Abstract

The duplication 17p11.2 syndrome, associated with dup(17)(p11.2p11.2), is a recently recognized syndrome of multiple congenital anomalies and mental retardation and is the first predicted reciprocal microduplication syndrome described—the homologous recombination reciprocal of the Smith-Magenis syndrome (SMS) microdeletion (del(17)(p11.2p11.2)). We previously described seven subjects with dup(17)(p11.2p11.2) and noted their relatively mild phenotype compared with that of individuals with SMS. Here, we molecularly analyzed 28 additional patients, using multiple independent assays, and also report the phenotypic characteristics obtained from extensive multidisciplinary clinical study of a subset of these patients. Whereas the majority of subjects (22 of 35) harbor the homologous recombination reciprocal product of the common SMS microdeletion (∼3.7 Mb), 13 subjects (∼37%) have nonrecurrent duplications ranging in size from 1.3 to 15.2 Mb. Molecular studies suggest potential mechanistic differences between nonrecurrent duplications and nonrecurrent genomic deletions. Clinical features observed in patients with the common dup(17)(p11.2p11.2) are distinct from those seen with SMS and include infantile hypotonia, failure to thrive, mental retardation, autistic features, sleep apnea, and structural cardiovascular anomalies. We narrow the critical region to a 1.3-Mb genomic interval that contains the dosage-sensitive RAI1 gene. Our results refine the critical region for Potocki-Lupski syndrome, provide information to assist in clinical diagnosis and management, and lend further support for the concept that genomic architecture incites genomic instability. The duplication 17p11.2 syndrome, associated with dup(17)(p11.2p11.2), is a recently recognized syndrome of multiple congenital anomalies and mental retardation and is the first predicted reciprocal microduplication syndrome described—the homologous recombination reciprocal of the Smith-Magenis syndrome (SMS) microdeletion (del(17)(p11.2p11.2)). We previously described seven subjects with dup(17)(p11.2p11.2) and noted their relatively mild phenotype compared with that of individuals with SMS. Here, we molecularly analyzed 28 additional patients, using multiple independent assays, and also report the phenotypic characteristics obtained from extensive multidisciplinary clinical study of a subset of these patients. Whereas the majority of subjects (22 of 35) harbor the homologous recombination reciprocal product of the common SMS microdeletion (∼3.7 Mb), 13 subjects (∼37%) have nonrecurrent duplications ranging in size from 1.3 to 15.2 Mb. Molecular studies suggest potential mechanistic differences between nonrecurrent duplications and nonrecurrent genomic deletions. Clinical features observed in patients with the common dup(17)(p11.2p11.2) are distinct from those seen with SMS and include infantile hypotonia, failure to thrive, mental retardation, autistic features, sleep apnea, and structural cardiovascular anomalies. We narrow the critical region to a 1.3-Mb genomic interval that contains the dosage-sensitive RAI1 gene. Our results refine the critical region for Potocki-Lupski syndrome, provide information to assist in clinical diagnosis and management, and lend further support for the concept that genomic architecture incites genomic instability. Nonallelic homologous recombination (NAHR) between region-specific low-copy repeats (LCRs) (also known as “segmental duplications”) is a major cause of DNA rearrangements associated with many genomic disorders.1Lupski JR Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits.Trends Genet. 