:methods*