title: Whole-genome Linkage Analysis and Sequence Analysis of Candidate Loci in Familial Breast Cancer.
abstract: BACKGROUND
  Known breast cancer-predisposing genes account for fewer than 25% of all familial breast cancer cases and further studies are required to find the remaining high- and moderate-risk genes. We set-out to couple linkage analysis using microsatellite marker data and sequence analysis of linked regions in 13 non-BRCA1/2 families in order to find novel susceptibility loci and high-penetrant genes.
  
  
  METHODS
  Genotyping with 540 fluorescently-labeled microsatellite markers located on the 23 chromosomes at 7.25 cM resolution was used for primary linkage analysis and an additional 40 markers were used for fine-mapping of loci with a logarithm of odds (LOD) or heterogeneity LOD (HLOD) score greater than one. Whole-exome sequencing data of 28 members from all 13 families were used for the bioinformatics sequence analysis on the linked regions of these families.
  
  
  RESULTS
  Linkage analysis identified three loci on chromosome 18q as a putative region of interest (overall LOD=1, HLOD=1.2). Sequencing analysis of the three linked regions on 18q and mutation prediction algorithms did reveal three probable damaging variants.
  
  
  CONCLUSIONS
  Overall, our study identified three weakly linked loci on 18q and three probable damaging variants of interest in the 13 families with breast cancer.
authors.affiliation: Center for Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Rajeshwari
authors.initials: R
authors.lastname: Marikkannu
authors.affiliation: Center for Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden Department of Clinical Genetics, Rudbecklaboratoriet, Akademiska University Hospital, Uppsala, Sweden.
authors.forename: Christos
authors.initials: C
authors.lastname: Aravidis
authors.affiliation: Center for Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Rantala
authors.affiliation: Center for Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Simone
authors.initials: S
authors.lastname: Picelli
authors.affiliation: Center for Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Adamovic
authors.affiliation: Center for Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Markku
authors.initials: M
authors.lastname: Keihas
authors.affiliation: Center for Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Center for Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Vinaykumar
authors.initials: V
authors.lastname: Kontham
authors.affiliation: Center for Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nilsson
authors.affiliation: Center for Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden annika.lindblom@ki.se.
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D010375:Pedigree
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; C551750:BRCA2 protein, human
keywords: Familial breast cancer; linkage analysis; microsatellite markers; next generation sequencing; sequencing analysis