1998; 14: 417-422Abstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar, 2Stankiewicz P Lupski JR Genome architecture, rearrangements and genomic disorders.Trends Genet. 2002; 18: 74-82Abstract Full Text Full Text PDF PubMed Scopus (666) Google Scholar The proximal short arm of chromosome 17 is particularly rich in LCRs and is a regional locus for four genomic disorders, including Charcot-Marie-Tooth disease type 1A (CMT1A [MIM 118220]),3Pentao L Wise CA Chinault AC Patel PI Lupski JR Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit.Nat Genet. 1992; 2: 292-300Crossref PubMed Scopus (335) Google Scholar hereditary neuropathies with liabilities to pressure palsies (HNPP [MIM 162500]),4Reiter LT Murakami T Koeuth T Pentao L Muzny DM Gibbs RA Lupski JR A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element.Nat Genet. 1996; 12: 288-297Crossref PubMed Scopus (272) Google Scholar Smith-Magenis syndrome (SMS [MIM 182290]),5Chen K-S Manian P Koeuth T Potocki L Zhao Q Chinault AC Lee CC Lupski JR Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome.Nat Genet. 1997; 17: 154-163Crossref PubMed Scopus (323) Google Scholar and the recently recognized duplication 17p11.2 syndrome.6Potocki L Chen K-S Park S-S Osterholm DE Withers MA Kimonis V Summers AM Meschino WS Anyane-Yeboa K Kashork CD et al.Molecular mechanism for duplication 17p11.2—the homologous recombination reciprocal of the Smith-Magenis microdeletion.Nat Genet. 2000; 24: 84-87Crossref PubMed Scopus (249) Google Scholar The proximal and distal SMS LCRs (called “SMS-REPs”)7Park S-S Stankiewicz P Bi W Shaw C Lehoczky J Dewar K Birren B Lupski JR Structure and evolution of the Smith-Magenis syndrome repeat gene clusters, SMS-REPs.Genome Res. 2002; 12: 729-738Crossref PubMed Scopus (74) Google Scholar mediate the common deletion and reciprocal duplication at meiosis, resulting in SMS and duplication 17p11.2 syndrome, respectively.8Shaw CJ Bi W Lupski JR Genetic proof of unequal meiotic crossovers in reciprocal deletion and duplication of 17p11.2.Am J Hum Genet. 2002; 71: 1072-1081Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 9Bi W Park S-S Shaw CJ Withers MA Patel PI Lupski JR Reciprocal crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome 17p11.2.Am J Hum Genet. 2003; 73: 1302-1315Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar The architectural features of the genome in this region also stimulate nonrecurrent constitutional chromosomal rearrangements that yield different-sized deletions and duplications,10Shaw CJ Shaw CA Yu W Stankiewicz P White LD Beaudet AL Lupski JR Comparative genomic hybridisation using a proximal 17p BAC/PAC array detects rearrangements responsible for four genomic disorders.J Med Genet. 2004; 41: 113-119Crossref PubMed Scopus (63) Google Scholar, 11Stankiewicz P Shaw CJ Dapper JD Wakui K Shaffer LG Withers M Elizondo L Park S-S Lupski JR Genome architecture catalyzes nonrecurrent chromosomal rearrangements.Am J Hum Genet. 2003; 72: 1101-1116Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar translocations,11Stankiewicz P Shaw CJ Dapper JD Wakui K Shaffer LG Withers M Elizondo L Park S-S Lupski JR Genome architecture catalyzes nonrecurrent chromosomal rearrangements.Am J Hum Genet. 2003; 72: 1101-1116Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar marker chromosomes,12Stankiewicz P Parka S-S Holder SE Waters CS Palmer RW Berend SA Shaffer LG Potocki L Lupski JR Trisomy 17p10-p12 resulting from a supernumerary marker chromosome derived from chromosome 17: molecular analysis and delineation of the phenotype.Clin Genet. 