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Detailed Characterization Of, and Clinical Correlations In, 10 Patients

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Detailed Characterization Of, and Clinical Correlations In, 10 Patients August 2008 ⅐ Vol. 10 ⅐ No. 8 article Detailed characterization of, and clinical correlations in, 10 patients with distal deletions of chromosome 9p Xueya Hauge, PhD1, Gordana Raca, PhD2, Sara Cooper, MS2, Kristin May, PhD3, Rhonda Spiro, MD4, Margaret Adam, MD2, and Christa Lese Martin, PhD2 Purpose: Deletions of distal 9p are associated with trigonocephaly, mental retardation, dysmorphic facial features, cardiac anomalies, and abnormal genitalia. Previous studies identified a proposed critical region for the consensus phenotype in band 9p23, between 11.8 Mb and 16 Mb from the 9p telomere. Here we report 10 new patients with 9p deletions; 9 patients have clinical features consistent with 9pϪ syndrome, but possess terminal deletions smaller than most reported cases, whereas one individual lacks the 9pϪ phenotype and shows a 140-kb interstitial telomeric deletion inherited from his mother. Methods: We combined fluorescence in situ hybridization and microarray analyses to delineate the size of each deletion. Results: The deletion sizes vary from 800 kb to 12.4 Mb in our patients with clinically relevant phenotypes. Clinical evaluation and comparison showed little difference in physical features with regard to the deletion sizes. Severe speech and language impairment were observed in all patients with clinically relevant phenotypes. Conclusion: The smallest deleted region common to our patients who demonstrate a phenotype consistent with 9pϪ is Ͻ2 Mb of 9pter, which contains six known genes. These genes may contribute to some of the cardinal features of 9p deletion syndrome. Genet Med 2008:10(8): 599–611. Key Words: 9p deletion, FISH, genotype-phenotype correlation, aCGH The 9p deletion syndrome is characterized by trigonoceph- points in 24 patients with visible 9p deletions and breakpoints aly, moderate to severe mental retardation, low-set, mal- at 9p22 or 9p23. Markers D9S274 (14.2 Mb from the telomere) formed ears, and dysmorphic facial features, such as up-slant- and D9S286 (8 Mb) were absent in all 24 patients with 9pϪ, ing palpebral fissures and a long philtrum.1,2 Furthermore, whereas D9S285 (16 Mb) was present in a subset of these pa- abnormal genitalia are found in some 9pϪ patients who have a tients. Thus, the minimal deleted segment in this group of chromosomal complement of 46, XY,3 and hypopigmentation patients included 16 Mb of the 9p terminus. Wagstaff and He- has also been described in two independent studies.4,5 Since the mann4 described a patient with typical features of 9pϪsyndrome original report of the syndrome in 1973,6 over 140 cases of 9p and an interstitial deletion between 8 Mb and 19 Mb of 9p. Based deletion have been documented. The breakpoints occur in on the data of Wagstaff and Hemann,4 and from their own data, bands from 9p22 to 9p24, and the large majority of patients Christ et al.,2 modified their critical region, i.e., the distal 16 Mb of have either terminal deletions or translocations involving an- 9p, and concluded that the critical region for the 9pϪsyndrome other chromosome. lies in an ϳ8-Mb region between D9S285 and D9S286, encom- Previous studies have delineated the size of 9p deletions in passing bands 9p22-9p23. an attempt to develop genotype-phenotype correlations. In Among a number of recent publications, Muroya et al.,7 one large study, Christ et al.,2 characterized the deletion break- determined the breakpoints in six patients with 9p deletions using microsatellite markers. Of these, two patients who did From the 1Department of Biology and Physics, Kennesaw State University, Kennesaw, Geor- not show the typical phenotype observed with 9pϪsyndrome 2 gia; Department of Human Genetics, Emory University School of Medicine, Atlanta, Geor- had small deletions (ϳ3 Mb) of 9pter, as the marker at 2.8 Mb gia; 3Department of Pediatrics, University of Tennessee College of Medicine, Chattanooga Unit, Chattanooga, Tennessee; and 4National Birth Defect Center, Waltham, Massachusetts. (D9S1136) from 9pter was present, whereas the marker at 2.1 Christa Lese Martin, PhD, Department of Human Genetics, Emory University School of Mb (D9S143) was absent. But neither of these cases had pure Medicine, 615 Michael Street, Suite 301, Atlanta, GA 30322. E-mail: clmartin@genetics. deletions: one had a duplication of 9p (9p12-p24), and the emory.edu. other had a trisomy of 4p (4p13-pter). Kawara et al.,5 described First two authors contributed equally to this work. one patient who had a complex translocation and insertion Disclosure: The authors declare no conflict of interest. involving chromosomes 2 and 9p. The major clinical features Submitted for publication December 21, 2007. of this patient included trigonocephaly, mental retardation, Accepted for publication