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- W1973202954 abstract "Campomelic dysplasia (CD) is a semilethal skeletal malformation syndrome with or without XY sex reversal. In addition to the multiple mutations found within the sex-determining region Y–related high-mobility group box gene (SOX9) on 17q24.3, several chromosome anomalies (translocations, inversions, and deletions) with breakpoints scattered over 1 Mb upstream of SOX9 have been described. Here, we present a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with a mild acampomelic CD with Robin sequence. Both chromosome breakpoints have been identified by fluorescence in situ hybridization and have been sequenced using a somatic cell hybrid. The 17q24.3 breakpoint maps ∼900 kb upstream of SOX9, which is within the same bacterial artificial chromosome clone as the breakpoints of two other reported patients with mild CD. We also report a prenatal identification of acampomelic CD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype, 46,XY,t(4;7;8;17)(4qter→4p15.1::17q25.1→17qter;7qter→7p15.3::4p15.1→4pter;8pter→8q12.1::7p15.3→7pter;17pter→17q25.1::8q12.1→8qter). Surprisingly, the 17q breakpoint maps ∼1.3 Mb downstream of SOX9, making this the longest-range position effect found in the field of human genetics and the first report of a patient with CD with the chromosome breakpoint mapping 3′ of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, we identified a candidate upstream cis-regulatory element, SOX9cre1. We provide evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. The potential molecular mechanism responsible for the position effect is discussed. Campomelic dysplasia (CD) is a semilethal skeletal malformation syndrome with or without XY sex reversal. In addition to the multiple mutations found within the sex-determining region Y–related high-mobility group box gene (SOX9) on 17q24.3, several chromosome anomalies (translocations, inversions, and deletions) with breakpoints scattered over 1 Mb upstream of SOX9 have been described. Here, we present a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with a mild acampomelic CD with Robin sequence. Both chromosome breakpoints have been identified by fluorescence in situ hybridization and have been sequenced using a somatic cell hybrid. The 17q24.3 breakpoint maps ∼900 kb upstream of SOX9, which is within the same bacterial artificial chromosome clone as the breakpoints of two other reported patients with mild CD. We also report a prenatal identification of acampomelic CD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype, 46,XY,t(4;7;8;17)(4qter→4p15.1::17q25.1→17qter;7qter→7p15.3::4p15.1→4pter;8pter→8q12.1::7p15.3→7pter;17pter→17q25.1::8q12.1→8qter). Surprisingly, the 17q breakpoint maps ∼1.3 Mb downstream of SOX9, making this the longest-range position effect found in the field of human genetics and the first report of a patient with CD with the chromosome breakpoint mapping 3′ of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, we identified a candidate upstream cis-regulatory element, SOX9cre1. We provide evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. The potential molecular mechanism responsible for the position effect is discussed. Mammalian gene expression is regulated at many levels. Despite the near completion of the human genome sequence, little is known about the genomic aspects of gene regulation in humans. A useful model for studying such regulation is provided by genomic rearrangements that result in diseases and in which chromosome breakpoints do not disrupt the causative gene but instead map outside the intact gene. Kleinjan and van Heyningen (Kleinjan and van Heyningen, 1998Kleinjan D-J van Heyningen V Position effect in human genetic disease.Hum Mol Genet. 