Prevalence of fragile X syndrome among patients with mental retardation in the west of Iran

Abstract

BACKGROUND: Fragile X syndrome (FXS), an X-linked disorder, is the most common cause of inherited mental retardation. This is caused by a trinucleotide CGG repeat expansion (>200) on the fragile X mental retardation 1 gene (FMR1) becoming methylated leading to a deficiency or absence of the FMR1 protein. Determining FXS prevalence in the mentally retarded individuals in the west of Iran was the aim of this study.

METHODS: 200 patients with moderate mental retardation who were clinically suspicious to FXS were screened using cytogenetic and molecular methods. Blood samples were collected and cultured in the specific culture media. The G-Banding method was used for karyotyping and DNA sequencing performed for verifying the results of the cytogenetic tests.

RESULTS: 16 patients (8%) were found to have fragile X syndrome. The results showed that there is no significant association between the fragile X syndrome and economic status and place of residence, however, the relationship between fragile X syndrome and mental retardation in the family history is significant.

CONCLUSION: The frequency of FXS was similar to other reports in the preselected patients. For diagnosis of FXS, chromosome analysis must be accompanied by molecular studies.

Key words： genetic diseases; inborn; FMR1; karyotype; diagnosis; mental retardation

Acknowledgments

We are grateful for the supports of Ilam University of Medical Sciences.

Conflict of interests

The authors have no conflict of interests. The current study was approved by the ethics committee of Ilam University of Medical Sciences following the principles of the revised Declaration of Helsinki. Written informed consent obtained from each participant for sample collections and data usage for performing this investigation.

References

1 Arvio M(2016). Fragile-X syndrome–a 20-year follow-up study of male patients. Clinical genetics, 89 (1399–0004 (Electronic)): 55–9.

2 Ashley C T, Sutcliffe J S- Kunst C B, Kunst C B- Leiner H A, Leiner HA- Eichler E E, Eichler E E- Nelson D L, Nelson D l- Warren S T, Warren S T (1993) . Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG-repeat. Nature genetics, 4 (1061–4036 (Print)): 244–251

3 Berry-Kravis E, Des Portes V, Hagerman R, Jacquemont S, Charles P, Visootsak J, Brinkman M, Rerat K, Koumaras B, Zhu L, Barth G M, Jaecklin T, Apostol G, von Raison F (2016) . Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials. Sci Trans Med, 8 (1946–6242 (Electronic)): 321ra5

4 Bilgen T, Keser I, Mihci E, Mihci E, Haspolat S, Haspolat S, Tacoy S, Tacoy S, Luleci G, Luleci G (2005). Molecular analysis of fragile X syndrome in Antalya Province. Ind J Med Sci, 59 (0019–5359 (Print)): 150–155

5 Brown W T, Houck Ge Jr- Jeziorowska A, Jeziorowska A, Levinson F N, Levinson F n, Ding X, Ding X, Dobkin C, Dobkin C, Zhong N, Zhong N, Henderson J, Henderson J, Brooks S S, Brooks S s, Jenkins E C, Jenkins E C (‎1993) . Rapid fragile X carrier screening and prenatal diagnosis using a nonradioactive PCR test. JAMA, 270 (13): 1569–1575

6 Budimirovic D B, Kaufmann W E (2011). What can we learn about autism from studying fragile X syndrome? Dev Neurosci, 33 (5) :379

7 Butler M G, Hamill T (1995). Blood specimens from patients referred for cytogenetic analysis: Vanderbilt University experience from 1985 to 1992. Southern medical journal, 88 (0038–4348 (Print)): 309–314

8 Carpenter N J, Leichtman L G, Leichtman L G, Say B, Say B (1982). Fragile X-linked mental retardation. A survey of 65 patients with mental retardation of unknown origin. Am J Dis Child, 136 (0002–922X (Print)): De Boulle K, Verkerk A J, Reyniers E, Vits L, Hendrickx J, Van Roy B, Van den Bos F, de Graaff E, Oostra B A, Willems P J (1993). A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nat Genet, 3(1): 31–35

9 Demirhan O, Taştemir D, Diler R S, Firat S, Avci A (2003). A cytogenetic study in 120 Turkish children with intellectual disability and characteristics of fragile X syndrome. Yonsei Med J, 44(4): 583–592

PMID

10 Dewald G W, Buckley D D, Spurbeck J L, Jalal S M (1992). Cytogenetic guidelines for fragile X studies tested in routine practice. Am J Med Genet, 44(6): 816–821

PMID

11 Dolen G, Osterweil E, Rao B S S, Rao B S, Smith G B, Smith G B, Auerbach B D,Auerbach B D, Chattarji S, Chattarji S, Bear M F, Bear M F (2007). Correction of fragile X syndrome in mice. Neuron, 56 (0896–6273 (Print)): 955–962

