Epidemiology of fragile X syndrome: A systematic review and meta-analysis

American Journal of Medical Genetics, Part A

Volumn 164, Issue 7, 2014, Pages 1648-1658

  Hunter, Jessica ^a   Rivero Arias, Oliver ^b   Angelov, Angel ^c   Kim, Edward ^c   Fotheringham, Iain ^d   Leal, Jose ^b  

^a EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF OXFORD   (United Kingdom)

^c NOVARTIS PHARMA AG   (Switzerland)

^d OXFORD PHARMAGENESIS LTD   (United Kingdom)

Author keywords

Epidemiology; Fragile X syndrome; Full mutation; Premutation

Indexed keywords

ARTICLE; EPIDEMIOLOGICAL DATA; FRAGILE X SYNDROME; GENE MUTATION; GENETIC HETEROGENEITY; HETEROZYGOTE; HUMAN; INTELLECTUAL IMPAIRMENT; MEASUREMENT ACCURACY; MUTATION RATE; POLYMERASE CHAIN REACTION; PREVALENCE; PRIORITY JOURNAL; SENSITIVITY ANALYSIS; SEX DIFFERENCE; SOUTHERN BLOTTING; SYSTEMATIC REVIEW; FEMALE; GENETICS; HEALTH SURVEY; INTELLECTUAL DISABILITY; MALE; META ANALYSIS; MUTATION;

FRAGILE X MENTAL RETARDATION PROTEIN;

FEMALE; FRAGILE X MENTAL RETARDATION PROTEIN; FRAGILE X SYNDROME; HETEROZYGOTE; HUMANS; INTELLECTUAL DISABILITY; MALE; MUTATION; POPULATION SURVEILLANCE; PREVALENCE; SEX FACTORS;

EID: 84902546132     PISSN: 15524825     EISSN: 15524833     Source Type: Journal    
DOI: 10.1002/ajmg.a.36511     Document Type: Article

References (89)

