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Heterozygous Aggrecan Variants Are Associated with Short Stature and Brachydactyly: Description of 16 Probands and a Review of the Literature

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Heterozygous Aggrecan Variants Are Associated with Short Stature and Brachydactyly: Description of 16 Probands and a Review of the Literature This is a repository copy of Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature.. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/132516/ Version: Accepted Version Article: Sentchordi-Montané, L. orcid.org/0000-0002-4083-3352, Aza-Carmona, M., Benito-Sanz, S. et al. (17 more authors) (2018) Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature. Clinical Endocrinology, 88 (6). pp. 820-829. https://doi.org/10.1111/cen.13581 Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Clinical Endocrinology Heterozygous aggrecan mutations cause short stature with brachydactyly: Description of 16 probands and a review of the literature. Journal:For Clinical Peer Endocrinology Review Manuscript ID CEN-2017-001066.R1 Manuscript Type: 1 riginal Article - U$, Europe Date Submitted by the Author: 19-Jan-201, Complete -ist o. Authors: SENTC/ RDI-M NTANE, -UCIA0 /ospital In.anta -eonor, 1ediatrics0 /ospital Uni2ersitario -a 1a3, Institute o. Medical and Molecular Medicine, INGEMM0 /ospital Uni2ersitario -a 1a3, S5eletal dysplasia Multidisciplinary Unit 6UMDE7 A3a-Carmona, Miriam0 /ospital Uni2ersitario -a 1a3, Institute o. Medical and Molecular Medicine 6INGEMM70 /ospital Uni2ersitario -a 1a3, S5eletal dysplasia Multidisciplinary Unit 6UMDE70 Instituto de Salud Carlos III, CI8ERER 8enito-San3, Sara0 /ospital Uni2ersitario -a 1a3, Institute o. Medical and Molecular Medicine 6INGEMM70 Instituto de Salud Carlos III, CI8ERER 8arreda-8onis, Ana C.0 /ospital Uni2ersitario -a 1a3, 1ediatric Endocrinology0 /ospital Uni2ersitario -a 1a3, S5eletal dysplasia Multidisciplinary Unit 6UMDE7 S9nche3-4arre, Consuelo0 /ospital de Terrassa, 1ediatric Endocrinology 1rieto-Matos, 1ablo0 /ospital Uni2ersitario de Salamanca, 1ediatric Endocrinology0 Instituto de In2estigaci:n 8iom;dica Salamanca, 1ediatrics Rui3- ca<a, 1ablo0 /ospital Uni2ersitario 1uerta del Mar, 1ediatric Endocrinology -echuga-Sancho, Al.onso0 /ospital Uni2ersitario 1uerta del Mar, 1ediatric Endocrinology Carca2illa-Urqu>, Atilano0 /ospital Virgen de la Salud, 1ediatric Endocrinology Mulero-Collantes, In;s0 /ospital Uni2ersitario Rio /ortega, 1ediatric Endocrinology Martos-Moreno, 4abriel A.0 /ospital In.antil Uni2ersitario Nino Jesus, 1ediatric Endocrinology0 Uni2ersidad Aut:noma de Madrid, 1ediatr>a0 Instituto de Salud Carlos III, CI8ER Fisiopatolog>a de la besidad y Nutrici:n del 1o3o, Angela0 /ospital Uni2ersitario -a 1a3, Institute o. Medical and Molecular Medicine 6INGEMM70 Instituto de Salud Carlos III, CI8ERER Vallesp>n, Elena0 /ospital Uni2ersitario -a 1a3, Institute o. Medical and Molecular Medicine 6INGEMM70 Instituto de Salud Carlos III, CI8ERER ..iah, Ama5a0 She..ield ChildrenAs