2001; 60: 336-344Crossref PubMed Scopus (26) Google Scholar, 13Shaw CJ Stankiewicz P Bien-Willner G Bello SC Shaw CA Carrera M Perez Jurado L Estivill X Lupski JR Small marker chromosomes in two patients with segmental aneusomy for proximal 17p.Hum Genet. 2004; 115: 1-7Crossref PubMed Scopus (20) Google Scholar, 14Yatsenko SA Treadwell-Deering D Krull K Lewis RA Glaze D Stankiewicz P Lupski JR Potocki L Trisomy 17p10-p12 due to mosaic supernumerary marker chromosome: delineation of molecular breakpoints and clinical phenotype, and comparison to other proximal 17p segmental duplications.Am J Med Genet A. 2005; 138: 175-180Crossref Scopus (19) Google Scholar and somatic rearrangements involving 17p11.2.15Barbouti A Stankiewicz P Nusbaum C Cuomo C Cook A Hoglund M Johansson B Hagemeijer A Park S-S Mitelman F et al.The breakpoint region of the most common isochromosome, i(17q), in human neoplasia is characterized by a complex genomic architecture with large, palindromic, low-copy repeats.Am J Hum Genet. 2004; 74: 1-10Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar SMS is a well-characterized syndrome comprising multiple congenital anomalies and mental retardation and is associated with a heterozygous 17p11.2 deletion or point mutation of the retinoic acid inducible 1 gene (RAI1 [MIM 607642]) that maps within 17p11.2.16Greenberg F Guzzetta V Montes de Oca-Luna R Magenis RE Smith AC Richter SF Kondo I Dobyns WB Patel PI Lupski JR Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2).Am J Hum Genet. 1991; 49: 1207-1218PubMed Google Scholar, 17Greenberg F Lewis RA Potocki L Glaze D Parke J Killian J Murphy MA Williamson D Brown F Dutton R et al.Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2).Am J Med Genet. 1996; 62: 247-254Crossref PubMed Scopus (255) Google Scholar, 18Potocki L Shaw CJ Stankiewicz P Lupski JR Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)].Genet Med. 2003; 5: 430-434Crossref PubMed Scopus (87) Google Scholar, 19Slager RE Newton TL Vlangos CN Finucane B Elsea SE Mutations in RAI1 associated with Smith-Magenis syndrome.Nat Genet. 2003; 33: 466-468Crossref PubMed Scopus (229) Google Scholar, 20Bi W Saifi GM Shaw CJ Walz K Fonseca P Wilson M Potocki L Lupski JR Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome.Hum Genet. 2004; 115: 515-524Crossref PubMed Scopus (83) Google Scholar, 21Madduri N Peters SU Voigt RG Llorente AM Lupski JR Potocki L Cognitive and adaptive behavior profiles in Smith-Magenis syndrome.J Dev Behav Pediatr. 2006; 27: 188-192Crossref PubMed Scopus (39) Google Scholar, 22Goldman AM Potocki L Walz K Lynch JK Glaze DG Lupski JR Noebels JL Epilepsy and chromosomal rearrangements in Smith-Magenis syndrome [del(17)(p11.2p11.2)].J Child Neurol. 2006; 21: 93-98Crossref PubMed Scopus (27) Google Scholar Of the patients with SMS who harbor the deletion, ∼70%–80% have the recurrent ∼3.7-Mb common deletion mediated by NAHR with the proximal and distal SMS-REPs as recombination substrates,5Chen K-S Manian P Koeuth T Potocki L Zhao Q Chinault AC Lee CC Lupski JR Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome.Nat Genet. 1997; 17: 154-163Crossref PubMed Scopus (323) Google Scholar, 18Potocki L Shaw CJ Stankiewicz P Lupski JR Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)].Genet Med. 2003; 5: 430-434Crossref PubMed Scopus (87) Google Scholar whereas the remainder have smaller or larger deletions apparently stimulated by other LCRs in the region.11Stankiewicz P Shaw CJ Dapper JD Wakui K Shaffer LG Withers M Elizondo L Park S-S Lupski JR Genome architecture catalyzes nonrecurrent chromosomal rearrangements.Am J Hum Genet. 