April 29, 2008. and facial features commonly seen in the 9pϪsyndrome. Using DOI: 10.1097/GIM.0b013e31817e2bde fluorescence in situ hybridization (FISH) analysis, the region Genetics IN Medicine 599 Hauge et al. deleted from 9p was mapped to a 6.6-Mb region between 11.8 Case 1 has long-standing difficulties with excessive weight Mb and 18 Mb of the 9p terminus. Based on these data and gain. At 1 year of age, his weight was 16.3 kg (ϾϾ97th centile; those of Christ et al.,2 the authors concluded that the critical 50th centile for 3–3/4 years). He also has experienced an un- region for the 9pϪsyndrome lies in a 4.7-Mb region between usual sleep pattern; once or twice every few months he will 11.4 Mb and 16 Mb of 9p; they furthermore proposed cerbe- have episodes in which he sleeps between 12 and 48 hours. rus-related 1 (CER1) as a candidate gene for trigonocephaly. During these times his family cannot rouse him. Afterward he Faas et al.,8 described another patient who had a 14.8 Mb de- has slurred speech and regression in both emotional and de- letion of 9pter (9p22.3-pter) and a 50.9 Mb duplication of velopmental milestones. It takes him about 7–10 days to fully chromosome 9 (9p22.3-q12). The patient had trigonocephaly recover. A head magnetic resonance image (MRI) was normal, and facial features consistent with 9pϪsyndrome. Based on the but the patient does have a known seizure disorder. It is unclear data published by Kawara et al.,5 the authors concluded that a whether these episodes of sleeping are a manifestation of sei- 3.5 Mb region, between 11.4 Mb and 14.9 Mb, is the critical zure activity. region for 9pϪsyndrome. On physical examination at 4 years, Case 1 weighed 23.6 kg In three studies2,5,8 the deletions of 9p were cytogenetically (ϾϾ97th centile; 50th centile for 7–1/4 years). His height was visible and the breakpoints were more than 10 Mb from 9pter. 95.9 cm (50th centile), and his head circumference was 49.5 cm In fact, only a few cases with 9p deletions smaller than 10 Mb (50th centile). No dysmorphic features were noted. Aside from have been reported to date, which is not unexpected, since the his weight and mild hypotonia, his physical examination was detection of subtle telomeric deletions presents a challenge in normal, as was a cardiology evaluation. routine G-banded cytogenetic studies. With the availability of Case 1 had a normal 46, XY karyotype at 625 bands. Meth- higher-resolution methods to detect and characterize copy num- ylation studies for Prader-Willi syndrome were negative and ber imbalances in the human genome, including FISH and array he had a normal muscle biopsy. Molecular studies for fragile X comparative genomic hybridization (aCGH), individuals with and FRAXE were normal. Telomere FISH analysis demon- cryptic 9p deletions have been identified in recent years.9–11 strated a deletion of the 9p telomere. Parental studies showed We have identified five patients with cryptic 9p telomere that his mother also had this same 9p deletion. deletions and five cases with cytogenetically visible deletions. The mother has had several medical issues herself. She has a Of these 10 new cases, 4 have pure, terminal deletions, 4 have history of petit mal seizures with onset at 13 years. She has been unbalanced translocations, one has a terminal deletion and an seizure-free off antiseizure medication since age 18. She is de- adjacent duplication, and one has an interstitial telomeric de- velopmentally normal. letion. FISH and aCGH were utilized to map the breakpoints in these cases. In addition, the clinical phenotypes of these indi- Case 2 viduals were compared. Based on our mapping data and phe- Case 2 is now a 6-year-old girl born at 37–1/2 weeks by notype comparisons, we have contributed to the delineation of repeat C-section. Her birth weight was 2.72 kg (10th–25th cen- genotype-phenotype correlations for the 9p deletion syn- tile) with a birth length of 45.7 cm (5th centile). Although she drome. had failure to thrive as an infant, this has since resolved. During childhood she was diagnosed with moderate mental retarda- MATERIALS AND METHODS tion. She has also been described as having autistic-like fea- Case descriptions tures. A physical examination demonstrated arching eyebrows, a long philtrum with thin upper lip, posteriorly rotated and Patients were ascertained through the Clinical Cytogenetic low-set ears, and clinobrachydactyly. No major malformations Laboratories at Emory University and the University of Chi- have been noted, but she does have a history of mild hypotonia. cago and through referrals to our telomere research project. Formal vision and hearing tests have been normal. A routine This study was carried out under protocols approved either by chromosome analysis was normal, as was a molecular study for the Institutional Review Board at Emory University or the Uni- fragile X. The patient was found to have a de novo cryptic versity of Chicago.
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