1998; 7: 1611-1618Crossref PubMed Scopus (286) Google Scholar) reviewed position effects of chromosomal rearrangements and proposed a few possible mechanisms that may cause such effects: (1) separation of the gene from its enhancer or promoter region, (2) juxtaposition with an enhancer element from another gene, (3) removal of the long-range insulator or boundary element, (4) competition with another enhancer, and (5) position-effect variegation—that is, the insertion of the gene in a new heterochromatin environment. Recently, Tufarelli et al. (Tufarelli et al., 2003Tufarelli C Stanley JAS Garrick D Sharpe JA Ayyub H Wood WG Higgs DR Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease.Nat Genet. 2003; 34: 157-165Crossref PubMed Scopus (437) Google Scholar) described yet another mechanism of position-effect–related gene regulation, “antisense-mediated cis-acting methylation utilizing non-coding RNA,” which is similar to XIST/TSIX–mediated X-chromosome inactivation (Kleinjan and van Heyningen Kleinjan and van Heyningen, 2003Kleinjan DA van Heyningen V Turned off by RNA.Nat Genet. 2003; 34: 125-126Crossref PubMed Scopus (4) Google Scholar). Cis-acting regulatory elements in humans as distant as 1 Mb 5′ from the target gene have been described (de Kok et al. de Kok et al., 1996de Kok YJM Vossenaar ER Cremers CWRJ Dahl N Laporte J Hu LJ Lacombe D Fischel-Ghodsian N Friedman RA Parnes LS Thorpe P Bitner-Glindzicz M Pander H-J Heilbronner H Graveline J den Dunnen JT Brunner HG Ropers H-H Cremers FPM Identification of a hot spot for microdeletions in patients with X-linked deafness type 3 (DFN3) 900 kb proximal to the DFN3 gene POU3F4.Hum Mol Genet. 1996; 5: 1229-1235Crossref PubMed Scopus (129) Google Scholar; Davies et al. Davies et al., 1999Davies AF Mirza G Flinter F Ragoussis J An intersititial deletion of 6p24-p25 proximal to the FKHL7 locus and including AP-2α that affects anterior eye chamber development.J Med Genet. 1999; 36: 708-710PubMed Google Scholar; Pfeifer et al. Pfeifer et al., 1999Pfeifer D Kist R Dewar K Devon K Lander ES Birren B Korniszewski L Back E Scherer G Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region.Am J Hum Genet. 1999; 65: 111-124Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar; Jamieson et al. Jamieson et al., 2002Jamieson RV Perveen R Kerr B Carette M Yardley J Heon E Wirth MG van Heyningen V Donnai D Munier F Black GCM Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma.Hum Mol Genet. 2002; 11: 33-42Crossref PubMed Scopus (218) Google Scholar; Lettice et al. Lettice et al., 2002Lettice LA Horikoshi T Heaney SJH van Baren MJ van der Linde HC Breedveld GJ Joosse M Akarsu N Oostra BA Endo N Shibata M Suzuki M Takahashi E Shinka T Nakahori Y Ayusawa D Nakabayashi K Scherer SW Heutink P Hill RE Noji S Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly.Proc Natl Acad Sci USA. 2002; 99: 7548-7553Crossref PubMed Scopus (355) Google Scholar; Nobrega et al. Nobrega et al., 2003Nobrega MA Ovcharenko I Afzal V Rubin EM Scanning human gene deserts for long-range enhancers.Science. 2003; 302: 413Crossref PubMed Scopus (485) Google Scholar). In addition, it has been proposed that abnormal chromosome structure and/or chromatin remodeling affect gene expression (Bickmore and Maarel Bickmore and van der Maarel, 2003Bickmore WA van der Maarel SM Perturbations of chromatin structure in human genetic disease: recent advances.Hum Mol Genet. 2003; 12: R207-R213Crossref PubMed Scopus (48) Google Scholar; Cho et al. Cho et al., 2004Cho KS Elizondo LI Boerkoel CF Advances in chromatin remodeling and human disease.Curr Opin Genet Dev. 2004; 14: 308-315Crossref PubMed Scopus (88) Google Scholar). Haploinsufficiency of the sex-determining region Y (SRY)–related high-mobility group box gene (SOX9) is known to cause campomelic dysplasia (CD [MIM 114290]), a clinically distinct syndrome characterized by skeletal anomalies, such as bowed femurs and tibiae, hypoplastic scapulae, 11 pairs of ribs, pelvic malformations, Robin sequence, and clubbed feet (Foster et al. Foster et al., 1994Foster JW Dominguez-Steglich MA Guioli S Kwok C Weller PA Stevanovic M Weissenbach J Mansour S Young ID Goodfellow PN Brook JD Schafer AJ Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.Nature. 