title: Simultaneous Detection of Both Single Nucleotide Variations and Copy Number Alterations by Next-Generation Sequencing in Gorlin Syndrome.
abstract: Gorlin syndrome (GS) is an autosomal dominant disorder that predisposes affected individuals to developmental defects and tumorigenesis, and caused mainly by heterozygous germline PTCH1 mutations. Despite exhaustive analysis, PTCH1 mutations are often unidentifiable in some patients; the failure to detect mutations is presumably because of mutations occurred in other causative genes or outside of analyzed regions of PTCH1, or copy number alterations (CNAs). In this study, we subjected a cohort of GS-affected individuals from six unrelated families to next-generation sequencing (NGS) analysis for the combined screening of causative alterations in Hedgehog signaling pathway-related genes. Specific single nucleotide variations (SNVs) of PTCH1 causing inferred amino acid changes were identified in four families (seven affected individuals), whereas CNAs within or around PTCH1 were found in two families in whom possible causative SNVs were not detected. Through a targeted resequencing of all coding exons, as well as simultaneous evaluation of copy number status using the alignment map files obtained via NGS, we found that GS phenotypes could be explained by PTCH1 mutations or deletions in all affected patients. Because it is advisable to evaluate CNAs of candidate causative genes in point mutation-negative cases, NGS methodology appears to be useful for improving molecular diagnosis through the simultaneous detection of both SNVs and CNAs in the targeted genes/regions.
authors.affiliation: Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.|Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.|Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kei-ichi
authors.initials: K
authors.lastname: Morita
authors.affiliation: Department of Stress Science, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Naruto
authors.affiliation: Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.|Genome Laboratory, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.|Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Tanimoto
authors.affiliation: Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Yasukawa
authors.affiliation: Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Oikawa
authors.affiliation: Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Imoto
authors.affiliation: Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.|Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan.|Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
authors.affiliation: Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.|Hard Tissue Genome Research Center, Tokyo Medical and Dental University, Tokyo, Japan.|Oral Cancer Center, Tokyo General Hospital, Tokyo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Omura
authors.affiliation: Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Harada
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001478:Basal Cell Nevus Syndrome / Q000235:genetics*; D015415:Biomarkers / Q000032:analysis*; D002648:Child; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D015415:Biomarkers