1. Abuelo D, Castree K, Pueschel S, Padre-Mendoza T, Zolnierz K. 1985. Frequency of fragile X chromosome in normal females. Clin Genet 28:97-99.
2. ACOG. 2010. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 469: Carrier screening for fragile X syndrome. Obstet Gynecol 116:1008-1010.
3. Arinami T, Asano M, Kobayashi K, Yanagi H, Hamaguchi H. 1993. Data on the CGG repeat at the fragile X site in the non-retarded Japanese population and family suggest the presence of a subgroup of normal alleles predisposing to mutate. Hum Genet 92:431-436.
4. Arvio M, Peippo M, Simola KO. 1997. Applicability of a checklist for clinical screening of the fragile X syndrome. Clin Genet 52:211-215.
5. Asthana JC, Sinha S, Haslam JS, Kingston HM. 1990. Survey of adolescents with severe intellectual handicap. Arch Dis Child 65:1133-1136.
6. Bagni C, Tassone F, Neri G, Hagerman R. 2012. Fragile X syndrome: Causes, diagnosis, mechanisms, and therapeutics. J Clin Invest 122:4314-4322.
7. Bailey DB Jr, Raspa M, Bishop E, Mitra D, Martin S, Wheeler A, Sacco P. 2012. Health and economic consequences of fragile X syndrome for caregivers. J Dev Behav Pediatr 33:705-712.
8. Bailey DB, Raspa M, Holiday D, Bishop E, Olmsted M. 2009. Functional skills of individuals with fragile x syndrome: A lifespan cross-sectional analysis. Am J Intellect Dev Disabil 114:289-303.
9. Berkenstadt M, Ries-Levavi L, Cuckle H, Peleg L, Barkai G. 2007. Preconceptional and prenatal screening for fragile X syndrome: Experience with 40, 000 tests. Prenat Diagn 27:991-994.
10. Berry-Kravis E, Knox A, Hervey C. 2011. Targeted treatments for fragile X syndrome. J Neurodev Disord 3:193-210.
11. Blomquist HK, Gustavson KH, Holmgren G, Nordenson I, Palsson-Strae U. 1983. Fragile X syndrome in mildly mentally retarded children in a northern Swedish county. A prevalence study. Clin Genet 24:393-398.
12. Brooks SP, Gelman A. 1998. General methods for monitoring convergence of iterative simulations. J Comput Graph Stat 7:434-455.
13. Chiang SC, Lee YM, Wang TR, Hwu WL. 1999. Allele distribution at the FMR1 locus in the general Chinese population. Clin Genet 55:352-355.
14. Chonchaiya W, Schneider A, Hagerman RJ. 2009. Fragile X: A family of disorders. Adv Pediatr 56:165-186.
15. Chow JC, Chen DJ, Lin CN, Chiu CY, Huang CB, Chiu PC, Lin CH, Lin SJ, Tzeng CC. 2003. Feasibility of blood spot PCR in large-scale screening of fragile X syndrome in southern Taiwan. J Formos Med Assoc 102:12-16.
16. Coffee B, Keith K, Albizua I, Malone T, Mowrey J, Sherman SL, Warren ST. 2009. Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet 85:503-514.
17. Crawford DC, Meadows KL, Newman JL, Taft LF, Scott E, Leslie M, Shubek L, Holmgreen P, Yeargin-Allsopp M, Boyle C, et al. 2002. Prevalence of the fragile X syndrome in African-Americans. Am J Med Genet 110:226-233.
18. Cronister A, DiMaio M, Mahoney MJ, Donnenfeld AE, Hallam S. 2005. Fragile X syndrome carrier screening in the prenatal genetic counseling setting. Genet Med 7:246-250.
19. Dawson AJ, Chodirker BN, Chudley AE. 1995. Frequency of FMR1 premutations in a consecutive newborn population by PCR screening of Guthrie blood spots. Biochem Mol Med 56:63-69.
20. de Vries BB, van den Ouweland AM, Mohkamsing S, Duivenvoorden HJ, Mol E, Gelsema K, van Rijn M, Halley DJ, Sandkuijl LA, Oostra BA, Tibben A, Niermeijer MF. 1997. Screening and diagnosis for the fragile X syndrome among the mentally retarded: An epidemiological and psychological survey. Collaborative Fragile X Study Group. Am J Hum Genet 61:660-667.
21. Dombrowski C, Levesque S, Morel ML, Rouillard P, Morgan K, Rousseau F. 2002. Premutation and intermediate-size FMR1 alleles in 10572 males from the general population: Loss of an AGG interruption is a late event in the generation of fragile X syndrome alleles. Hum Mol Genet 11:371-378.
22. Drasinover V, Ehrlich S, Magal N, Taub E, Libman V, Shohat T, Halpern GJ, Shohat M. 2000. Increased transmission of intermediate alleles of the FMR1 gene compared with normal alleles among female heterozygotes. Am J Med Genet 93:155-157.
23. Eichler EE, Hammond HA, Macpherson JN, Ward PA, Nelson DL. 1995. Population survey of the human FMR1 CGG repeat substructure suggests biased polarity for the loss of AGG interruptions. Hum Mol Genet 4:2199-2208.