1994; 372: 525-530Crossref PubMed Scopus (1280) Google Scholar; Wagner et al. Wagner et al., 1994Wagner T Wirth J Meyer J Zabel B Held M Zimmer J Pasantes J Bricarelli FD Keutel J Hustert E Wolf U Tommerup N Schempp W Scherer G Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.Cell. 1994; 79: 1111-1120Abstract Full Text PDF PubMed Scopus (1251) Google Scholar). In two-thirds of individuals with CD with a 46,XY karyotype, male-to-female sex reversal has been described (Houston et al. Houston et al., 1983Houston CS Opitz JM Spranger JW Macpherson RI Reed MH Gilbert EF Herrmann J Schinzel A The campomelic syndrome: review, report of 17 cases, and follow-up on the currently 17-year-old boy first reported by Maroteaux et al. in 1971.Am J Med Genet. 1983; 15: 3-28Crossref PubMed Scopus (235) Google Scholar; Mansour et al. Mansour et al., 1995Mansour S Hall CM Pembrey ME Young ID A clinical and genetic study of campomelic dysplasia.J Med Genet. 1995; 32: 415-420Crossref PubMed Scopus (183) Google Scholar). The two mechanisms responsible for SOX9 haploinsufficiency are intragenic mutations (such as point mutations, insertions, and deletions) and chromosome rearrangements (Maraia et al. Maraia et al., 1991Maraia R Saal HM Wangsa D A chromosome 17q de novo paracentric inversion in a patient with campomelic dysplasia: case report and etiologic hypothesis.Clin Genet. 1991; 39: 401-408Crossref PubMed Scopus (32) Google Scholar; Young et al. Young et al., 1992Young ID Zuccollo JM Maltby EL Broderick NJ Campomelic dysplasia associated with a de novo 2q;17q reciprocal translocation.J Med Genet. 1992; 29: 251-252Crossref PubMed Scopus (37) Google Scholar; Tommerup et al. Tommerup et al., 1993Tommerup N Schempp W Meinecke P Pedersen S Bolund L Brandt C Goodpasture C Guldberg P Held K Reinwein H Saugstad OD Scherer G Skjeldal O Toder R Westvik J van der Hagen CB Wolf U Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to 17q24.3-q25.1.Nat Genet. 1993; 4: 170-174Crossref PubMed Scopus (160) Google Scholar; Foster et al. Foster et al., 1994Foster JW Dominguez-Steglich MA Guioli S Kwok C Weller PA Stevanovic M Weissenbach J Mansour S Young ID Goodfellow PN Brook JD Schafer AJ Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.Nature. 1994; 372: 525-530Crossref PubMed Scopus (1280) Google Scholar; Wagner et al. Wagner et al., 1994Wagner T Wirth J Meyer J Zabel B Held M Zimmer J Pasantes J Bricarelli FD Keutel J Hustert E Wolf U Tommerup N Schempp W Scherer G Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.Cell. 1994; 79: 1111-1120Abstract Full Text PDF PubMed Scopus (1251) Google Scholar; Kwok et al. Kwok et al., 1995Kwok C Weller PA Guioli S Foster JW Mansour S Zuffardi O Punnett HH Dominguez-Steglich MA Brook JD Young ID Goodfellow PN Schafer AJ Mutations in SOX9, the gene responsible for campomelic dysplasia and autosomal sex reversal.Am J Hum Genet. 1995; 57: 1028-1036PubMed Google Scholar; Cameron et al. Cameron et al., 1996Cameron FJ Hageman RM Cooke-Yarborough C Kwok C Goodwin LL Sillence DO Sinclair AH A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal.Hum Mol Genet. 1996; 5: 1625-1630Crossref PubMed Scopus (72) Google Scholar; Meyer et al. Meyer et al., 1997Meyer J Südbeck P Held M Wagner T Schmitz ML Bricarelli FD Eggermont E Friedrich U Haas OA Kobelt A Leroy JG Van Maldergem L Michel E Mitulla B Pfeiffer RA Schinzel A Schmidt H Scherer G Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations.Hum Mol Genet. 1997; 6: 91-98Crossref PubMed Scopus (150) Google Scholar; Goji et al. Goji et al., 1998Goji K Nishijima E Tsugawa C Nishio H Pokharel RK Matsuo M Novel missense mutation in the HMG box of SOX9 gene in a Japanese XY male resulted in campomelic dysplasia and severe defect in masculinization.Hum Mutat Suppl. 1998; 1: S114-S116Crossref PubMed Scopus (11) Google Scholar; Hageman et al. Hageman et al., 1998Hageman RM Cameron FJ Sinclair AH Mutation analysis of the SOX9 gene in a patient with campomelic dysplasia.Hum Mutat Suppl. 1998; 1: S112-S113Crossref PubMed Scopus (23) Google Scholar; Pfeifer et al. Pfeifer et al., 1999Pfeifer D Kist R Dewar K Devon K Lander ES Birren B Korniszewski L Back E Scherer G Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region.Am J Hum Genet. 