A 17-year-old girl presented with a distinct phenotype mainly featuring craniofacial dysmorphism, including a disproportioned large, round, elongated face; hypertelorism; deep-set eyes with short palpebral fissures; obesity (BMI 37), and a neuropsychiatric disorder with high-functioning autism. Postnatal conventional cytogenetic analyses from peripheral blood revealed a mosaic small supernumerary marker chromosome (sSMC) with a mos 47,XX,+mar[7]/46,XX[43] karyotype. By cenM-FISH technique, the sSMC was identified as a ring derivative of chromosome 5. Metaphase FISH analysis with a set of dedicated probes defined its origin from the pericentromeric region of chromosome 5, including the NIPBL gene at 5p13.2. Such sSMCs, exceedingly rare in the literature, underlie proximal trisomy 5p. In order to delineate a core phenotype of proximal trisomy 5p, we compared our patient's features with those of 6 patients found in the literature with similar der(5) chromosomes. Furthermore, a dozen individuals with 5p13 (micro)duplication syndrome was compared and discussed. We identified highly distinctive craniofacial dysmorphism, obesity, and intellectual disability and/or autism spectrum disorder as typical features of proximal 5p trisomy. In the critical region (band 5p13), the NIPBL gene is likely to be a major determinant of the neurobehavioral phenotype, and its presence at the sSMC level may be relevant to predict clinical outcome.

Keywords:
Autism spectrum disorder, FISH, Intellectual disability, Microduplication syndrome 5p13, NIPBL, Obesity, Partial 5p trisomy, Small supernumerary marker chromosome
1.
Avansino JR, Dennis TR, Spallone P, Stock AD, Levin ML: Proximal 5p trisomy resulting from a marker chromosome implicates band 5p13 in 5p trisomy syndrome. Am J Med Genet 87:6-11 (1999).
2.
Carrascosa Romero MC, García Hoyo R, Calvente M, Baquero Cano M, González Castillo L, Suela J: Neonatal detection of 5p13.2 duplication and delineation of the phenotype. Am J Med Genet A 158A:877-881 (2012).
3.
Cervera M, Sánchez S, Molina B, Alcántara MA, Del Castillo V, et al: Trisomy of the short arm of chromosome 5 due to a de novo inversion and duplication (5)(p15.3 p13.3). Am J Med Genet A 136A:381-385 (2005).
4.
Chia NL, Bousfield LR, Johnson BH: A case report of a de novo tandem duplication (5p) (p14-pter). Clin Genet 31:65-69 (1987).
5.
Crolla JA: FISH and molecular studies of autosomal supernumerary marker chromosomes excluding those derived from chromosome 15: II. Review of the literature. Am J Med Genet 75:367-381 (1998).
6.
D'Amato Sizonenko L, Ng D, Oei P, Winship I: Supernumerary marker chromosomes 5: confirmation of a critical region and resultant phenotype. Am J Med Genet 111:19-26 (2002).
7.
de Carvalho AF, da Silva Bellucco FT, Kulikowski LD, Toralles MB, Melaragno MI: Partial 5p monosomy or trisomy in 11 patients from a family with a t(5;15)(p13.3;p12) translocation. Hum Genet 124:387-392 (2008).
8.
Douyard J, Hawley P, Shaham M, Kimonis V: Duplication of 5q15-q23.2: case report and literature review. Birth Defects Res A Clin Mol Teratol 76:272-276 (2006).
9.
Grosso S, Cioni M, Garibaldi G, Pucci L, Galluzzi P, et al: De novo complete trisomy 5p: clinical and neuroradiological findings. Am J Med Genet 112:56-60 (2002).
10.
ISCN (2013): An International System for Human Cytogenetic Nomenclature, Shaffer LG, McGowan-Jordan J, Schmid M (eds) (Karger, Basel 2013).
11.
King DA, Jones WD, Crow YJ, Dominiczak AF, Foster NA, et al: Mosaic structural variation in children with developmental disorders. Hum Mol Genet 24:2733-2745 (2015).
12.
Leite R, Souto M, Carvalho B, Martins M, Chaves R, et al: Identification, characterization and clinical implications of two markers detected at prenatal diagnosis. Prenat Diagn 26:920-924 (2006).
13.
Liehr T, Thoma K, Kammler K, Gehring C, Ekici A, et al: Direct preparation of uncultured EDTA-treated or heparinized blood for interphase FISH analysis. Appl Cytogenet 21:185-188 (1995).