24. Elbaz A, Suedois J, Duquesnoy M, Beldjord C, Berchel C, Merault G. 1998. Prevalence of fragile-X syndrome and FRAXE among children with intellectual disability in a Caribbean island, Guadeloupe, French West Indies. J Intellect Disabil Res 42:81-89.
25. Elias MH, Ankathil R, Salmi AR, Sudhikaran W, Limprasert P, Zilfalil BA. 2011. A new method for FMR1 gene methylation screening by multiplex methylation-specific real-time polymerase chain reaction. Genet Test Mol Biomarkers 15:387-393.
26. Fernandez-Carvajal I, Lopez Posadas B, Pan R, Raske C, Hagerman PJ, Tassone F. 2009a. Expansion of an FMR1 grey-zone allele to a full mutation in two generations. J Mol Diagn 11:306-310.
27. Fernandez-Carvajal I, Walichiewicz P, Xiaosen X, Pan R, Hagerman PJ, Tassone F. 2009b. Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population. J Mol Diagn 11:324-329.
28. Field M, Christie L, Boyle J, Rogers C, Hansen J, Wotton T, Wiley V, Bennets B. 2011. Results of a feasibility study of newborn screening for fragile X syndrome. Abstract presented at the 35th Human Genetics Society of Australasia Annual Scientific Meeting, Gold Coast, Australia. August 2011.
29. Geva E, Yaron Y, Shomrat R, Ben-Yehuda A, Zabari S, Peretz H, Naiman T, Yeger H, Orr-Urtreger A. 2000. The risk of fragile X premutation expansion is lower in carriers detected by general prenatal screening than in carriers from known fragile X families. Genet Test 4:289-292.
30. Godler DE, Tassone F, Loesch DZ, Taylor AK, Gehling F, Hagerman RJ, Burgess T, Ganesamoorthy D, Hennerich D, Gordon L, Evans A, Choo KH, Slater HR. 2010. Methylation of novel markers of fragile X alleles is inversely correlated with FMRP expression and FMR1 activation ratio. Hum Mol Genet 19:1618-1632.
31. Gross C, Berry-Kravis EM, Bassell GJ. 2011. Therapeutic strategies in fragile X syndrome: Dysregulated mGluR signaling and beyond. Neuropsychopharmacology.
32. Gross C, Berry-Kravis EM, Bassell GJ. 2012. Therapeutic strategies in fragile X syndrome: Dysregulated mGluR signaling and beyond. Neuropsychopharmacology 37:178-195.
33. Gustavson KH, Blomquist HK, Holmgren G. 1986. Prevalence of the fragile-X syndrome in mentally retarded boys in a Swedish county. Am J Med Genet 23:581-587.
34. Hagerman PJ. 2008. The fragile X prevalence paradox. J Med Genet 45:498-499.
35. Hagerman RJ, Leavitt BR, Farzin F, Jacquemont S, Greco CM, Brunberg JA, Tassone F, Hessl D, Harris SW, Zhang L, Jardini T, Gane LW, Ferranti J, Ruiz L, Leehey MA, Grigsby J, Hagerman PJ. 2004. Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 74:1051-1056.
36. Hampson DR, Adusei DC, Pacey LK. 2011. The neurochemical basis for the treatment of autism spectrum disorders and Fragile X syndrome. Biochem Pharmacol 81:1078-1086.
37. Hantash FM, Goos DM, Crossley B, Anderson B, Zhang K, Sun W, Strom CM. 2011. FMR1 premutation carrier frequency in patients undergoing routine population-based carrier screening: Insights into the prevalence of fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency in the United States. Genet Med 13:39-45.
38. Hartley SL, Seltzer MM, Raspa M, Olmstead M, Bishop E, Bailey DB. 2011. Exploring the adult life of men and women with fragile X syndrome: Results from a national survey. Am J Intellect Dev Disabil 116:16-35.
39. Holden JJ. 1995. Distribution and frequency of FMRl CGG repeat numbers in the general population. Dev Brain dysfunct 8:405-407.
40. Huang KF, Chen WY, Tsai YC, Lin CC, Chen SH, Tseng CY, Tzeng CC. 2003. Original article pilot screening for fragile X carrier in pregnant women of southern Taiwan. J Chin Med Assoc 66:204-209.
41. Hwang D, Cho D, Choe J, Lee DA, Yang Y. 2010. Preenatal screening for fragile X syndrome in Korean Women: Experience with over 80, 000 tests. Abstract presented at the 15th International Conference on Prenatal Diagnosis Diagnosis and Therapy, Amsterdam, Holland
42. Indhumathi N, Singh D, Chong SS, Thelma BK, Arabandi R, Srisailpathy CR. 2012. Fragile X CGG repeat variation in Tamil Nadu, South India: A comparison of radioactive and methylation-specific polymerase chain reaction in CGG repeat sizing. Genet Test Mol Biomarkers 16:113-122.
43. Jacobs PA, Bullman H, Macpherson J, Youings S, Rooney V, Watson A, Dennis NR. 1993. Population studies of the fragile X: A molecular approach. J Med Genet 30:454-459.