1999; 65: 111-124Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar). Although no consistent phenotype-genotype correlations have been established on the basis of intragenic mutations, the patients with chromosome rearrangements tend to have milder phenotypes (Pfeifer et al. Pfeifer et al., 1999Pfeifer D Kist R Dewar K Devon K Lander ES Birren B Korniszewski L Back E Scherer G Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region.Am J Hum Genet. 1999; 65: 111-124Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar). The analysis of 12 patients with CD who had apparently balanced chromosome rearrangements showed the breakpoints to be scattered ∼140–950 kb upstream of the SOX9 gene, whereas the gene itself was intact (Wunderle et al. Wunderle et al., 1998Wunderle VM Critcher R Hastie N Goodfellow PN Schedl A Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia.Proc Natl Acad Sci USA. 1998; 95: 10649-10654Crossref PubMed Scopus (141) Google Scholar; Pfeifer et al. Pfeifer et al., 1999Pfeifer D Kist R Dewar K Devon K Lander ES Birren B Korniszewski L Back E Scherer G Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region.Am J Hum Genet. 1999; 65: 111-124Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar; Erdel et al. Erdel et al., 2004Erdel M Lane AH Fresser F Probst P Utermann G Scherer G A new campomelic dysplasia translocation breakpoint maps 400 kb from SOX9 [abstract P0249]. European Society of Human Genetics Munich.Eur J Hum Genet Suppl. 2004; 12: 136Google Scholar). Recently, Pop et al. (Pop et al., 2004Pop R Conz C Lindenberg KS Blesson S Schmalenberger B Briault S Pfeifer D Scherer G Screening of the 1 Mb SOX9 5′ control region by array CGH identifies a large deletion in a case of campomelic dysplasia with XY sex reversal.J Med Genet. 2004; 41: e47Crossref PubMed Scopus (68) Google Scholar) reported an ∼1.5-Mb microdeletion located ∼380 kb upstream of SOX9 in a patient with CD. It is interesting that Huang et al. (Huang et al., 1999Huang B Wang S Ning Y Lamb AN Bartley J Autosomal XX sex reversal caused by duplication of SOX9.Am J Med Genet. 1999; 87: 349-353Crossref PubMed Scopus (319) Google Scholar) described a chromosome duplication, dup(17)(q24.1q24.3), associated with XX female-to-male sex reversal and that Bishop et al. (Bishop et al., 2000Bishop CE Whitworth DJ Qin Y Agoulnik AI Agoulnik IU Harrison WR Behringer RR Overbeek PA A transgenic insertion upstream of Sox9 is associated with dominant XX sex reversal in the mouse.Nat Genet. 2000; 26: 490-494Crossref PubMed Scopus (309) Google Scholar) reported XX female-to-male sex reversal in a transgenic mouse with a 134-kb insertional deletion resulting from a recombinant construct insertion 0.98 Mb upstream of SOX9. Qin et al. (Qin et al., 2004Qin Y Kong Lk Poirier C Truong C Overbeek PA Bishop CE Long-range activation of Sox9 in Odd Sex (Ods) mice.Hum Mol Genet. 2004; 13: 1213-1218Crossref PubMed Scopus (92) Google Scholar) proposed that the transgenic insertion of a promoter from the recombinant construct in these mice interacts with gonad-specific enhancer elements leading to sex reversal (Qin et al. Qin et al., 2004Qin Y Kong Lk Poirier C Truong C Overbeek PA Bishop CE Long-range activation of Sox9 in Odd Sex (Ods) mice.Hum Mol Genet. 2004; 13: 1213-1218Crossref PubMed Scopus (92) Google Scholar). Thus, both the chondrogenic and gonadal functions of SOX9 appear to be precisely regulated by elements located as far as 1 Mb from the gene itself. Detailed DNA analysis of the genomic region extending up to 1 Mb proximal to SOX9 failed to uncover any protein-coding genes, suggesting that the chromosomal rearrangements remove one or more cis-regulatory elements from an extended SOX9 region (Pfeifer et al. Pfeifer et al., 1999Pfeifer D Kist R Dewar K Devon K Lander ES Birren B Korniszewski L Back E Scherer G Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region.Am J Hum Genet. 