14.
Liehr T, Mrasek K, Weise A, Dufke A, Rodriguez L, et al: Small supernumerary marker chromosomes - progress towards a genotype-phenotype correlation. Cytogenet Genome Res 112:23-34 (2006).
15.
Lorda-Sánchez I, Urioste M, Villa A, Carrascosa MC, Vázquez MS, et al: Proximal partial 5p trisomy resulting from a maternal (19;5) insertion. Am J Med Genet 68:476-480 (1997).
16.
Loscalzo ML, Becker TA, Sutcliffe M: A patient with an interstitial duplication of chromosome 5p11-p13.3 further confirming a critical region for 5p duplication syndrome. Eur J Med Genet 51:54-60 (2008).
17.
Lucarelli E, Pasca MG, Fanizza I, Trabacca A: Electroclinical characteristics and neuropsychological profile of a female child with chromosome 5p13.2 duplication syndrome. Neurol Sci 38:915-917 (2017).
18.
Masuno M, Imaizumi K, Ishii T, Kimura J, Kuroki Y: Supernumerary ring chromosome 5 identified by FISH. Am J Med Genet 84:381 (1999).
19.
Melo JB, Backx L, Vermeesch JR, Santos HG, Sousa AC, et al: Chromosome 5 derived small supernumerary marker: towards a genotype/phenotype correlation of proximal chromosome 5 imbalances. J Appl Genet 52:193-200 (2011).
20.
Nietzel A, Rocchi M, Starke H, Heller A, Fiedler W, et al: A new multicolor-FISH approach for the characterization of marker chromosomes: centromere-specific multicolor-FISH (cenM-FISH). Hum Genet 108:199-204 (2001).
21.
Novara F, Alfei E, D'Arrigo S, Pantaleoni C, Beri S, et al: 5p13 microduplication syndrome: a new case and better clinical definition of the syndrome. Eur J Med Genet 56:54-58 (2013).
22.
Oexle K, Hempel M, Jauch A, Meitinger T, Rivera-Brugués N, et al: 3.7 Mb tandem microduplication in chromosome 5p13.1-p13.2 associated with developmental delay, macrocephaly, obesity, and lymphedema. Further characterization of the dup(5p13) syndrome. Eur J Med Genet 54:225-230 (2011).
23.
Pasini A, D'Agati E, Pitzianti Mb, Casarelli L, Curatolo P: Motor examination in children with attention-deficit/hyperactivity disorder and Asperger syndrome. Acta Paediatr 101:e15-18 (2012).
24.
Pitzianti Mb, D'Agati E, Pontis M, Baratta A, Casarelli L, et al: Comorbidity of ADHD and high-functioning autism: a pilot study on the Utility of the Overflow Movements Measure. J Psychiatr Pract 22:22-30 (2016).
25.
Reichenbach H, Holland H, Dalitz E, Demandt C, Meiner A, et al: De novo complete trisomy 5p: clinical report and FISH studies. Am J Med Genet 85:447-451 (1999).
26.
Sarri C, Gyftodimou Y, Grigoriadou M, Pandelia E, Kalogirou S, et al: Supernumerary marker chromosome 5 diagnosed by M-FISH in a child with congenital heart defect and unusual face. Cytogenet Genome Res 114:330-337 (2006).
27.
Stankiewicz P, Bocian E, Jakubów-Durska K, Obersztyn E, Lato E, et al: Identification of supernumerary marker chromosomes derived from chromosomes 5, 6, 19, and 20 using FISH. J Med Genet 37:114-120 (2000).
28.
Starke H, Nietzel A, Weise A, Heller A, Mrasek K, et al: Small supernumerary marker chromosomes (SMCs): genotype-phenotype correlation and classification. Hum Genet 114:51-67 (2003).
29.
Velagaleti GV, Morgan DL, Tonk VS: Trisomy 5. A case report and review. Ann Genet 43:143-145 (2000).
30.
Wulffaert J, van Berckelaer-Onnes I, Kroonenberg P, Scholte E, Bhuiyan Z, Hennekam R: Simultaneous analysis of the behavioural phenotype, physical factors, and parenting stress in people with Cornelia de Lange syndrome. J Intellect Disabil Res 53:604-619 (2009).
31.
Yan J, Zhang F, Brundage E, Scheuerle A, Lanpher B, et al: Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange. J Med Genet 46:626-634 (2009).
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2017
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