Copy-number mutations on chromosome 17q24.2-q24.3 in congenital generalized hypertrichosis terminalis with or without gingival hyperplasia.
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.
Sun
Miao
M
McKusick-Zhang Center for Genetic Medicine and State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Li
Ning
N
Dong
Wu
W
Chen
Zugen
Z
Liu
Qing
Q
Xu
Yiming
Y
He
Guang
G
Shi
Yongyong
Y
Li
Xin
X
Hao
Jiajie
J
Luo
Yang
Y
Shang
Dandan
D
Lv
Dan
D
Ma
Fen
F
Zhang
Dai
D
Hua
Rui
R
Lu
Chaoxia
C
Wen
Yaran
Y
Cao
Lihua
L
Irvine
Alan D
AD
McLean
W H Irwin
WH
Dong
Qi
Q
Wang
Ming-Rong
MR
Yu
Jun
J
He
Lin
L
Lo
Wilson H Y
WH
Zhang
Xue
X
D000293:Adolescent; D000328:Adult; D002675:Child, Preschool; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D008040:Genetic Linkage; D015894:Genome, Human; D005885:Gingival Hyperplasia / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006983:Hypertrichosis / Q000151:congenital* / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D055758:SOX9 Transcription Factor / Q000235:genetics
D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human