12 Dölen G, Carpenter R L, Ocain T D, Bear M F (2010). Mechanism-based approaches to treating fragile X. Pharmacol Ther, 127(1): 78–93

PMID

13 Eichler E E, Holden Jj- Popovich B W, Popovich Bw- Reiss A L, Reiss A L, Snow K, Snow K, Thibodeau S N, Thibodeau Sn- Richards C S, Richards C S, Ward P A, Ward P A, Nelson D L, Nelson D L (1994) . Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nature genetics, 8 (1061–4036 (Print)): 88–94.9

14 Eichler E E, Richards S, Gibbs R A, Gibbs R A, Nelson D L, Nelson D L (1993). Fine structure of the human FMR1 gene. Hum Mol Genet, 2 (8): 684-685

15 Feng Y, Lakkis L, Devys D, Devys D, Warren S T, Warren S T (1995). Quantitative comparison of FMR1 gene expression in normal and premutation alleles. Am J Hum Genet, 56 (0002–9297 (Print)): 106–113

16 Eichler E E, Richards S, Gibbs R A, Gibbs R A, Nelson D L, Nelson D L. Fine structure of the human FMR1 gene 19931105 DCOM- 19931105.

17 Froster-Iskenius U, Felsch G, Schirren C, Schwinger E (1983). Screening for fra(X)(q) in a population of mentally retarded males. Hum Genet, 63(2): 153–157

PMID

18 Froster-Iskenius U, Felsch G, Felsch G- Schirren C, Schirren C, Schwinger E, Schwinger E (1983). Screening for fra(X)(q) in a population of mentally retarded males. Hum Genet, 63 (0340–6717 (Print)): 153–7.

19 Fu Y H, Kuhl D P, Pizzuti A, Pizzuti A, Pieretti M, Pieretti M, Sutcliffe J S, Sutcliffe J S, Richards S, Richards S, Verkerk A J, Verkerk A J, Holden J J, Holden J J, Fenwick R G, Jr., Fenwick RG Jr, Warren S T, Warren S T (1991) . Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell, 67 (0092–8674 (Print)): 1047–1058

20 Grigsby J (2016). The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology. The Clinical neuropsychologist, 30 (1744–4144 (Electronic)): 815–33.

21 Gustavson K H, Blomquist H K, Blomquist H K, Holmgren G, Holmgren G (1986) . Prevalence of the fragile-X syndrome in mentally retarded boys in a Swedish county. American journal of medical genetics, 23 (0148–7299 (Print)): 581–7

22 Hagerman R J, Berry-Kravis E, Kaufmann W E, Kaufmann W E, Ono M Y, Ono M Y, Tartaglia N, Tartaglia N- Lachiewicz A, Lachiewicz A, Kronk R, Kronk R, Delahunty C, Delahunty C, Hessl D, Hessl D, Visootsak J, Visootsak J, Picker J, Picker J, Gane L,Gane L, Tranfaglia M, Tranfaglia M (2009). Advances in the treatment of fragile X syndrome. Pediatrics, 123 (1098–4275 (Electronic)): 378–390

23 Hagerman R J, Berry-Kravis E, Kaufmann W E, Ono M Y, Tartaglia N, Lachiewicz A, Kronk R, Delahunty C, Hessl D, Visootsak J, Picker J, Gane L, Tranfaglia M (2009). Advances in the treatment of fragile X syndrome. Pediatrics, 123(1): 378–390

PMID

24 Hinds H L, Ashley Ct- Sutcliffe J S, Sutcliffe J S, Nelson D L, Nelson D L, Warren S T, Warren St- Housman D E, Housman De- Schalling M, Schalling M (1993) . Tissue specific expression of FMR-1 provides evidence for a functional role in fragile X syndrome. Nat Genet, 3 (1061–4036 (Print)): 36–43

25 Iqbal M A, Sakati N- Nester M, Nester M- Ozand P, Ozand P (2000). Cytogenetic diagnosis of fragile X syndrome: study of 305 suspected cases in Saudi Arabia. Annals of Saudi medicine, 20 (0256–4947 (Print)): 214–217

26 Jenkins E C, Genovese M, Duncan C J, Gu H, Stark-Houck S, Li S Y, Henderson J, Morys I, Brown W T (1994). Occurrence of aneuploidy for the X chromosome in over 1,300 unrelated specimens screened for the fragile X chromosome. Am J Med Genet, 51(4): 452–453

PMID

27 Jiraanont P A-Ohoo, Kumar M, Tang H T, Espinal G, Hagerman P J, Hagerman R J, Chutabhakdikul N, Tassone F (2017) . Size and methylation mosaicism in males with Fragile X syndrome. Expert review of molecular diagnostics, 17 (1744–8352 (Electronic)): 1023–1032

28 Kunst C B, Warren S T (1994) . Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell, 77 (0092–8674 (Print)): 853–861

29 Lozano R, Martinez-Cerdeno V, Hagerman R J (2015) . Advances in the Understanding of the Gabaergic Neurobiology of FMR1 Expanded Alleles Leading to Targeted Treatments for Fragile X Spectrum Disorder. Current pharmaceutical design, 21 (1873–4286 (Electronic)): 4972–9.