2003; 72: 1101-1116Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 23Shaw CJ Withers MA Lupski JR Uncommon deletions of the Smith-Magenis syndrome region can be recurrent when alternate low-copy repeats act as homologous recombination substrates.Am J Hum Genet. 2004; 75: 75-81Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Like SMS, duplication 17p11.2 syndrome is also associated with congenital anomalies and neurodevelopmental and behavioral phenotypes, yet the clinical features of each syndrome are distinct. Cytogenetic and clinical features of persons with partial trisomy of proximal 17p have been described, mostly in isolated case reports or literature reviews, and nonspecific and noncharacterizing findings include developmental delay, mental retardation, and dysmorphic features.12Stankiewicz P Parka S-S Holder SE Waters CS Palmer RW Berend SA Shaffer LG Potocki L Lupski JR Trisomy 17p10-p12 resulting from a supernumerary marker chromosome derived from chromosome 17: molecular analysis and delineation of the phenotype.Clin Genet. 2001; 60: 336-344Crossref PubMed Scopus (26) Google Scholar, 14Yatsenko SA Treadwell-Deering D Krull K Lewis RA Glaze D Stankiewicz P Lupski JR Potocki L Trisomy 17p10-p12 due to mosaic supernumerary marker chromosome: delineation of molecular breakpoints and clinical phenotype, and comparison to other proximal 17p segmental duplications.Am J Med Genet A. 2005; 138: 175-180Crossref Scopus (19) Google Scholar, 24Docherty Z Hulten MA Honeyman MM De novo tandem duplication 17p11→cen.J Med Genet. 1983; 20: 138-142Crossref PubMed Scopus (17) Google Scholar, 25Magenis RE Brown MG Allen L Reiss J De novo partial duplication of 17p [dup(17)(p12→p11.2)]: clinical report.Am J Med Genet. 1986; 24: 415-420Crossref PubMed Scopus (33) Google Scholar, 26Kozma C Meck JM Loomis KJ Galindo HC De novo duplication of 17p [dup(17)(p12→p11.2)]: report of an additional case with confirmation of the cytogenetic, phenotypic, and developmental aspects.Am J Med Genet. 1991; 41: 446-450Crossref PubMed Scopus (28) Google Scholar, 27Brown A Phelan MC Patil S Crawford E Rogers RC Schwartz C Two patients with duplication of 17p11.2: the reciprocal of the Smith-Magenis syndrome deletion?.Am J Med Genet. 1996; 63: 373-377Crossref PubMed Scopus (27) Google Scholar, 28Balarin MA da Silva Lopes VL Varella-Garcia M A dup(17)(p11.2p11.2) detected by fluorescence in situ hybridization in a boy with Alport syndrome.Am J Med Genet. 1999; 82: 183-186Crossref PubMed Scopus (17) Google Scholar, 29Moog U Engelen JJ Weber BW Van Gelderen M Steyaert J Baas F Sijstermans HM Fryns JP Hereditary motor and sensory neuropathy (HMSN) IA, developmental delay and autism related disorder in a boy with duplication (17)(p11.2p12).Genet Couns. 2004; 15: 73-80PubMed Google Scholar, 30Shaw CJ Stankiewicz P Christodoulou J Smith E Jones K Lupski JR A girl with duplication 17p10-p12 associated with a dicentric chromosome.Am J Med Genet A. 2004; 124: 173-178Crossref Scopus (11) Google Scholar Many cases of 17p duplication have been defined only by routine G-banded chromosome analyses and FISH, and, in these reports, the duplicated regions are not well characterized at the molecular level. Elsewhere, we described patients with the predicted reciprocal recombination product of the common SMS deletion, dup(17)(p11.2p11.2), and we found, from the limited information available, that the phenotype was mild compared with that of individuals with del(17)(p11.2p11.2).6Potocki L Chen K-S Park S-S Osterholm DE Withers MA Kimonis V Summers AM Meschino WS Anyane-Yeboa K Kashork CD et al.Molecular mechanism for duplication 17p11.2—the homologous recombination reciprocal of the Smith-Magenis microdeletion.Nat Genet. 