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Chromosome Breakage Hotspots and Delineation of the Critical Region for the 9P-Deletion Syndrome Laurie A

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Chromosome Breakage Hotspots and Delineation of the Critical Region for the 9P-Deletion Syndrome Laurie A View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Am. J. Hum. Genet. 65:1387–1395, 1999 Chromosome Breakage Hotspots and Delineation of the Critical Region for the 9p-Deletion Syndrome Laurie A. Christ,1 Carol A. Crowe,2 Mark A. Micale,1 Jeffrey M. Conroy,1 and Stuart Schwartz1 1Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland; and 2Department of Pediatrics, Case Western Reserve University and MetroHealth Medical Center, Cleveland Summary somy 9pϪ syndrome [MIM 158170]). The major clini- cal features in this syndrome include mental retardation, The clinical features of the 9p-deletion syndrome include trigonocephaly, midface hypoplasia, upward-slanting dysmorphic facial features (trigonocephaly, midface hy- palpebral fissures, and a long philtrum (Young et al. poplasia, upward-slanting palpebral fissures, and a long 1982; Huret et al. 1988). Trigonocephaly and upward- philtrum) and mental retardation. The majority of these slanting palpebral fissures are found in virtually all pa- patients appear to have similar cytogenetic breakpoints tients with this syndrome. In 1100 patients, features fre- in 9p22, but some cases show phenotypic heterogeneity. quently seen in this condition include hypertelorism, ep- To define the breakpoints of the deleted chromosomes, icanthus, small palpebral fissures, flat nasal bridge, we studied 24 patients with a deletion of 9p, by high- anteverted nares, low-set malformed posteriorly angu- resolution cytogenetics, FISH with 19 YACs, and PCR lated ears, microstomia, micrognathia, short-appearing using 25 different sequence-tagged sites. Of 10 different neck, widely spaced nipples, square hyperconvex nails, breakpoints identified, 9 were localized within an ∼5- dolichomesophalangy, and hypotonia. Less frequently, Mb region, in 9p22-p23, that encompasses the interval other malformations have been seen, which include car- between D9S1869 (telomeric) and D9S162 (centromer- diac defects, hernias, omphaloceles, choanal atresia, ab- ic). Eight unrelated patients had a breakpoint (group 1) normal genitalia, and scoliosis (Breg et al. 1976; Huret in the same interval, between D9S274 (948h1) and et al. 1988; Taylor et al. 1991; Bennett et al. 1993; Teebi D9S285 (767f2), suggesting a chromosome-breakage et al. 1993; Shashi et al. 1994). Nonketotic hypergly- hotspot. Among 12 patients, seven different breakpoints cemia has been recognized in a small number of patients (groups 3–9) were localized to a 2-Mb genomic region (Burton et al. 1989). between D9S1709 and D9S162, which identified a In a review of 80 literature cases with deletions of 9p, breakpoint-cluster region. The critical region for the 9p- Huret et al. (1988) found that approximately half were deletion syndrome maps to a 4–6-Mb region in 9p22- due to de novo deletions and that the remaining half p23. The results from this study have provided insight were due to unbalanced rearrangements. The majority into both the heterogeneous nature of the breakage in (39/41) of the unbalanced rearrangements were familial. this deletion syndrome and the resultant phenotype-kar- Cytogenetics studies have suggested that breaks can oc- yotype correlations. cur in 9p21-p23. To date, two studies have used addi- tional molecular techniques to characterize a small num- ber of cases (Teebi et al. 1993; Wagstaff and Hemann 1995). Teebi et al. (1993) characterized two rearranged chromosomes 9 by using chromosome-specific libraries. Introduction Wagstaff and Hemann (1995), utilizing microsatellite markers, characterized two deletions and initially re- The chromosome-9p deletion was initially characterized ported the 9p deletion–syndrome critical region as in- in 1973 by Alfi et al., who reported a characteristic phe- cluding the interval between D9S286 and D9S162. notype observed in six patients (Alfi et al. 1973) (mono- The lack of high-resolution chromosome analysis and molecular analysis can lead to both misassignment of Received March 31, 1997; accepted for publication August 30, 1999; electronically published October 8, 1999. the breakpoint and failure to detect additional chro- Address for correspondence and reprints: Dr. Stuart Schwartz, mosomal material or a derived chromosome 9 and can Center for Human Genetics, Case Western Reserve University, 10524 obscure phenotype/karyotype correlations. To define the Euclid Avenue, Sixth Floor, Cleveland, OH 44106-9959. E-mail: breakpoints in all of the rearrangements in a large group [email protected] ᭧ 1999 by The American Society of Human Genetics. All rights reserved. of patients, we first determined whether these are de- 0002-9297/1999/6505-0021$02.00 letions or cryptic unbalanced rearrangements and, sec- 1387 1388 Am. J. Hum. Genet. 