Copy-Number Mutations on Chromosome 17q24.2-q24.3 in Congenital Generalized Hypertrichosis Terminalis with or without Gingival Hyperplasia

• Published in: American journal of human genetics 2009-06, Vol.84 (6), p.807-813
• Main Authors: Sun, Miao, Li, Ning, Dong, Wu, Chen, Zugen, Liu, Qing, Xu, Yiming, He, Guang, Shi, Yongyong, Li, Xin, Hao, Jiajie, Luo, Yang, Shang, Dandan, Lv, Dan, Ma, Fen, Zhang, Dai, Hua, Rui, Lu, Chaoxia, Wen, Yaran, Cao, Lihua, Irvine, Alan D., McLean, W.H. Irwin, Dong, Qi, Wang, Ming-Rong, Yu, Jun, He, Lin, Lo, Wilson H.Y., Zhang, Xue
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Biological and medical sciences; Child, Preschool; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 17 - genetics; Dermatology; Female; Fundamental and applied biological sciences. Psychology; Gene Dosage; Gene loci; General aspects. Genetic counseling; Genetic disorders; Genetic Linkage; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human; Genomics; Gingival Hyperplasia - genetics; Hair and nails disorders; Haplotypes - genetics; Humans; Hypertrichosis - congenital; Hypertrichosis - genetics; Male; Medical genetics; Medical sciences; Microsatellite Repeats; Middle Aged; Molecular and cellular biology; Mutation; Mutation - genetics; Pedigree; SOX9 Transcription Factor - genetics; Studies
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2009.04.018

Congenital generalized hypertrichosis terminalis (CGHT) is a rare condition characterized by universal excessive growth of pigmented terminal hairs and often accompanied with gingival hyperplasia. In the present study, we describe three Han Chinese families with autosomal-dominant CGHT and a sporadic case with extreme CGHT and gingival hyperplasia. We first did a genome-wide linkage scan in a large four-generation family. Our parametric multipoint linkage analysis revealed a genetic locus for CGHT on chromosome 17q24.2-q24.3. Further two-point linkage and haplotyping with microsatellite markers from the same chromosome region confirmed the genetic mapping and showed in all the families a microdeletion within the critical region that was present in all affected individuals but not in unaffected family members. We then carried out copy-number analysis with the Affymetrix Genome-Wide Human SNP Array 6.0 and detected genomic microdeletions of different sizes and with different breakpoints in the three families. We validated these microdeletions by real-time quantitative PCR and confirmed their perfect cosegregation with the disease phenotype in the three families. In the sporadic case, however, we found a de novo microduplication. Two-color interphase FISH analysis demonstrated that the duplication was inverted. These copy-number variations (CNVs) shared a common genomic region in which CNV is not reported in the public database and was not detected in our 434 unrelated Han Chinese normal controls. Thus, pathogenic copy-number mutations on 17q24.2-q24.3 are responsible for CGHT with or without gingival hyperplasia. Our work identifies CGHT as a genomic disorder.