44. Jacquemont S, Hagerman RJ, Leehey MA, Hall DA, Levine RA, Brunberg JA, Zhang L, Jardini T, Gane LW, Harris SW, Herman K, Grigsby J, Greco CM, Berry-Kravis E, Tassone F, Hagerman PJ. 2004. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 291:460-469.
45. Kahkonen M, Alitalo T, Airaksinen E, Matilainen R, Launiala K, Autio S, Leisti J. 1987. Prevalence of the fragile X syndrome in four birth cohorts of children of school age. Hum Genet 77:85-87.
46. Krueger DD, Bear MF. 2011. Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu Rev Med 62:411-429.
47. Larsen LA, Armstrong JS, Gronskov K, Hjalgrim H, Macpherson JN, Brondum-Nielsen K, Hasholt L, Norgaard-Pedersen B, Vuust J. 2000. Haplotype and AGG-interspersion analysis of FMR1 (CGG)(n) alleles in the Danish population: Implications for multiple mutational pathways towards fragile X alleles. Am J Med Genet 93:99-106.
48. Levenga J, de Vrij FM, Oostra BA, Willemsen R. 2010. Potential therapeutic interventions for fragile X syndrome. Trends Mol Med 16:516-527.
49. Levesque S, Dombrowski C, Morel ML, Rehel R, Cote JS, Bussieres J, Morgan K, Rousseau F. 2009. Screening and instability of FMR1 alleles in a prospective sample of 24, 449 mother-newborn pairs from the general population. Clin Genet 76:511-523.
50. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. 2009. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. BMJ 339:b2700.
51. Lunn DJ, Thomas A, Best N, Spiegelhalter D. 2000. WinBUGS-A Bayesian modelling framework: Concepts, structure, and extensibility. Stat Comput 10:325-337.
52. Matilainen R, Airaksinen E, Mononen T, Launiala K, Kaariainen R. 1995. A population-based study on the causes of mild and severe mental retardation. Acta Paediatr 84:261-266.
53. Mazurczak T, Bocian E, Milewski M, Obersztyn E, Stanczak H, Bal J, Szamotulska K, Karwacki MW. 1996. Frequency of Fra X syndrome among institutionalized mentally retarded males in Poland. Am J Med Genet 64:184-186.
54. McLennan Y, Polussa J, Tassone F, Hagerman R. 2011. Fragile X syndrome. Curr Genomics 12:216-224.
55. Meguid NA, Abdel-Raouf ER, Dardir AA, El Awady MK. 2007. Prevalence of fragile X syndrome among school-age Egyptian males. World J Pediatr 3:271-275.
56. Mitchell RJ, Holden JJ, Zhang C, Curlis Y, Slater HR, Burgess T, Kirkby KC, Carmichael A, Heading KD, Loesch DZ. 2005. FMR1 alleles in Tasmania: A screening study of the special educational needs population. Clin Genet 67:38-46.
57. Movafagh A, Pear-Zadeh Z, Hajiseyed-Javadi M, Mohammed FM, Ghaderian SMH, Heidari MH, Ghasemi-Barghi R. 2008. Occurance of congenital anomalies and genetic diseases in a population on Ghazvin Province, Iran: A study of 33, 380 cases. Pak J Med Sci 24:80-85.
58. Murray A, Youings S, Dennis N, Latsky L, Linehan P, McKechnie N, Macpherson J, Pound M, Jacobs P. 1996. Population screening at the FRAXA and FRAXE loci: Molecular analyses of boys with learning difficulties and their mothers. Hum Mol Genet 5:727-735.
59. Murray J, Cuckle H, Taylor G, Hewison J. 1997. Screening for fragile X syndrome. Health Technol Assess 1:1-71.
60. Otsuka S, Sakamoto Y, Siomi H, Itakura M, Yamamoto K, Matumoto H, Sasaki T, Kato N, Nanba E. 2010. Fragile X carrier screening and FMR1 allele distribution in the Japanese population. Brain Dev 32:110-114.
61. Pang CP, Poon PM, Chen QL, Lai KY, Yin CH, Zhao Z, Zhong N, Lau CH, Lam ST, Wong CK, et al. 1999. Trinucleotide CGG repeat in the FMR1 gene in Chinese mentally retarded patients. Am J Med Genet 84:179-183.
62. Pembrey ME, Barnicoat AJ, Carmichael B, Bobrow M, Turner G. 2001. An assessment of screening strategies for fragile X syndrome in the UK. Health Technol Assess 5:1-95.
63. Pesso R, Berkenstadt M, Cuckle H, Gak E, Peleg L, Frydman M, Barkai G. 2000. Screening for fragile X syndrome in women of reproductive age. Prenat Diagn 20:611-614.
64. Puusepp H, Kahre T, Sibul H, Soo V, Lind I, Raukas E, Ounap K. 2008. Prevalence of the fragile X syndrome among Estonian mentally retarded and the entire children's population. J Child Neurol 23:1400-1405.
65. Reiss AL, Kazazian HH Jr, Krebs CM, McAughan A, Boehm CD, Abrams MT, Nelson DL. 1994. Frequency and stability of the fragile X premutation. Hum Mol Genet 3:393-398.