2000; 24: 84-87Crossref PubMed Scopus (249) Google Scholar Only one of the patients (patient 990) participated in a systematic clinical evaluation in the General Clinical Research Center (GCRC) at Texas Children’s Hospital, and more-detailed findings are described here. Interestingly, patient 990 and the patient described by Moog et al.29Moog U Engelen JJ Weber BW Van Gelderen M Steyaert J Baas F Sijstermans HM Fryns JP Hereditary motor and sensory neuropathy (HMSN) IA, developmental delay and autism related disorder in a boy with duplication (17)(p11.2p12).Genet Couns. 2004; 15: 73-80PubMed Google Scholar were reported to have features of autism. Patients with duplication of only the RAI1 locus have not been described. Here, the molecular assays of 35 subjects with dup(17)(p11.2p11.2) are reported. Of these subjects, 22 harbor a “common” duplication (∼3.7 Mb), and 13 harbor nonrecurrent duplications ranging in size from 1.3 to 15.2 Mb, as determined by multiple independent molecular assays. Phenotypic characterization of this microduplication syndrome is achieved, not only by review of the medical literature and available medical records, but also by systemic multidisciplinary clinical evaluations through a clinical protocol in the GCRC of a subset of 10 subjects, including 1 subject who harbors the smallest duplication identified to date. Apart from developmental delay, language impairment, and cognitive impairment, the most frequent clinical features in persons with dup(17)(p11.2p11.2) are hypotonia, poor feeding and failure to thrive in infancy, oral-pharyngeal dysphasia, autistic features, obstructive and central sleep apnea, structural cardiovascular abnormalities, electroencephalogram (EEG) abnormalities, and hypermetropia. Features reported in >50% of patients with the SMS deletion17Greenberg F Lewis RA Potocki L Glaze D Parke J Killian J Murphy MA Williamson D Brown F Dutton R et al.Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2).Am J Med Genet. 1996; 62: 247-254Crossref PubMed Scopus (255) Google Scholar, 18Potocki L Shaw CJ Stankiewicz P Lupski JR Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)].Genet Med. 2003; 5: 430-434Crossref PubMed Scopus (87) Google Scholar that either are not observed or are seen only infrequently in the duplication 17p11.2 syndrome include short stature, hearing impairment, otolaryngologic abnormalities, ophthalmic abnormalities such as myopia and iris hamartomata, genitourinary and/or renal anomalies, clinically significant scoliosis, and hypercholesterolemia. Because duplication 17p11.2 syndrome is a distinct clinical entity from its recombination reciprocal and because the cytogenetic nomenclature can be cumbersome when used to refer to affected individuals, we propose that this newly characterized microduplication syndrome be referred to by the eponym “Potocki-Lupski syndrome” (PLS). Thirty-five subjects (table 1) with duplication of the proximal short arm of chromosome 17 were enrolled in a molecular protocol that was approved by the Baylor College of Medicine (BCM) Institutional Review Board (IRB). Of these subjects, 10 (age range 25 mo to 14.5 years; 6 males) also participated in a BCM IRB–approved multidisciplinary clinical study through the GCRC at the Texas Children’s Hospital. Informed consent was obtained from the participants and parents or legal guardians. All but two were ascertained through an abnormal G-banded chromosome analysis, although many subjects had at least one chromosome analysis