Clinical and molecular delineation of Tetrasomy 9p syndrome: Report of 12 new cases and literature review Laïla El Khattabi, Sylvie Jaillard, Joris Andrieux, Laurent Pasquier, Laurence Perrin, Yline Capri, Abdelmadjid Benmansour, Annick Toutain, Pascale Marcorelles, Catherine Vincent-Delorme, et al. To cite this version: Laïla El Khattabi, Sylvie Jaillard, Joris Andrieux, Laurent Pasquier, Laurence Perrin, et al.. Clin- ical and molecular delineation of Tetrasomy 9p syndrome: Report of 12 new cases and litera- ture review. American Journal of Medical Genetics Part A, Wiley, 2015, 167 (6), pp.1252–1261. 10.1002/ajmg.a.36932. hal-01165441 HAL Id: hal-01165441 https://hal-univ-rennes1.archives-ouvertes.fr/hal-01165441 Submitted on 16 Sep 2015 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Page 2 of 20 El Khattabi et al., 1 1 2 3 Title: Clinical and molecular delineation of Tetrasomy 9p syndrome: report of 12 new cases and 4 5 literature review 6 Running title: elineation of Tetrasomy 9p syndrome 7 8 Authors: 9 Laïla El Khattabi1,2, Sylvie $aillard3, $oris Andrieux4, Laurent Pasquier5, Laurence Perrin,, -line 10 , 0 2 9 11 Capri , Abdelmad.id /enmansour , Annic1 Toutain , Pascale 3arcorelles , Catherine 4incent5 12 elorme10, 7ubert $ournel11, Catherine 7enry3, Claire e /arace12, Louise evisme13, Christèle 13 14,15 5 3 3,15 1, 14 ubourg , :lorence emurger , $osette Lucas , 3arc5Antoine /elaud5Rotureau , $eanne Amiel , 15 4alérie 3alan10, 3arie5Christine e /lois10, Loïc e Pontual12, Nathalie Le >2, ominique 16 19 20 21 , , 17 Germain , $ean53arc Pinard , Eva Pipiras , Anne5Claude Tabet , Azzedine Aboura , Alain 18 4erloes,,22 19 20 21 1. Cochin Anstitute, ANSER3 B101,, Paris, :rance 22 23 2. Cytogenetics epartment, A)7P, Cochin 7ospital, Paris escartes Bniversity, Paris, :rance 24 3. Cytogenetics and Cell /iology epartement, Rennes Bniversity 7ospital, Rennes, :rance 25 26 4. 3edical Genetics epartment, Lille 7ospital, Lille, :rance 27 5. 3edical Genetics epartment, Rennes Bniversity 7ospital, Rennes, :rance 28 29 ,. epartment of Genetics, A)7P-Robert ebré Bniversity 7ospital, Paris, :rance 30 31 0. Pediatrician, Cran, Algeria 32 2. epartment of Genetics, Tours Bniversity 7ospital, Tours, :rance 33 34 9. epartment of Pathology, C7B /rest, :rance 35 10. epartment of Genetics, Arras 7ospital, Arras, :rance 36 37 11. epartment of 3edical Genetics, C7/A, 4annes, :rance 38 12. epartment of Pediatrics, Saint-/rieuc 7ospital, Saint5/rieuc, :rance 39 40 13. epartment of Anatomy and Cell Pathology, C7RB Lille, :rance 41 14. 3olecular Genetics epartment, Rennes Bniversity 7ospital, Rennes, :rance 42 43 15. B3R ,290, AG R, 3edical School, Rennes, :rance 44 1,. epartment of Genetics, A)7P, Nec1er5Enfants 3alades Bniversity 7ospital, Paris, :rance 45 46 10. Laboratory of Cytogenetics, AP7P, Nec1er5Enfants 3alades 7ospital, Paris escartes Bniversity, 47 Paris, :rance 48 49 12. epartment of Pediatrics, $ean54erdier 7ospital, A)7P, Paris 13 Bniversity, /ondy, :rance 50 19. epartment of Genetics, Raymond Poincaré Bniversity 7ospital, Garches, :rance 51 52 20. epartment of Neuropediatrics, Raymond Poincaré Bniversity 7ospital, Garches, :rance 53 21. Cytogenetics, A)7P, $ean54erdier Bniversity 7ospital, /ondy D Paris 13, Sorbonne Paris Cité, 54 55 B:R SM/7, /obigny, :rance; Anserm, B,0,, Paris, France 56 57 22. ANSER3 B,0,, and Paris 4AA5 enis iderot 3edical School, Paris, :rance; 58 59 60 Page 3 of 20 El Khattabi et al., 2 1 2 3 Correspondence to: 4 5 r Laïla El Khattabi 6 Laboratoire de Cytogénétique 7 8 7Epital Cochin, AP-7P 9 53, Avenue de lFCbservatoire 10 11 05014 Paris 12 :rance 13 14 Tel: G33 152 413 530 15 Fax: G33 152 413 531 16 17 [email protected] 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 4 of 20 El Khattabi et al., 3 1 2 3 Abstract 4 5 Tetrasomy 9p is a generic term describing the presence of a supernumerary chromosome incorporating 6 two copies of the 9p arm. Two varieties exist: isodicentric chromosome 9p Ii(9p)), where the two 9p 7 8 arms are lin1ed by a single centromeric region, and pseudodicentric 9p IidicI9p)), where one active 9 and one inactive centromere are lin1ed together by a proximal segment of 9q that may incorporate 10 11 euchromatic material. An living patients, i(9p) and idicI9p) are usually present in a mosaic state. :ifty 12 four cases, including fetuses, have been reported, of which only two have been molecularly 13 14 characterized using array5CG7. Tetrasomy 9p leads to a variable phenotype ranging from multiple 15 congenital anomalies with severe intellectual disability and growth delay to subnormal mental and 16 17 physical developments. 