1999; 65: 111-124Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar; Bagheri-Fam et al. Bagheri-Fam et al., 2001Bagheri-Fam S Ferraz C Demaille J Scherer G Pfeifer D Comparative genomics of the SOX9 region in human and Fugu rubripes: conservation of short regulatory sequence elements within large intergenic regions.Genomics. 2001; 78: 73-82Crossref PubMed Scopus (82) Google Scholar; Pop et al. Pop et al., 2004Pop R Conz C Lindenberg KS Blesson S Schmalenberger B Briault S Pfeifer D Scherer G Screening of the 1 Mb SOX9 5′ control region by array CGH identifies a large deletion in a case of campomelic dysplasia with XY sex reversal.J Med Genet. 2004; 41: e47Crossref PubMed Scopus (68) Google Scholar; Qin et al. Qin et al., 2004Qin Y Kong Lk Poirier C Truong C Overbeek PA Bishop CE Long-range activation of Sox9 in Odd Sex (Ods) mice.Hum Mol Genet. 2004; 13: 1213-1218Crossref PubMed Scopus (92) Google Scholar). Here, we report two new patients with acampomelic CD with chromosomal breakpoints mapping ∼900 kb upstream and ∼1.3 Mb downstream of SOX9. Patient 1: The proband AA is a 6-year-old white girl, the second child born to a 31-year-old mother and a 32-year-old father. Her prenatal history is uneventful, with the mother undergoing amniocentesis because of a reciprocal chromosome translocation t(4;17) segregating in the family. Amniotic fluid chromosome analysis showed that the proband is a carrier of the same balanced t(4;17). The proband was delivered vaginally at term without complications. She was diagnosed with Robin sequence; the cleft palate was repaired at age 3 years. She also had tracheostenosis. A tracheostomy was performed at 10 wk, and she received a G-tube and underwent fundoplication. She had a history of frequent croup as a child and also required speech therapy. On physical examination at age 6 years, her height was 103 cm and her weight was 15 kg (both <5th percentile). She had flat malar surfaces, a depressed nasal bridge, prominent eyes, and 11 pairs of ribs. Her left ear was posteriorly rotated. Skeletal survey revealed hypoplastic scapulae and iliac wings, as well as an irregularity of the end plates of the thoracic vertebrae. There was an anomaly of the upper cervical spine, consisting of underdevelopment of the neural arch of C2, a congenital defect of C2, and probable fibrous occipitalization of C1. The dens was slightly hypoplastic, but there was no instability of the cervical spine on flexion. To characterize whether the balanced t(4;17) was involved in the pathophysiology of these conditions, repeat chromosome studies were requested for all family members. G-banded chromosome analysis from phytohemagglutinin-stimulated peripheral blood lymphocytes showed that the proband is a carrier of a balanced reciprocal translocation with the karyotype 46,XX,t(4;17)(q28.3;q24.3). Chromosome analysis of the parents showed that the proband’s father was a carrier of the same translocation, whereas the karyotype of the mother was normal. The proband’s older brother was also found to be a carrier of this translocation. The brother and father have many of the same clinical features as the proband (fig. 1). In addition, both the brother and the father have myopia, and hearing impairment was present in the father. An initial differential diagnosis included acampomelic CD and Stickler syndrome; however, a thorough physical examination and skeletal survey diagnosed mild acampomelic CD with Robin sequence. FISH with a set of several BAC probes mapped the 17q breakpoint within BAC clone RP11-879D6 (fig. 2A). The der(4) breakpoint was mapped between BAC clones RP11-79M4 and RP11-11I23. To narrow the chromosome 17q breakpoint within BAC clone RP11-879D6, we used a 6,234-bp long-range PCR product, amplified using forward primer 5′-GTAGCTATCTTAGCCCTGGCTGACAGTCACTT-3′ and reverse primer 5′-GGACACTTGCCAGATAAGAACTGGGTAGAC-3′ (Takara Bio), as a probe in FISH mapping. The breakpoint was localized to the distal one-third portion of the BAC clone and was further narrowed by a standard PCR walking method with the use of DNA from a somatic cell hybrid. DNA sequencing of the 1.2-kb PCR product obtained with forward