66. Reyniers E, Vits L, De Boulle K, Van Roy B, Van Velzen D, de Graaff E, Verkerk AJ, Jorens HZ, Darby JK, Oostra B, et al. 1993. The full mutation in the FMR-1 gene of male fragile X patients is absent in their sperm. Nat Genet 4:143-146.
67. Rife M, Badenas C, Mallolas J, Jimenez L, Cervera R, Maya A, Glover G, Rivera F, Mila M. 2003. Incidence of fragile X in 5, 000 consecutive newborn males. Genet Test 7:339-343.
68. Ryynanen M, Heinonen S, Makkonen M, Kajanoja E, Mannermaa A, Pertti K. 1999. Feasibility and acceptance of screening for fragile X mutations in low-risk pregnancies. Eur J Hum Genet 7:212-216.
69. Sacco P, Capkun-Niggli G, Zhang X, Jose R. 2013. The economic burden of fragile X syndrome: Healthcare resource utilization in the United States. Am Health Drug Benefits 6:73-83.
70. Saul RA, Friez M, Eaves K, Stapleton GA, Collins JS, Schwartz CE, Stevenson RE. 2008. Fragile X syndrome detection in newborns-pilot study. Genet Med 10:714-719.
71. Seltzer MM, Baker MW, Hong J, Maenner M, Greenberg J, Mandel D. 2012. Prevalence of CGG expansions of the FMR1 gene in a US population-based sample. Am J Med Genet B Neuropsychiatr Genet 159B:589-597.
72. Sherman S, Pletcher BA, Driscoll DA. 2005. Fragile X syndrome: Diagnostic and carrier testing. Genet Med 7:584-587.
73. Sherman SL. 2000. Premature ovarian failure in the fragile X syndrome. Am J Med Genet 97:189-194.
74. Sofocleous C, Kolialexi A, Mavrou A. 2009. Molecular diagnosis of Fragile X syndrome. Expert Rev Mol Diagn 9:23-30.
75. Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A. 2003. Screening for fragile X syndrome: A literature review and modelling study. Health Technol Assess 7:1-106.
76. Spence WC, Black SH, Fallon L, Maddalena A, Cummings E, Menapace-Drew G, Bick DP, Levinson G, Schulman JD, Howard-Peebles PN. 1996. Molecular fragile X screening in normal populations. Am J Med Genet 64:181-183.
77. Spiegelhalter DJ, Best NG, Carlin BP, Van der Linde A. 2002. Bayesian measures of model complexity and fit (with Discussion). J R Stat Soc Series B Stat Methodol 64:583-616.
78. Tassone F, Pan R, Amiri K, Taylor AK, Hagerman PJ. 2008. A rapid polymerase chain reaction-based screening method for identification of all expanded alleles of the fragile X (FMR1) gene in newborn and high-risk populations. J Mol Diagn 10:43-49.
79. Tassone F, Tong T, Pou K, Berry-Kravis E, Nguyen DV, Skinner D, Bailey DB, Gane L, Hagerman R. 2011. Newborn screening in fragile X syndrome: A pilot study. J Inherit Metab Dis 34:S17-S48.
80. Temtamy SA, Kandil MR, Demerdash AM, Hassan WA, Meguid NA, Afifi HH. 1994. An epidemiological/genetic study of mental subnormality in Assiut Governorate, Egypt. Clin Genet 46:347-351.
81. Todorov T, Todorova A, Georgieva B, Mitev V. 2010. A unified rapid PCR method for detection of normal and expanded trinucleotide alleles of CAG repeats in huntington chorea and CGG repeats in fragile X syndrome. Mol Biotechnol 45:150-154.
82. Toledano-Alhadef H, Basel-Vanagaite L, Magal N, Davidov B, Ehrlich S, Drasinover V, Taub E, Halpern GJ, Ginott N, Shohat M. 2001. Fragile-X carrier screening and the prevalence of premutation and full-mutation carriers in Israel. Am J Hum Genet 69:351-360.
83. Turner G, Robinson H, Laing S, Purvis-Smith S. 1986. Preventive screening for the fragile X syndrome. N Engl J Med 315:607-609.
84. Tzeng CC, Cho WC, Kuo PL, Chen RM. 1999. Pilot fragile X screening in normal population of Taiwan. Diagn Mol Pathol 8:152-156.
85. Tzeng CC, Tsai LP, Hwu WL, Lin SJ, Chao MC, Jong YJ, Chu SY, Chao WC, Lu CL. 2005. Prevalence of the FMR1 mutation in Taiwan assessed by large-scale screening of newborn boys and analysis of DXS548-FRAXAC1 haplotype. Am J Med Genet Part A 133A:37-43.
86. Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP, et al. 1991. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65:905-914.
87. Webb TP, Bundey SE, Thake AI, Todd J. 1986. Population incidence and segregation ratios in the Martin-Bell syndrome. Am J Med Genet 23:573-580.
88. Welt CK. 2008. Primary ovarian insufficiency: A more accurate term for premature ovarian failure. Clin Endocrinol 68:499-509.
89. Wotton T, Wiley V, Wilcken B, Bennets B, Field M, Christie L, Carolyn R. 2011. The feasability of newborn screening for fragile X syndrome using a DNA based first tier assay. J Inherit Metab Dis 34.