7ypertelorism, dysplastic ears, microretrognathia and bulbous nose are the 18 most common dysmorphic traits. 3icrocephaly, growth retardation, .oint dislocation, scoliosis, cardiac 19 20 and renal anomalies were reported in several cases. Those physical anomalies are often, but not 21 universally, accompanied by intellectual deficiency. The most recurrent brea1points, defined by 22 23 conventional cytogenetics, are 9p10, 9q12 and 9q13. We report on twelve new patients with tetrasomy 24 9p I3 i(9p), 2 idicI9p) and 1 structurally uncharacterized), including the first case of parental germline 25 26 mosaicism. All rearrangements have been characterized by NA microarray. /ased on our results and 27 a review of the literature, we further delineate the prenatal and postnatal clinical spectrum of this 28 29 imbalance. Cur results show poor genotype5phenotype correlations and underline the need of precise 30 31 molecular characterization of the supernumerary mar1er. 32 33 34 Keywords: tetrasomy 9p, isochromosome, microarray, mosaicism 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 5 of 20 El Khattabi et al., 4 1 2 3 INTRODUCTION 4 5 9p tetrasomy IT9p) is a rare chromosomal imbalance defined by the presence of a supernumerary 6 chromosome, either an isochromosome or an isodicentric chromosome derived from the short arm of 7 8 chromosome 9. Ghymers described the first patient in 1903 LGhymers et al., 1903M. Schematically, the 9 two 9p arms can be separated by: a single centromeric region, leading to an isochromosome IiI9)), or 10 11 by two centromeres, forming either a dicentric IidicI9)) or a pseudodicentric Ipsu idicI9)) 12 chromosome, when only one of the two centromeres is active. An idicI9), the two 9p arms are lin1ed 13 14 together either by a segment of the pericentromeric heterochromatin from 9q or by a wider 9q5derived 15 segment that incorporates heterochromatic and proximal euchromatic material. An liveborns, T9p is 16 17 almost always observed in a mosaic state. 18 :ifty four cases have been reported in 40 years LAbe et al., 1900; Andou et al., 1994; /alestrazzi et al., 19 20 1923; Calvieri et al., 1922D Cavalcanti et al., 1920; Cazorla Calle.a et al., 2003; Chen et al., 2000D 21 Chen et al., 2012; Chen et al., 2014D Coman et al., 2002; Cuoco et al., 1922; de Azevedo 3oreira et 22 23 al., 2003D eurloo et al., 2004; handha et al., 2002; di 4era et al., 2002; utly et al., 1992; 24 Eggermann et al., 1992D Garcia5Cruz et al., 1922D Ghymers et al., 1903; Grass et al., 1993; 25 26 7engstschlager et al., 2004; 7enriques5Coelho et al., 2005D $alal et al., 1991; Leichtman et al., 199,; 27 Lloveras et al., 2004; 3cAuliffe et al., 2005; 3c owall et al., 1929D 3elaragno et al., 1992; 28 29 3oed.ono et al., 1920; Na1amura5Pereira et al., 2009D Na1amura et al., 1990; Cgino et al., 2000; Crye 30 31 et al., 1905; Papenhausen et al., 1990D Papoulidis et al., 2012; Par1 et al., 1995; Peters et al., 1922; 32 Podols1y et al., 2011D Rutten et al., 1904; Schaefer et al., 1991D Shapiro et al., 1925D Shehab et al., 33 34 2011; Stumm et al., 1999D Tan et al., 2000; Tang et al., 2004; Ton1 1990D 4an 7ove et al., 1994; 35 Wisniews1i et al., 1902M, among which 20 were prenatally diagnosed LCazorla Calle.a et al., 2003; 36 37 Chen et al., 2000; Chen et al., 2014D Coman et al., 2002D eurloo et al., 2004D handha et al., 2002D di 38 4era et al., 2002D utly et al., 1992D Eggermann et al., 1992; Grass et al., 1993; 7engstschlager et al., 39 40 2004; 3c owall et al., 1929D Na1amura5Pereira et al., 2009; Par1 et al., 1995; Podols1y et al., 2011; 41 Tan et al., 2000; Tang et al., 2004; 4an 7ove et al., 1994M. T9p leads to a variable phenotype ranging 42 43 from multiple congenital anomalies with severe intellectual disability and growth delay to subnormal 44 mental and physical developments. 7ypertelorism or telecanthus, dysplastic, low5set ears, 45 46 microretrognathia and bulbous nose are the most common dysmorphic traits. 3icrocephaly, growth 47 retardation, .oint dislocation, scoliosis, cardiac defects and renal anomalies were reported in several 48 49 cases ITable 1). Those physical anomalies are often, but not universally accompanied by intellectual 50 deficiency. Cnly two previously reported patients have been studied by microarray technology LChen 51 52 et al., 2014; Shehab et al., 2011M. We report here twelve new cases of T9p with different 53 rearrangements, all studied by NA microarray.