NHS Foundation Trust, Department o. ncology and Metabolism. Academic Unit o. Child /ealth 1arr:n-1aBares, Manuel0 /ospital Uni2ersitario -a 1a3, 1ediatric Radiology0 /ospital Uni2ersitario -a 1a3, S5eletal dysplasia Multidisciplinary Unit Page 1 of 29 Clinical Endocrinology 1 2 3 4 6UMDE7 Dinis, Isabel0 Centro /ospitalar e Uni2ersitario de Coimbra E1E, 1ediatric 5 Endocrinology 6 Sousa, Sergio 8.0 Centro /ospitalar e Uni2ersitario de Coimbra E1E, 7 Medical 4enetics Unit 8 Ros-1;re3, 1uri.icaci:n0 /ospital Uni2ersitario 1uerta del /ierro 9 MaBadahonda, 1ediatric Endocrinology 10 4on39le3-Casado, Isabel0 /ospital Uni2ersitario -a 1a3, 1ediatric Endocrinology0 /ospital Uni2ersitario -a 1a3, S5eletal dysplasia 11 Multidisciplinary Unit 6UMDE7 12 E. /eath, $aren0 /ospital Uni2ersitario -a 1a3, Institute o. Medical C 13 Molecular 4enetics0 /ospital Uni2ersitario -a 1a3, S5eletal dysplasia 14 Multidisciplinary Unit 6UMDE70 Instituto de Salud Carlos III, CI8ERER 15 $ey Dords: s5eletal dysplasia, short stature, aggrecan, ACAN, brachydactyly 16 17 18 19 For Peer Review 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 Clinical Endocrinology Page 2 of 29 1 2 3 1 Heterozygous aggrecan mutations cause short stature with brachydactyly: 4 5 2 Description of 16 probands and a review of the literature. 6 7 3 8 9 4 Short title: ACAN Clinical spectrum 10 11 5 12 13 6 Lucía Sentchordi-Montané1,2,3, Miriam Aza-Carmona2,3,4, Sara enito-Sanz2,4, Ana C. 14 15 7 arreda- onis3,5, Consuelo S#nchez-Garre6, Pablo Prieto-Matos7, Pablo Ruiz-Oca+a,, 16 17 8 Alfonso Lechu.a-Sancho,, Atilano Carcavilla-0r1u2, Inés Mulero-Collantes10, Gabriel A. 18 19 9 Martos-Moreno11, An.elaFor del Pozo Peer2,4, Elena 6allespn Review2,4, Ama7a Offiah12, Manuel Parr8n- 20 21 10 Pa9ares3,13, I. Dinis14, Ser.io . Sousa15, Purificaci8n Ros-Pérez16, Isabel Gonz#lez- 22 23 11 Casado3,5, Karen E. Heath2,3,4 24 25 12 26 27 13 1. Dept. of Pediatrics, Hospital 0niversitario Infanta Leonor, Madrid, Spain 28 29 14 2. Institute of Medical and Molecular Genetics (INGEMM), Hospital 0niversitario La Paz, 30 31 15 0niversidad Auton8ma de Madrid, IdiPAZ, Madrid, Spain 32 33 16 3. S7eletal displasia Multidisciplinary 0nit (0MDE), Hospital 0niversitario La Paz, 34 17 35 Madrid, Spain 36 37 18 4. CI ERER, ISCIII, Madrid, Spain 38 39 19 5. Dept. of Pediatric Endocrinolo.y, Hospital 0niversitario La Paz, Madrid, Spain 40 41 20 6. Dept. of Pediatric Endocrinolo.y, Hospital de Aerrassa, Aerrassa ( arcelona), Spain 42 43 21 44 7. Dept. of Pediatrics, Hospital 0niversitario Salamanca, Instituto de Investi.aci8n 45 22 iomédica de Salamanca (I SAL), Salamanca, Spain 46 47 23 ,. Dept. of Pediatrics, Hospital 0niversitario Puerta del Mar, C#diz, Spain 48 49 24 50 2. Dept. of Pediatrics, Hospital 6ir.en de la Salud, Aoledo, Spain 51 52 25 10. Dept. of Pediatrics, Hospital 0niversitario Ro Horte.a, 6alladolid, Spain 53 54 55 56 57 58 1 59 60 Page 3 of 29 Clinical Endocrinology 1 2 3 26 11. Dept. of Endocrinolo.y, Hospital Infantil 0niversitario Ni+o BesCs, 0niversidad 4 27 Auton8ma de Madrid, Instituto