65:1387–1395, 1999 ond, established molecular breakpoints to determine the Table 1 pattern and mechanism of breakage in these patients. Patient Population, Cytogenetic Abnormality, and Origin of Rearrangement Patients and Methods Parental Patient Rearrangement (Type) Origin Clinical Population Group 1: a A total of 24 patients with deletions or rearrangements 1 Deletion (de novo) Paternal 2a Deletion (de novo) Paternal in the short arm of chromosome 9 were ascertained for 3 Unbalanced translocationb (familial) Maternal this study (table 1). Four of these samples (GM10994, 4a Deletion (de novo) Paternal GM01667, GM02356, and GM00870) were obtained 5 Deletion (de novo) Unknown from the National Institute of General Medical Sciences’ 6 Unbalanced translocationc (de Maternal Genetic Mutant Cell Repository. The other 20 samples novo) 7d Deletion (unknown) Unknown were obtained directly from patients either seen at Case 8 Deletion (de novo) Maternal Western Reserve University and involved with the Group 1/2: Chromosome 9pϪ Network or referred from other lab- 9a Deletion (de novo) Paternal oratories. All of these patients were reported to have Group 2: a trigonocephaly and features compatible with the 9p-de- 10 Deletion (de novo) Paternal Group 3: letion syndrome. The patient records for these latter 20 11e Deletion (unknown) Unknown patients were reviewed by one of the authors (C.A.C.), 12a Deletion (de novo) Maternal to identify those clinical features of the 9p-deletion syn- Group 4: drome. Photographs were reviewed when patients were 13 Unbalanced translocationf (familial) Maternal not available for physical examination. Group 5: 14 Deletion (de novo) Paternal Group 6: Cytogenetic Studies 15a Deletion (de novo) Paternal 16a Inversion/deletiong (de novo) Paternal Metaphase chromosomes were prepared either from 17a Deletion (de novo) Maternal phytohemagglutinin (PHA)-stimulated cultures or from Group 7: lymphoblast or fibroblast cultures, by standard proce- 18h Deletion (unknown) Unknown dures. Leukocytes from peripheral blood of the pro- Group 8: 19a Deletion (de novo) Maternal bands were cultured to obtain chromosomes at 20a Deletion (de novo) Maternal у600–750-band level (Yunis 1976; Ikeuchi 1984). Group 8/9: PHA-stimulated blood leukocytes were cultured for ∼72 21 Duplication/deletioni (de novo) Maternal h in RPMI 1640 with 17% fetal bovine serum. The Group 9: a cultures were synchronized by the addition of thymidine 22 Deletion (de novo) Maternal Group 10: for the last 16.5 h of culture, followed by the addition 23a Deletion (de novo) Paternal of ethidium bromide and colcemid for the last 45 min 24j Deletion (de novo) Unknown and 25 min of culture, respectively. The cells were treated a Reported by Micale et al. (1995). for 8 min with 0.075 M KCl and were fixed in 3:1 b 46,XX,der(9)t(3;9)(p26.2;p22.3)mat. methanol–acetic acid prior to staining. The chromo- c 46,XX,der(9)t(7;9)(p21.3;p22.1). somes were GTG-banded, and у20 chromosomal d GM10094. spreads were examined (Seabright 1971). e GM01667. f 46,XY,der(9)t(3;9)(p24.2;p22.1)mat. g 46,XX,del(9)(:q12rp22.3::q12rqter). FISH Studies h GM2356. i mos46,XX,del(9)(p22.1)/46,XX,der(9)t(9;9)(:p11rp22.1:: FISH was performed with YACs and chromosome- p22.1rqter). specific paints on the unstained slides, according to the j GM00870. technique of Pinkel et al. (1986, 1988), with minor mod- ifications (Sullivan et al. 1996). At least 10—and, in most cases, 20—metaphases were analyzed for the presence Digital images were captured by a confocal micro- of probe on both the normal and the rearranged chro- scope and/or Zeiss epifluorescent microscope equipped mosome. All of the YACs utilized in this study were with a cooled CCD camera (Photometrics CG250) con- obtained from Research Genetics, after examination of trolled by an Apple MacIntosh computer. Gray-scale the Whitehead Institute for Biomedical Research/MIT source images were captured separately with DAPI, pro- Center for Genome Research database. All of the YACs pidium iodide fluorescein, and rhodamine filter sets and used in this study were mapped on the basis of sequence- were merged and pseudocolored by Gene Join software tagged site (STS) content (fig. 1 and table 2). (Yale University). Christ et al.: Chromosome Breakage in 9p Deletion Sx 1389 Molecular Studies Table 2 Highly polymorphic microsatellite markers within or Delineation of Breakpoint Groups adjacent to the deleted region for each patient—and for STATUS OF YAC/STS their parents, when DNA from the latter was available GROUP Deleted Present (table 1)—were analyzed by PCR, by means of standard techniques. Primer sequences for microsatellite analysis 1 948h1 767f2 2 D9S285 V767f2 (reduced signal) (Operon Technologies or Research Genetics) were ob- 3 D9S156 742e6 tained from the Whitehead Institute for Biomedical Re- 4 718el 769h3 search/MIT Center for Genome Research and The Ge- 5 D9S157 877g2 nome Database and were used with standard methods 6 769h3 791h3 (Micale et al. 1995). Molecular distances in this study 7 791h3 776c5 8 776c5 950g5 were estimated by radiation hybrid data from the White- 9 950g5 924e7 head Institute for Biomedical Research/MIT Center for 10 924e7 778h8 Genome Research.
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  • FISH Mapping of the Sex-Reversal Region on Human Chromosome 9P in Two XY Females and in Primates
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