that was interpreted as normal. The diagnosis for two recently identified patients was confirmed by a commercially available array comparative genomic hybridization (array CGH) performed after a normal G-banded chromosome analysis (patients 2543 and 2555) and subtelomeric FISH analysis (patient 2543).Table 1Summary of Cytogenetic and Molecular Analyses of SubjectsBreakpointcThese breakpoint data are from array CGH. “Outside” indicates that the breakpoint is outside array detection.SubjectaLaboratory numbers are given, and citations of references are included if the subject was described elsewhere.KaryotypeDuplication Type (Size in Mb)MechanismbM = maternal; P = paternal; inter = interchromosomal; intra = intrachromosomal.DistalProximal5046Potocki L Chen K-S Park S-S Osterholm DE Withers MA Kimonis V Summers AM Meschino WS Anyane-Yeboa K Kashork CD et al.Molecular mechanism for duplication 17p11.2—the homologous recombination reciprocal of the Smith-Magenis microdeletion.Nat Genet. 2000; 24: 84-87Crossref PubMed Scopus (249) Google Scholar, 26Kozma C Meck JM Loomis KJ Galindo HC De novo duplication of 17p [dup(17)(p12→p11.2)]: report of an additional case with confirmation of the cytogenetic, phenotypic, and developmental aspects.Am J Med Genet. 1991; 41: 446-450Crossref PubMed Scopus (28) Google Scholar, 31Roa BB Greenberg F Gunaratne P Sauer CM Lubinsky MS Kozma C Meck JM Magenis RE Shaffer LG Lupski JR Duplication of the PMP22 gene in 17p partial trisomy patients with Charcot-Marie-Tooth type-1A neuropathy.Hum Genet. 1996; 97: 642-649PubMed Google Scholar46,XY,dir dup(17)(pter-p11.2:p12-p11.2:p11.2-qter)CommonP, inter……52731Roa BB Greenberg F Gunaratne P Sauer CM Lubinsky MS Kozma C Meck JM Magenis RE Shaffer LG Lupski JR Duplication of the PMP22 gene in 17p partial trisomy patients with Charcot-Marie-Tooth type-1A neuropathy.Hum Genet. 1996; 97: 642-649PubMed Google Scholar, 32Lupski JR Wise CA Kuwano A Pentao L Parke JT Glaze DG Ledbetter DH Greenberg F Patel PI Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A.Nat Genet. 1992; 1: 29-33Crossref PubMed Scopus (226) Google Scholar46,XY,dup(17)(p11.2p12)(10.5)M, intraRP11-756K11RP11-822E2356325Magenis RE Brown MG Allen L Reiss J De novo partial duplication of 17p [dup(17)(p12→p11.2)]: clinical report.Am J Med Genet. 1986; 24: 415-420Crossref PubMed Scopus (33) Google Scholar, 31Roa BB Greenberg F Gunaratne P Sauer CM Lubinsky MS Kozma C Meck JM Magenis RE Shaffer LG Lupski JR Duplication of the PMP22 gene in 17p partial trisomy patients with Charcot-Marie-Tooth type-1A neuropathy.Hum Genet. 1996; 97: 642-649PubMed Google Scholar46,XX,dup(17)(p11.2p12)(5.5)PRP11-726O12RP11-98L1462131Roa BB Greenberg F Gunaratne P Sauer CM Lubinsky MS Kozma C Meck JM Magenis RE Shaffer LG Lupski JR Duplication of the PMP22 gene in 17p partial trisomy patients with Charcot-Marie-Tooth type-1A neuropathy.Hum Genet. 1996; 97: 642-649PubMed Google Scholar46,XY,inv dup(17)(p13.3p11.2)ComplexMOutsideRP11-45M229906Potocki L Chen K-S Park S-S Osterholm DE Withers MA Kimonis V Summers AM Meschino WS Anyane-Yeboa K Kashork CD et al.Molecular mechanism for duplication 17p11.2—the homologous recombination reciprocal of the Smith-Magenis microdeletion.Nat Genet. 2000; 24: 84-87Crossref PubMed Scopus (249) Google Scholar46,XY,dup(17)(p11.2p11.2)CommonP, inter……10066Potocki L Chen K-S Park S-S Osterholm DE Withers MA Kimonis V Summers AM Meschino WS Anyane-Yeboa K Kashork CD et al.Molecular mechanism for duplication 17p11.2—the homologous recombination reciprocal of the Smith-Magenis microdeletion.Nat Genet. 