de Investi.aci8n Sanitaria La PrincesaD Dept. of 5 6 28 Pediatrics, 0niversidad Aut8noma de Madrid, and CI ERO N, ISCIII, Madrid, Spain 7 8 29 12. Department of Oncolo.y and Metabolism. Academic 0nit of Child Health. Sheffield 9 30 ChildrenEs NHS Foundation Arust, 0nited Kin.dom 10 11 12 31 13. Dept.of Pediatric Radiolo.y, Hospital 0niversitario La Paz, Madrid, Spain 13 14 32 14. Dept. of Pediatric Endocrinolo.y, Diabetes and Growth 0nit, Hospital Pedi#trico, 15 33 Centro Hospitalar e 0niversit#rio de Coimbra, Portu.al 16 17 18 34 15. Medical Genetics 0nit, Hospital Pedi#trico, Centro Hospitalar de Coimbra, Portu.al 19 For Peer Review 20 35 16. Dept. of Pediatrics, Hospital 0niversitario Puerta de Hierro Ma9adahonda, Madrid, 21 36 Spain 22 23 24 37 25 26 38 27 28 39 Corresponding author: Karen Heath, Institute of Medical H Molecular Genetics (INGEMM)D 29 30 40 Paseo Castellana 261, 2,046 Madrid, Spain. E-mailI 7aren.heathJsalud.madrid.or.D FaxI 31 32 41 L34 21 207 1040. 33 42 34 35 43 36 Acknowledgements: 37 44 38 Ahe authors would li7e to than7 the families for their participation in this study. Ahis wor7 was 39 45 40 supported in part by the followin. .rantsI SAF2012-30,71, SAF2015-66,31-R from the 41 46 42 MINECO (to K.E.H) and Fundaci8n SEEP (L.S-M and K.E.H). S. -S was awarded a 43 47 44 postdoctoral CI ERER fellowship. 45 48 46 47 49 48 Disclosure statement: Ahe authors have nothin. to disclose. 49 50 51 52 53 54 55 56 57 58 2 59 60 Clinical Endocrinology Page 4 of 29 1 2 3 50 SUMMARY 4 5 51 Objecti e: Mutations in the a..recan .ene (ACAN) have been identified in two autosomal 6 52 7 dominant s7eletal dysplasias, Spondyloepiphyseal dysplasia, Kimberley type (SEDK) and 8 53 9 osteochondritis dissecans, as well as in a severe recessive dysplasia, 10 54 11 Spondyloepimetaphyseal dysplasia, a..recan type. Next .eneration se1uencin. (NGS) has 12 55 13 aided the identification of heterozy.ous ACAN mutations in individuals with short stature, 14 56 15 minor s7eletal defects and mild facial dysmorphisms, some of whom have advanced bone 16 57 17 a.e ( A), poor pubertal spurt and early .rowth cessation as well as precocious osteoarthritis. 18 58 19 Design & methods: ClinicalFor and Peer .enetic characterization Review of 16 probands with heterozy.ous 20 59 21 ACAN variants, 14 with short stature and mild s7eletal defects (.roup 1) and two with SEDK 22 60 23 (.roup 2). Subse1uently, we reviewed the literature to determine the fre1uency of the 24 61 different clinical characteristics in ACAN positive individuals. 25 26 62 Results: A total of 16 ACAN variants were located throu.hout the .ene, six patho.enic 27 28 63 mutations and 10 variants of un7nown si.nificance (60S). Interestin.ly, brachydactyly was 29 30 64 observed in all probands. Probands from .roup 1, with a patho.enic mutation tended to be 31 32 65 shorter and 60M had an advanced A compared to 0M in those with a 60S. A hi.her 33 34 66 incidence of coxa val.a was observed in individuals with a 60S (37M v 0M).
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