Identification of De Novo Copy Number Variants Associated with Human Disorders of Sexual Development

被引:115
作者
Tannour-Louet, Mounia [1 ]
Han, Shuo [2 ]
Corbett, Sean T. [1 ]
Louet, Jean-Francois [2 ]
Yatsenko, Svetlana [3 ]
Meyers, Lindsay [3 ]
Shaw, Chad A. [3 ]
Kang, Sung-Hae L. [3 ]
Cheung, Sau Wai [3 ]
Lamb, Dolores J. [1 ,2 ]
机构
[1] Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[3] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
来源
PLOS ONE | 2010年 / 5卷 / 10期
关键词
CHROMOSOMAL MICROARRAY ANALYSIS; MICRODELETION SYNDROME; BETA-CATENIN; REVERSAL; CRYPTORCHIDISM; HYPOSPADIAS; DIFFERENTIATION; GENE; DUPLICATIONS; POLYMORPHISM;
D O I
10.1371/journal.pone.0015392
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Disorders of sexual development (DSD), ranging in severity from genital abnormalities to complete sex reversal, are among the most common human birth defects with incidence rates reaching almost 3%. Although causative alterations in key genes controlling gonad development have been identified, the majority of DSD cases remain unexplained. To improve the diagnosis, we screened 116 children born with idiopathic DSD using a clinically validated array-based comparative genomic hybridization platform. 8951 controls without urogenital defects were used to compare with our cohort of affected patients. Clinically relevant imbalances were found in 21.5% of the analyzed patients. Most anomalies (74.2%) evaded detection by the routinely ordered karyotype and were scattered across the genome in gene-enriched subtelomeric loci. Among these defects, confirmed de novo duplication and deletion events were noted on 1p36.33, 9p24.3 and 19q12-q13.11 for ambiguous genitalia, 10p14 and Xq28 for cryptorchidism and 12p13 and 16p11.2 for hypospadias. These variants were significantly associated with genitourinary defects (P = 6.08 x 10(-12)). The causality of defects observed in 5p15.3, 9p24.3, 22q12.1 and Xq28 was supported by the presence of overlapping chromosomal rearrangements in several unrelated patients. In addition to known gonad determining genes including SRY and DMRT1, novel candidate genes such as FGFR2, KANK1, ADCY2 and ZEB2 were encompassed. The identification of risk germline rearrangements for urogenital birth defects may impact diagnosis and genetic counseling and contribute to the elucidation of the molecular mechanisms underlying the pathogenesis of human sexual development.
引用
收藏
页数:13
相关论文
共 38 条
  • [1] Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans
    Aitman, TJ
    Dong, R
    Vyse, TJ
    Norsworthy, PJ
    Johnson, MD
    Smith, J
    Mangion, J
    Roberton-Lowe, C
    Marshall, AJ
    Petretto, E
    Hodges, MD
    Bhangal, G
    Patel, SG
    Sheehan-Rooney, K
    Duda, M
    Cook, PR
    Evans, DJ
    Domin, J
    Flint, J
    Boyle, JJ
    Pusey, CD
    Cook, HT
    [J]. NATURE, 2006, 439 (7078) : 851 - 855
  • [2] Loss of Fgfr2 leads to partial XY sex reversal
    Bagheri-Fam, Stefan
    Sim, Helena
    Bernard, Pascal
    Jayakody, Irumini
    Taketo, Makoto M.
    Scherer, Gerd
    Harley, Vincent R.
    [J]. DEVELOPMENTAL BIOLOGY, 2008, 314 (01) : 71 - 83
  • [3] Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2
    Ballif, Blake C.
    Hornor, Sara A.
    Jenkins, Elizabeth
    Madan-Khetarpal, Suneeta
    Surti, Urvashi
    Jackson, Kelly E.
    Asamoah, Alexander
    Brock, Pamela L.
    Gowans, Gordon C.
    Conway, Robert L.
    Graham, John M., Jr.
    Medne, Livija
    Zackai, Elaine H.
    Shaikh, Tamim H.
    Geoghegan, Joel
    Selzer, Rebecca R.
    Eis, Peggy S.
    Bejjani, Bassem A.
    Shaffer, Lisa G.
    [J]. NATURE GENETICS, 2007, 39 (09) : 1071 - 1073
  • [4] A DOSAGE SENSITIVE LOCUS AT CHROMOSOME XP21 IS INVOLVED IN MALE TO FEMALE SEX REVERSAL
    BARDONI, B
    ZANARIA, E
    GUIOLI, S
    FLORIDIA, G
    WORLEY, KC
    TONINI, G
    FERRANTE, E
    CHIUMELLO, G
    MCCABE, ERB
    FRACCARO, M
    ZUFFARDI, O
    CAMERINO, G
    [J]. NATURE GENETICS, 1994, 7 (04) : 497 - 501
  • [5] FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias
    Beleza-Meireles, Ana
    Lundberg, Fredrik
    Lagerstedt, Kristina
    Zhou, Xiaolei
    Omrani, Davood
    Frisen, Louise
    Nordenskjold, Agneta
    [J]. EUROPEAN JOURNAL OF HUMAN GENETICS, 2007, 15 (04) : 405 - 410
  • [6] Development and validation of a CGH microarray for clinical cytogenetic diagnosis
    Cheung, SW
    Shaw, CA
    Yu, W
    Li, JZ
    Ou, ZS
    Patel, A
    Yatsenko, SA
    Cooper, ML
    Furman, P
    Stankiewicz, P
    Lupski, JR
    Chinault, AC
    Beaudet, AL
    [J]. GENETICS IN MEDICINE, 2005, 7 (06) : 422 - 432
  • [7] The Incidence of Disorders of Sexual Differentiation and Chromosomal Abnormalities of Cryptorchidism and Hypospadias Stratified by Meatal Location
    Cox, Michael J.
    Coplen, Douglas E.
    Austin, Paul F.
    [J]. JOURNAL OF UROLOGY, 2008, 180 (06) : 2649 - 2652
  • [8] Role of hormones, genes, and environment in human cryptorchidism
    Foresta, Carlo
    Zuccarello, Daniela
    Garolla, Andrea
    Ferlin, Alberto
    [J]. ENDOCRINE REVIEWS, 2008, 29 (05) : 560 - 580
  • [9] The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility
    Gonzalez, E
    Kulkarni, H
    Bolivar, H
    Mangano, A
    Sanchez, R
    Catano, G
    Nibbs, RJ
    Freedman, BI
    Quinones, MP
    Bamshad, MJ
    Murthy, KK
    Rovin, BH
    Bradley, W
    Clark, RA
    Anderson, SA
    O'Connell, RJ
    Agan, BK
    Ahuja, SS
    Bologna, R
    Sen, L
    Dolan, MJ
    Ahuja, SK
    [J]. SCIENCE, 2005, 307 (5714) : 1434 - 1440
  • [10] Generation of the floxed allele of the SIP1 (Smad-interacting protein 1) gene for Cre-mediated conditional knockout in the mouse
    Higashi, Y
    Maruhashi, M
    Nelles, L
    Van de Putte, T
    Verschueren, K
    Miyoshi, T
    Yoshimoto, A
    Kondoh, H
    Huylebroeck, D
    [J]. GENESIS, 2002, 32 (02) : 82 - 84