2000; 24: 84-87Crossref PubMed Scopus (249) Google Scholar, 33Potocki L Chen K-S Koeuth T Killian J Iannaccone ST Shapira SK Kashork CD Spikes AS Shaffer LG Lupski JR DNA rearrangements on both homologues of chromosome 17 in a mildly delayed individual with a family history of autosomal dominant carpal tunnel syndrome.Am J Hum Genet. 1999; 64: 471-478Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar46,XX,del(17)(p12p12)dup(17)(p11.2p11.2)CommonP, intraRP11-92B11RP11-434D211926Potocki L Chen K-S Park S-S Osterholm DE Withers MA Kimonis V Summers AM Meschino WS Anyane-Yeboa K Kashork CD et al.Molecular mechanism for duplication 17p11.2—the homologous recombination reciprocal of the Smith-Magenis microdeletion.Nat Genet. 2000; 24: 84-87Crossref PubMed Scopus (249) Google Scholar46,XX,dup(17)(p11.2p11.2)CommonP, inter……122946,XY,dup(17)(p11.2p11.2)(6.4)P, intraRP11-849N15Outside12516Potocki L Chen K-S Park S-S Osterholm DE Withers MA Kimonis V Summers AM Meschino WS Anyane-Yeboa K Kashork CD et al.Molecular mechanism for duplication 17p11.2—the homologous recombination reciprocal of the Smith-Magenis microdeletion.Nat Genet. 2000; 24: 84-87Crossref PubMed Scopus (249) Google Scholar, 34Schneider MC Hughes CR Forrester S Kimonis V Mild phenotype due to tandem duplication of 17p11.2.Am J Med Genet. 2000; 94: 296-299Crossref PubMed Scopus (12) Google Scholar46,XX,dup(17)(p11.2p11.2)CommonP, intra……13536Potocki L Chen K-S Park S-S Osterholm DE Withers MA Kimonis V Summers AM Meschino WS Anyane-Yeboa K Kashork CD et al.Molecular mechanism for duplication 17p11.2—the homologous recombination reciprocal of the Smith-Magenis microdeletion.Nat Genet. 2000; 24: 84-87Crossref PubMed Scopus (249) Google Scholar46,XY,dup(17)(p11.2p11.2)CommonM, inter……13646Potocki L Chen K-S Park S-S Osterholm DE Withers MA Kimonis V Summers AM Meschino WS Anyane-Yeboa K Kashork CD et al.Molecular mechanism for duplication 17p11.2—the homologous recombination reciprocal of the Smith-Magenis microdeletion.Nat Genet. 2000; 24: 84-87Crossref PubMed Scopus (249) Google Scholar46,XY,dup(17)(p11.2p11.2)CommonM, intra……145828Balarin MA da Silva Lopes VL Varella-Garcia M A dup(17)(p11.2p11.2) detected by fluorescence in situ hybridization in a boy with Alport syndrome.Am J Med Genet. 1999; 82: 183-186Crossref PubMed Scopus (17) Google Scholar46,XY,dup(17)(p11.2p11.2)(8.2)M, intraRP11-590H8Outside152946,XX,dup(17)(p11.2p11.2)Common………157946,XY,dup(17)(p11.2p11.2)CommonM, inter……160246,XY,dup(17)(p11.2p11.2)Common………161846,XY,dup(17)(p11.2p11.2)CommonP, inter……163246,XY,dup(17)(p11.2p11.2)CommonM, inter……167146,XX,dup(17)(p11.2p11.2)CommonM, intra……178646,XX,dup(17)(p11.2p11.2)CommonP, intra……178946,XX,dup(17)(p11.2p11.2)CommonP, intraRP11-92B11RP11-434D2183846,XY,dup(17)(p11.2p11.2)CommonP, intra……186130Shaw CJ Stankiewicz P Christodoulou J Smith E Jones K Lupski JR A girl with duplication 17p10-p12 associated with a dicentric chromosome.Am J Med Genet A. 2004; 124: 173-178Crossref Scopus (11) Google Scholar46,XX,dic(17)dup(17)(p10p11.2)(7.1)M, intraRP11-998F8Outside191346,XX,dup(17)(p11.2p11.2)CommonP, intraRP11-92B11RP11-434D2215346,XY,dup(17)(p11.2p12)ComplexP, interRP11-92B11RP11-434D2216746,XX,dup(17)(p11.2p11.2)CommonPRP11-92B11RP11-434D2221146,XY,dup(17)(p11.2p12)(8.2)M, intraRP11-590H8OutsideeThe proximal breakpoint is located within the pericentromeric region as determined by FISH.230646,XY,dup(17)(p11.2p11.2)CommonM, inter……2337dL. E. L. M. Vissers, P. Stankiewicz, S. A. Yatsenko, E. Crawford, H. Creswick, V. K. Proud, B. B. A. de Vries, R. Pfundt, C. L. M. Marcelis, J. Zackowski, W. Bi, A. Geurts van Kessel, J. R. Lupski, and