30 Motulsky A G (1993). Mendelian inheritance in man: catalogs of autosomal dominant, autosomal recessive, and X–linked phenotypes. JAMA, 269(15): 2003

31 Neri G, Sanfilippo S, Pavone L, Pavone L, Mollica F, Mollica F, Barberi I, Barberi I, Giuffre L, Giuffre L, Romano C, Romano C, Mattina T, Mattina T, Cammarata M, Cammarata M, Ragusa M G, Ragusa M G (1988) . The fragile X in Sicily: an epidemiological survey. American journal of medical genetics, 30 (0148–7299 (Print)): 665–672

32 Pouya A R, Abedini Ss- Mansoorian N, Mansoorian N, Behjati F, Behjati F, Nikzat N, Nikzat N- Mohseni M, Mohseni M, Nieh S E, Nieh S E, Abbasi Moheb L, Abbasi Moheb L, Darvish H, Darvish H, Monajemi G B, Monajemi Gb- Banihashemi S, Banihashemi S, Kahrizi K, Kahrizi K, Ropers H H, Ropers Hh- Najmabadi H, Najmabadi H (2009). Fragile X syndrome screening of families with consanguineous and non-consanguineous parents in the Iranian population. European journal of medical genetics, 52 (1878–0849 (Electronic)): 170–3.

33 Proops R, Webb T (1981). The ‘fragile’ X chromosome in the Martin-Bell-Renpenning syndrome and in males with other forms of familial mental retardation. J Med Genet, 18(5): 366–373

PMID

34 Raspa M, Wheeler A C, Riley C (2017). Public Health Literature Review of Fragile X Syndrome. Pediatrics, 139 (1098–4275 (Electronic)): S153–S71.

35 Rousseau F, Heitz D, Biancalana V, Biancalana V, Blumenfeld S, Blumenfeld S, Kretz C, Kretz C- Boue J, Boue J, Tommerup N, Tommerup N, Van Der Hagen C, Van Der Hagen C, De Lozier-Blanchet C, DeLozier-Blanchet C, Croquette M F, Croquette M F (1991). Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. The New England journal of medicine, 325 (0028–4793 (Print)): 1673–81.

36 Snow K, Doud L K, Hagerman R, Hagerman R, Pergolizzi R G, Pergolizzi R G, Erster S H, Erster S H, Thibodeau S N, Thibodeau S N (1993). Analysis of a CGG sequence at the FMR-1 locus in fragile X families and in the general population. Am J Hum Genet, 53 (0002–9297 (Print)): Snow K, Tester Dj- Kruckeberg K E, Kruckeberg Ke- Schaid D J, Schaid Dj- Thibodeau S N, Thibodeau S N.(1994) Sequence analysis of the fragile X trinucleotide repeat: implications for the origin of the fragile X mutation. Human molecular genetics, 3 (0964–6906 (Print)): 1543–51.

37 Sutherland G R (1977). Fragile sites on human chromosomes: demonstration of their dependence on the type of tissue culture medium. Science, 197 (0036–8075 (Print)): 265–266

38 Wohrle D, Kotzot D, Hirst M C, Hirst M C, Manca A, Manca A, Korn B, Korn B- Schmidt A, Schmidt A, Barbi G, Barbi G- Rott H D, Rott H D, Poustka A, Poustka A, Davies K E, Davies K E (1992) . A microdeletion of less than 250 kb, including the proximal part of the FMR-I gene and the fragile-X site, in a male with the clinical phenotype of fragile-X syndrome. American journal of human genetics, 51 (0002–9297 (Print)): 299–306.

39 Yu S, Pritchard M, Kremer E, Kremer E, Lynch M, Lynch M, Nancarrow J, Nancarrow J- Baker E, Baker E- Holman K, Holman K- Mulley J C, Mulley J C, Warren S T, Warren St- Schlessinger D, Schlessinger D (1991). Fragile X genotype characterized by an unstable region of DNA. Science, 252 (0036–8075 (Print)): 1179–81.

40 Zhang H, Xia J- Li L, Li L- Dai H, Dai H- Lu H, Lu H (1990). The high resolution G band of human chromosomes at 1200 band stage. Acta Genetica Sinica, 17 (0379–4172 (Print)):