Copy-number mutations on chromosome 17q24.2-q24.3 in congenital generalized hypertrichosis terminalis with or without gingival hyperplasia

TY - JOUR

T1 - Copy-number mutations on chromosome 17q24.2-q24.3 in congenital generalized hypertrichosis terminalis with or without gingival hyperplasia

AU - Sun, Miao

AU - Li, Ning

AU - Dong, Wu

AU - Chen, Zugen

AU - Liu, Qing

AU - Xu, Yiming

AU - He, Guang

AU - Shi, Yongyong

AU - Li, Xin

AU - Hao, Jiajie

AU - Luo, Yang

AU - Shang, Dandan

AU - Lv, Dan

AU - Ma, Fen

AU - Zhang, Dai

AU - Hua, Rui

AU - Lu, Chaoxia

AU - Wen, Yaran

AU - Cao, Lihua

AU - Irvine, Alan D.

AU - McLean, W. H. Irwin

AU - Dong, Qi

AU - Wang, Ming-Rong

AU - Yu, Jun

AU - He, Lin

AU - Lo, Wilson H. Y.

AU - Zhang, Xue

PY - 2009/6/12

Y1 - 2009/6/12

N2 - 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-c24.3. 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.

AB - 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-c24.3. 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.

KW - ZIMMERMANN-LABAND-SYNDROME

KW - HUMAN-DISEASE

KW - FIBROMATOSIS

KW - MKK6

KW - REARRANGEMENTS

KW - INVOLVEMENT

KW - DISORDERS

KW - 3P14.3

KW - LOCI

KW - MICE

U2 - 10.1016/j.ajhg.2009.04.018

DO - 10.1016/j.ajhg.2009.04.018

M3 - Article

C2 - 19463983

SN - 0002-9297

VL - 84

SP - 807

EP - 813

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -