Diagnostic screening identifies a wide range of mutations involving the SHOX gene, including a common 47.5kb deletion 160kb downstream with a variable phenotypic effect

American Journal of Medical Genetics, Part A

Volumn 161, Issue 6, 2013, Pages 1329-1338

  Bunyan, David J ^a,b   Baker, Kevin R ^a   Harvey, John F ^a,b   Thomas, N Simon ^a,b  

^a SALISBURY DISTRICT HOSPITAL   (United Kingdom)

^b UNIVERSITY OF SOUTHAMPTON   (United Kingdom)

Author keywords

Deletions; Duplications; Point mutations; SHOX

Indexed keywords

ADOLESCENT; ADULT; ARTICLE; BONE MALFORMATION; CHROMOSOME BREAKAGE; COHORT ANALYSIS; CONTROLLED STUDY; DYSCHONDROSTEOSIS; FEMALE; FRAMESHIFT MUTATION; GENE; GENE DELETION; GENE DUPLICATION; GENE EXPRESSION REGULATION; GENE MUTATION; GENETIC ASSOCIATION; GENOTYPE PHENOTYPE CORRELATION; HAPLOTYPE; HUMAN; LANGER MESOMELIC DYSPLASIA; MAJOR CLINICAL STUDY; MALE; MULTIPLEX LIGATION DEPENDENT PROBE AMPLIFICATION; NONSENSE MUTATION; PHENOTYPIC VARIATION; PRIORITY JOURNAL; SEQUENCE ANALYSIS; SHORT STATURE; SHOX GENE; CHILD; CHONDRODYSPLASIA; DWARFISM; FOLLOW UP; GENETIC ASSOCIATION STUDY; GENETIC SCREENING; GENETICS; GENOTYPE; GROWTH DISORDER; HETEROZYGOTE; HOMOZYGOTE; MUTATION; NUCLEOTIDE SEQUENCE; PEDIGREE; PHENOTYPE; PRESCHOOL CHILD;

HOMEODOMAIN PROTEIN; SHOX PROTEIN, HUMAN;

ADOLESCENT; BASE SEQUENCE; CHILD; CHILD, PRESCHOOL; COHORT STUDIES; DWARFISM; FEMALE; FOLLOW-UP STUDIES; GENETIC ASSOCIATION STUDIES; GENETIC TESTING; GENOTYPE; GROWTH DISORDERS; HETEROZYGOTE; HOMEODOMAIN PROTEINS; HOMOZYGOTE; HUMANS; MUTATION; OSTEOCHONDRODYSPLASIAS; PEDIGREE; PHENOTYPE; SEQUENCE DELETION;

EID: 84878241689     PISSN: 15524825     EISSN: 15524833     Source Type: Journal    
DOI: 10.1002/ajmg.a.35919     Document Type: Article

References (35)

1. Albuisson J, Schmitt S, Baron S, Bézieau S, Benito-Sanz S, Heath KE. 2012. Clinical utility gene card for: Leri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD). Eur J Hum Genet 20:e1-4. DOI: 10.1038/ejhg.2012.64.
2. Benito-Sanz S, Thomas NS, Huber C, Gorbenko del Blanco D, Aza-Carmona D, Crolla JA, Maloney V, Argente J, Campos-Barros A, Cormier-Daire V, Heath KE. 2005. A novel class of pseudoautosomal region 1 (PAR1) deletions downstream of SHOX is associated with Léri-Weill dyschondrosteosis (LWD). Am J Hum Genet 77:533-544.
3. Benito-Sanz S, Gorbenko del Blanco D, Huber C, Thomas NS, Aza-Carmona M, Bunyan D, Maloney V, Argente J, Cormier-Daire V, Campos-Barros A, Heath KE. 2006a. Characterisation of SHOX deletions in Léri-Weill dyschondrosteosis reveals genetic heterogeneity and no recombination hotspots. Am J Hum Genet 79:409-414.
4. Benito-Sanz S, Gorbenko del Blanco D, Aza-Carmona M, Magano LF, Lapunzina P, Argenta J, Campos-Barros A, Heath KE. 2006b. PAR1 deletions downstream of SHOX are the most frequent defect in a Spanish cohort of Léri-Weill dyschondrosteosis patients. Hum Mutation 27:1062.
5. Benito-Sanz S, Barroso E, Heine-Sunër D, Hisado-Oliva A, Romanelli V, Rosell J, Aragones A, Caimari M, Argente J, Ross JL, Zinn AR, Gracia R, Lapunzina P, Campos-Barros A, Heath KE. 2011. Clinical and molecular evaluation of SHOX/PAR1 duplications in Léri-Weill Dyschondrosteosis (LWD) and idiopathic short stature (ISS). J Clin Endocrinol Metab 96:E404-E412.
6. Benito-Sanz S, Royo JL, Barroso E, Paumard-Hernandez B, Barreda-Bonis AC, Liu P, Gracia R, Lupski JR, Campos-Barros A, Gomez-Skarmeta JL, Heath KE. 2012. Identification of the first recurrent PAR1 deletion in Léri-Weill Dyschondrosteosis and idiopathic short stature reveals the presence of a novel SHOX enhancer. J Med Genet 49:442-450.
7. Blaschke RJ, Topfer C, Marchini A, Steinbeisser H, Jansen JWG, Rappold GA. 2003. Transcriptional and translational regulation of the Léri-Weill and Turner syndrome homeobox gene SHOX. J Biol Chem 278:47820-47826.
8. Campos-Barros A, Benito-Sanz S, Ross JL, Zinn AR, Heath KE. 2007. Compound heterozygosity of SHOX-encompassing and downstream PAR1 deletions results in langer mesomelic dysplasia (LMD). Am J Med Genet Part A 143A:933-938.
9. Chen J, Wildhardt G, Zhong Z, Röth R, Weiss B, Steinberger D, Decker J, Blum WF, Rappold G. 2009. Enhancer deletions of the SHOX gene as a frequent cause of short stature: The essential role of a 250kb downstream regulatory domain. J Med Genet 46:834-839.
10. Durand C, Bangs F, Signolet J, Decker E, Tickle C, Rappold G. 2010. Enhancer elements upstream of the SHOX gene are active in the developing limb. Eur J Hum Genet 18:527-532.
11. Ellison JW, Wardak Z, Young MF, Gehron Robey P, Laig-Webster M, Chiong W. 1997. PHOG, a candidate gene for involvement in the short stature of Turner syndrome. Hum Mol Genet 6:1341-1347.
12. Fukami M, Nishi Y, Hasegawa Y, Miyoshi Y, Okabe T, Haga N, Nagai T, Tanaka T, Ogata T. 2004. Statural growth in 31 Japanese patients with SHOX haploinsufficiency: Support for disadvantageous effect of gonadal estrogens. Endocrine J 51:197-200.
13. Fukami M, Okuyama T, Yamamori S, Nishimura G, Ogata T. 2005. Microdeletion in the SHOX 3′ region associated with skeletal phenotypes of Langer mesomelic dysplasia in a 45, X/46, X, r(X) infant and Léri-Weill dyschondrosteosis in her 46, XX mother: Implication for the SHOX enhancer. Am J Med Genet Part A 137A:72-76.
14. Fukami M, Kato F, Tajima T, Yokoya S, Ogata T. 2006. Transactivation function of a ∼800bp evolutionally conserved sequence at the SHOX 3′ region: Implication for the downstream enhancer. Am J Hum Genet 78:167-170.
15. Gao K, Masuda A, Matsuura T, Ohno K. 2008. Human branch point consensus sequence is yUnAy Nucleic Acids Res 36:2257-2267.
16. Grigelioniene G, Eklöf O, Ivarsson SA, Westphal O, Neumeyer L, Kedra D, Dumanski J, Hagenäs L. 2000. Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia. Hum Genet 107:145-149.
17. Huber C, Cusin V, Le Merrer M, Mathieu M, Sulmont V, Dagoneau N, Munnich A, Cormier-Daire V. 2001. SHOX point mutations in dyschondrosteosis. J Med Genet 38:323.
18. Kosho T, Muroya K, Nagai T, Fujimoto M, Yokoya S, Sakamoto H, Hirano T, Terasaki H, Ohashi H, Nishimura G, Sato S, Matsuo N, Ogata T. 1999. Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: Implications for the development of Turner syndrome. J Clin Endocrinol Metabol 84:4613-4621.
19. Langer LO Jr. 1967. Mesomelic dwarfism of the hypoplastic ulna, fibula, mandible type. Radiology 89:654-660.
20. Losekoot M, Broekman S, de Wit C, Bos M, Janmaat V, Bakker E, Maarten Wit J, Kant S. 2011. Phenotypic characterization of patients with deletions in the 3′-flanking SHOX region. Horm Res Paediatr 76:216 (ESPE Poster P2-d2-689).
21. Marchini A, Marttila T, Winter A, Caldeira S, Malanchi I, Blaschke RJ, Hacker B, Rao E, Karperien M, Wit JM, Richter W, Tommasino M, Rappold GA. 2004. The short stature homeodomain protein SHOX induces cellular growth arrest and apoptosis and is expressed in human growth plate chondrocytes. J Biol Chem 279:37103-37114.
22. Morral N, Bertranpetit J, Estivill X, Nunes V, Casals T, Giménez J, Reis A, Varon-Mateeva R, Macek M Jr, Kalaydjieva L, Angelicheva D, Dancheva R, Romeo G, Russo MP, Garnerone S, Restagno G, Ferrari M, Magnani C, Claustres M, Desgeorges M, Schwartz M, Schwarz M, Dallapiccola B, Novelli G, Ferec C, de Arce M, Nemeti M, Kere J, Anvret M, Dahl N, Kadasi L. 1994. The origin of the major cystic fibrosis mutation (ΔF508) in European populations. Nat Genet 7:169-175.
23. Munns C, Glass IA, LaBrom R, Hayes M, Flanagan S, Berry M, Hyland VJ, Batch JA, Philips GE, Vickers D. 2001. Histopathological analysis of Léri-Weill dyschondrosteosis: Disordered growth plate. Hand Surgery 6:13-23.
24. Munns C, Haase HR, Crowther LM, Hayes MT, Blaschke R, Rappold G, Glass IA, Batch JA. 2004. Expression of SHOX in human fetal and childhood growth plate. J Clin Endocrinol Metabol 89:4130-4135.
25. Neuhausen SL, Mazoyer S, Friedman L, Stratton M, Offit K, Caligo A, Tomlinson G, Cannon-Albright L, Bishop T, Kelsell D, Solomon E, Weber B, Couch F, Struewing J, Tonin P, Durocher F, Narod S, Skolnick MH, Lenoir G, Serova O, Ponder B, Stoppa-Lyonnet D, Easton D, King MC, Goldgar DE. 1996. Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: Results of an international study. Am J Hum Genet 58:271-280.
26. Nicoletti A, Mazzanti L, Pirazzoli P, Menabó S, Boccone L, Scarano E, Cicognani A, Baldazzi L. 2011. Mutation spectrum of SHOX gene in 25 Italian pediatric patients with Léri-Weill dyschondrosteosis (LWD). Horm Res Paediatr 76:146 (ESPE Poster P2-d1-465).
27. Rao E, Weiss B, Fukami M, Rump A, Niesler B, Mertz A, Muroya K, Binder G, Kirsch S, Winkelmann M, Bordsiek G, Heinrich U, Breuning MH, Ranke MB, Rosenthal A, Ogata T, Rappold GA. 1997. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 16:54-563.
28. Rao E, Blaschke RJ, Marchini A, Niesler B, Burnett M, Rappold GA. 2001. The Léri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activator. Hum Mol Genet 10:3083-3091.
29. Sabherwal N, Bangs F, Roth R, Weiss B, Jantz K, Tiecke E, Hinkel GK, Spaich C, Hauffa BP, van der Kamp H, Kapeller J, Tickle C, Rappold G. 2007. Long-range conserved non-coding SHOX sequences regulate expression in developing chicken limb and are associated with short stature phenotypes in human patients. Hum Mol Genet 16:210-222.
30. Sarbajna S, Denniff M, Jeffreys AJ, Neumann R, Soler Artigas M, Veselis A, May CA. 2012. A major recombination hotspot in the XqYq pseudoautosomal region gives new insight into processing of human gene conversion events. Hum Mol Genet 21:2029-2038.
31. Schiller S, Spranger S, Schechinger B, Fukami M, Merker S, Drop SLS, Tröger J, Knoblauch H, Kunze J, Seidel J, Rappold GA. 2000. Phenotypic variation and genetic heterogeneity in Léri-Weill syndrome. Eur J Hum Genet 8:54-62.
32. Schneider KU, Sabherwal N, Jantz K, Roth R, Muncke N, Blum WF, Cutler GB Jr, Rappold G. 2005. Identification of a major recombination hotspot in patients with short stature and SHOX deficiency. Am J Hum Genet 77:89-96.
33. Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. 2002. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nuc Acid Res 30:e57.
34. Shears DJ, Vassal HJ, Goodman FR, Palmer RW, Readorn W, Superti-Furga A, Scambler PJ, Winter RM. 1998. Mutation and deletion of the pseudoautosomal gene SHOX cause Léri-Weill dyschondrosteosis. Nat Genet 19:70-73.
35. Thomas NS, Harvey JF, Bunyan DJ, Rankin J, Grigelioniene G, Bruno DL, Tan TY, Tomkins S, Hastings R. 2009. Clinical and molecular characterisation of duplications encompassing the human SHOX gene reveal a variable effect on stature. Am J Med Genet Part A 149A:1407-1414.