primer 5′-AATCATGAAGATGGCCTTGC-3′ (for chromosome 4) and reverse primer 5′-TCCAGCCAAAGGGAAGAGTA-3′ (for chromosome 17) identified the der(4) breakpoint at nucleotide position 69815055 on chromosome 17 (899,164 bp upstream of SOX9) and at 136261648 on chromosome 4 (UCSC Genome Browser, build 34, July 2003) (fig. 2B). The der(17) breakpoint was identified by PCR in genomic DNA by use of forward primer 5′-TTGATGTATGGCCTGAACCA-3′ and reverse primer 5′-CAGCAAGATGGGGTCTATCAA-3′. An associated deletion of 13 bp on chromosome 4 was found (fig. 2). The breakpoint on chromosome 4 maps within a mariner transposon-like element HSMAR2, suggesting its potential causative role in the formation of the translocation. In an effort to identify possible transcripts that may be responsible for the CD phenotype, we used several gene-prediction programs and identified seven hypothetical transcripts in the region that spans 100 kb in either direction from the breakpoint on chromosome 17—Ecgenes H17C12306.1 and H17C12308.1, SGP genes Chr17_1538.1 and Ch17_1539.1, Fgenesh++ gene C17001650, and Genscan genes NT_010641.44 and NT_010641.45. Expression of these genes was explored by PCR analyses of human gonadal and fetal brain tissue cDNAs, in which SOX9 transcription is known to occur. Only exons from transcripts H17C12306.1, H17C12308.1, and Chr17_1538.1 were expressed, but none of these transcripts overlapped the breakpoint, making it unlikely that any genes in this region contribute to the CD phenotype. However, it is also possible that the translocation breakpoint may have disrupted the regulation of one of these more proximally located transcripts. Mutation screening of SOX9 revealed only one heterozygous common polymorphism, PM 879 in exon 2, which is known to be not associated with a CD phenotype. Patient 2: A 15-year-old, G1P0 white woman was referred at 12 wk of gestation because of a family history of Down syndrome. Ultrasound examination showed multiple congenital anomalies, including increased nuchal fold, prominent cisterna magna, micrognathia, deviation of the cardiac axis, and hypoplasia of the middle phalanx of the fifth digit. After receiving genetic counseling, she elected to undergo amniocentesis. GTG-banding analysis of amniotic fluid chromosomes from in situ cultures showed a complex karyotype: 46,XY,t(4;7;8;17)(4qter→4p15.2::17q25→17qter;7qter→7p15::4p15.2→4pter;8pter→8q12.2::7p15→7pter;17pter→17q25::8q12.2→8qter). At the chromosome level, the complex translocation appeared to be balanced. Parental chromosomes were normal. Ultrasound examination showed a female fetus. On the basis of the presence of the 17q25 breakpoint, the XY sex reversal was inferred to be the result of SOX9 gene malfunction. At 38 wk of gestation, the fetus showed decreased movements. The amniotic fluid index was decreased, vaginal delivery was induced, and a baby girl was delivered. The Apgar scores were 5 and 8 at 1 min and 5 min, respectively. External examination revealed a weight of 2,720 g, with a head circumference of 33.4 cm. The infant was noted to have several congenital anomalies, including a cleft palate, micrognathia, small mouth, posteriorly rotated ears, and nail and digital abnormalities. Three days after birth, the baby was extubated but developed respiratory distress, immediately requiring reintubation. After 3 wk, because of the poor prognosis, the infant was extubated, after which she expired. At autopsy, additional multiple congenital malformations of the skeletal system were observed, including abnormally developed cartilage and bone, 11 pairs of ribs, and normal female genitalia with abnormally formed ovaries with no oocytes (fig. 3). Acampomelic CD with male-to-female sex reversal was diagnosed. The identified chromosome aberration was confirmed by whole-chromosome painting and SKY (Vysis) (data not shown). Each of the four chromosome breakpoints was then mapped at a BAC clone resolution: chromosome 4 within BAC clone RP11-93M12 (4p15.1), chromosome 7 between BAC clones RP11-764N24 and RP11-233O19 (7p15.3), chromosome 8 within