J. A. Veltman, personal communication.46,XY,der(17).ish del(17)(p13.3)dup(17)(p11.2p12) inv(17)(p11.2p13.3)ComplexM, intraRP11-131K5RP11-311F12236246,XY,dup(17)(p11.2p11.2)(6.9)…RP11-64B12RP11-822E23eThe proximal breakpoint is located within the pericentromeric region as determined by FISH.241446,XY,dup(17)(p11.2p11.2)Common…RP11-92B11RP11-434D2244046,XX,dup(17)(p11.2p11.2)(5.0)P, interRP11-385D13RP11-434D2248847,XYY,dup(17)(p11.2p11.2)(7.6)M, intraRP11-601N13RP11-822E23eThe proximal breakpoint is located within the pericentromeric region as determined by FISH.254346,XY(1.3)M, interRP1-48J14RP11-258F1255546,XXCommonM, interRP11-92B11RP11-434D2257146,XX,dup(17)(p11.2p11.2)CommonP, interRP11-92B11RP11-434D2Note.—Although initial chromosome analyses may have been normal, the result leading to referral is given. All subjects with a common ∼3.7-Mb duplication had an ∼1.1-Mb junction fragment evidenced by PFGE. No patient with a large or small duplication had this junction fragment. All subjects except 621 were duplicated by FISH analysis performed with FLI1 and/or RAI1.a Laboratory numbers are given, and citations of references are included if the subject was described elsewhere.b M = maternal; P = paternal; inter = interchromosomal; intra = intrachromosomal.c These breakpoint data are from array CGH. “Outside” indicates that the breakpoint is outside array detection.d L. E. L. M. Vissers, P. Stankiewicz, S. A. Yatsenko, E. Crawford, H. Creswick, V. K. Proud, B. B. A. de Vries, R. Pfundt, C. L. M. Marcelis, J. Zackowski, W. Bi, A. Geurts van Kessel, J. R. Lupski, and J. A. Veltman, personal communication.e The proximal breakpoint is located within the pericentromeric region as determined by FISH. Open table in a new tab Note.— Although initial chromosome analyses may have been normal, the result leading to referral is given. All subjects with a common ∼3.7-Mb duplication had an ∼1.1-Mb junction fragment evidenced by PFGE. No patient with a large or small duplication had this junction fragment. All subjects except 621 were duplicated by FISH analysis performed with FLI1 and/or RAI1. Clinical evaluations performed at the GCRC included physical examination, developmental and cognitive profiles, psychiatric history and diagnostic review, speech and language assessment, ophthalmologic and otolaryngologic examinations, audiologic assessment, swallow-function study, echocardiogram, electrocardiogram, overnight sleep study and multiple sleep latency test that included an EEG, renal ultrasound, scoliosis survey, radiographs of forearms and hands, fasting lipid profile, and thyroid function studies. Available medical records and previously reported data were reviewed for the subjects who did not participate in the multidisciplinary clinical protocol. Clinical information and/or partial molecular analyses have been reported elsewhere for subjects 504,6Potocki L Chen K-S Park S-S Osterholm DE Withers MA Kimonis V Summers AM Meschino WS Anyane-Yeboa K Kashork CD et al.Molecular mechanism for duplication 17p11.2—the homologous recombination reciprocal of the Smith-Magenis microdeletion.Nat Genet. 2000; 24: 84-87Crossref PubMed Scopus (249) Google Scholar, 26Kozma C Meck JM Loomis KJ Galindo HC De novo duplication of 17p [dup(17)(p12→p11.2)]: report of an additional case with confirmation of the cytogenetic, phenotypic, and developmental aspects.Am J Med Genet. 1991; 41: 446-450Crossref PubMed Scopus (28) Google Scholar, 31Roa BB Greenberg F Gunaratne P Sauer CM Lubinsky MS Kozma C Meck JM Magenis RE Shaffer LG Lupski JR Duplication of the PMP22 gene in 17p partial trisomy patients with Ch