title: Genome-wide linkage and exome analyses identify variants of HMCN1 for splenic epidermoid cyst.
abstract: BACKGROUND
  Splenic epidermoid cyst is a benign tumor-like lesion affecting the spleen and sometimes occurs in familial form. The causality of such rare diseases remain challenging, however recently, with the emergence of exome re-sequencing, the genetics of many diseases have been unveiled. In the present study, we performed a combinatorial approach of genome-wide parametric linkage and exome analyses for a moderate-sized Japanese family with frequent occurrence of splenic epidermoid cyst to identify the genetic causality of the disease.
  
  
  METHODS
  Twelve individuals from the family were subject to SNP typing and exome re-sequencing was done for 8 family members and 4 unrelated patients from Kosovo. Linkage was estimated using multi-point parametric linkage analysis assuming a dominant mode of inheritance. All of the candidate variants from exome analysis were confirmed by direct sequencing.
  
  
  RESULTS
  The parametric linkage analysis suggested two loci on 1q and 14q with a maximal LOD score of 2.5 . Exome generated variants were prioritized based on; impact on the protein coding sequence, novelty or rareness in public databases, and position within the linkage loci. This approach identified three variants; variants of HMCN1 and CNTN2 on 1q and a variant of DDHD1 on 14q. The variant of HMCN1 (p.R5205H) showed the best co-segregation in the family after validation with Sanger sequencing. Additionally, rare missense variants (p.A4704V, p.T5004I, and p.H5244Q) were detected in three unrelated Kosovo patients. The identified variants of HMCN1 are on conserved domains, particularly the two variants on calcium-binding epidermal growth factor domain.
  
  
  CONCLUSIONS
  The present study, by combining linkage and exome analyses, identified HMCN1 as a genetic causality of splenic epidermoid cyst. Understanding the biology of the disease is a key step toward developing innovative approaches of intervention.
authors.forename: Waleed H
authors.initials: WH
authors.lastname: Omer
authors.forename: Akira
authors.initials: A
authors.lastname: Narita
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Hosomichi
authors.forename: Shigeki
authors.initials: S
authors.lastname: Mitsunaga
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamashita
authors.forename: Avdyl
authors.initials: A
authors.lastname: Krasniqi
authors.forename: Yuri
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Masami
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Division of Human Genetics, National Institute of Genetics, The Graduate University for Advanced Studies (SOKENDAI), Yata 1111, Mishima 411-8540, Shizuoka, Japan. itinoue@nig.ac.jp.
authors.forename: Ituro
authors.initials: I
authors.lastname: Inoue
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D058969:Contactin 2 / Q000235:genetics; D030541:Databases, Genetic; D004814:Epidermal Cyst / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D013154:Spleen / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D014463:Ultrasonography
chemical_list: C548674:CNTN2 protein, human; D058969:Contactin 2; C488168:HMCN1 protein, human; D007136:Immunoglobulins