BAC clone RP11-17A4 (8q12.1), and chromosome 17 within two overlapping BAC clones, RP11-661C3 and RP11-449L23 (17q25.1). Using two-color interphase FISH with BAC clones RP11-1116I6 (SOX9 specific), RP11-879D6 (spanning the 17q upstream breakpoint), and RP11-661C3 (adjacent to the 17q downstream breakpoint on the centromeric side), we found no evidence of additional chromosome 17 rearrangements, such as paracentric inversion (data not shown). The patient's final karyotype was designated as 46,XY,t(4;7;8;17)(4qter→4p15.1::17q25.1→17qter;7qter→7p15.3::4p15.1→4pter;8pter→8q12.1::7p15.3→7pter;17pter→17q25.1::8q12.1→8qter). Genomic analysis of the breakpoint regions identified the disruption of the PCDH7 gene on chromosome 4. PCDH7 encodes a type I membrane protein and is predominantly expressed in the heart and brain. The chromosome 7 breakpoint is in the vicinity of RAPGEF5, a gene expressed in the brain that encodes a guanine nucleotide exchange factor. The breakpoint located on 17q25.1 likely interrupts the SDK2 gene (which encodes a protein involved in laminar-specific synaptic connectivity in the retina) ∼1.3 Mb downstream of SOX9. None of these genes are thought to contribute to the CD phenotype. Although the clinical features may be complicated by the disruption of genes in the other breakpoints, the classic CD features suggest that the chromosome 17 translocation is most likely responsible for the phenotype of this patient. It has been hypothesized that distal enhancers interact with promoters through a set of proteins that “bend” DNA to bring the enhancers within physical proximity of their respective target genes, thus regulating their function (Carter et al. Carter et al., 2002Carter D Chakalova L Osborne CS Dai YF Fraser P Long-range chromatin regulatory interactions in vivo.Nat Genet. 2002; 32: 623-626Crossref PubMed Scopus (488) Google Scholar; Tolhuis et al. Tolhuis et al., 2002Tolhuis B Palstra R-J Splinter E Grosveld F de Laat W Looping interaction between hypersensitive sites in the active β-globin locus.Mol Cell. 2002; 10: 1453-1465Abstract Full Text Full Text PDF PubMed Scopus (1004) Google Scholar; Palstra et al. Palstra et al., 2003Palstra R-J Tolhuis B Splinter E Nijmeijer R Grosveld F de Laat W The β-globin nuclear compartment in development and erythroid differentiation.Nat Genet. 2003; 35: 190-194Crossref PubMed Scopus (414) Google Scholar). To investigate the possibility of spatial proximity of cis-acting regulatory elements to SOX9, we performed a two-color interphase FISH assay with the use of the SOX9-specific BAC clone RP11-1116I6, the 17q upstream breakpoint–specific clone RP11-879D6 (∼1 Mb upstream from SOX9), and the BAC clone RP11-661C3, which is adjacent to the 17q downstream breakpoint on the proximal side (∼1.2 Mb downstream from SOX9) (fig. 4A). Probes that span the RAI1 gene on 17p11.2 (RP11-525O11) and a region ∼1 Mb proximal to RAI1 (RP11-28B23) that is not known to harbor enhancers for that gene were used as negative controls. As positive controls, BAC clones specific to the POU3F4 gene and its predicted enhancer localized ∼900 kb upstream (de Kok et al. de Kok et al., 1996de Kok YJM Vossenaar ER Cremers CWRJ Dahl N Laporte J Hu LJ Lacombe D Fischel-Ghodsian N Friedman RA Parnes LS Thorpe P Bitner-Glindzicz M Pander H-J Heilbronner H Graveline J den Dunnen JT Brunner HG Ropers H-H Cremers FPM Identification of a hot spot for microdeletions in patients with X-linked deafness type 3 (DFN3) 900 kb proximal to the DFN3 gene POU3F4.Hum Mol Genet. 1996; 5: 1229-1235Crossref PubMed Scopus (129) Google Scholar) were used (RP11-246G22 and RP11-54M14, respectively). The distances between SOX9 and its potential enhancer regions (∼1.1 Mb upstream and ∼1.3 Mb downstream) and that between POU3F4 and its predicted enhancer (∼900 kb upstream), the positive control, was measured in 50 cells. There were no statistically different distance measurements in any of these three intervals. Remarkably, these three distances were each signifi" @default.
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