Abstract
BackgroundSplenic 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.MethodsTwelve 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.ResultsThe 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-014-0115-4) contains supplementary material, which is available to authorized users.
Highlights
Splenic epidermoid cyst is a benign tumor-like lesion affecting the spleen and sometimes occurs in familial form
We performed sequential filtering steps based on the following criteria; first, based on the variant’s impact on the protein coding sequence; it is likely that the causal variant is an amino acid substitution, frame-shift mutation, or splicing site alteration, second, because familial splenic epidermoid cyst is a very rare disease, it is likely that the causal variant either has a low population frequency or not registered in public databases
Considering the previous criteria, we applied two separate filters; one for the novel variants that have not been reported previously in dbSNP or 1000 Genomes databases, while the second one for variants with minor allele frequency (MAF) of up to 2% in the Japanese or European population according to 1000 Genomes database
Summary
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, recently, with the emergence of exome re-sequencing, the genetics of many diseases have been unveiled. 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. In order to decipher the genetic factor, we recruited a Japanese family with frequent occurrences of splenic epidermoid cyst and performed genome-wide linkage analysis and exome capture followed by massive parallel sequencing. A series of filtering steps identified three candidate genes and patients recruited in Kosovo were used for replication to identify a single candidate gene
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