Cytogenetic and Molecular Investigation in Children with Possible Fragile X Syndrome

Year 2012, Volume: 37 Issue: 2, 76 - 83, 01.06.2012

Onur Özer Osman Demirhan Erdal Tunc Hüseyin Bağcı Dilara Karahan Nilgün Tanriverdi Bertan Yılmaz Ali İrfan Güzel İbrahim Keser

Abstract

Objective: Fragile X syndrome (FXS) is the most common cause of inherited mental retardation and is due to a mutation in the X-linked FMR1 gene. Molecular genetic testing and chromosome analysis are indicated for this disorder. In this context, we tried to determine the frequency of the FXS, and other chro¬mosomal abnormalities of Turkish pediatric neurology outpatients. Materials and Methods: Cytogenetic and molecular screenings were performed to esti-mate the prevalence of the fragile X in 107 patients with mental retardation, language disorders, hyperactivity, develop¬mental delay or fragile X syndrome phenotype. Only 26 out of 107 patients were screened, molecularly. Results: Cytogenetically fragile X-positive cells was found in 8 cases (7.5%) of 107 patients; in 4.7% of males and in 2.8% of females. The autosomal fragile sites (FS) was found in 14 (13.1%) cases. One (0.9%) patient had pericentric inversion of chromosome 9. Molecular analysis were performed for 26 patients and all patients showed normal CGG expansion. Conclusion: In diagnosis of fragile X syndrome, chromosome analysis must be run in conjunction with the molecular studies. It is recommended that all members of the fragile X family under risk should be screened both by cytogenetic and molecular methods. Genetic counseling can be useful to patients and families considering genetic testing.

Keywords

Fragile X syndrome, FMR1 gene, cytogenetic and molecular screenings

Frajil X Sendromu Olduklarından Şüphelenilen Çocuklarda Sitogenetik ve Moleküler Araştırmalar

Abstract

Amaç: Kalıtımla geçen mental retardasyonun en yaygın nedeni Frajil X sendromudur (FXS). X kromozomu üzerinde bulunan FMR1 geninde meydana gelen bir mutasyon, bu sendroma yol açmaktadır. Tanı için kromozom analizi ve moleküler genetik testlerden birine veya her ikisine birden başvurulabilmektedir. Bu çalışmada, hasta grubundaki (türk pediyatrik nöroloji hastalarında) FXS frekansı belirlenmeye çalışıldı. Yöntem: Bu çalışmada mental retardasyon, konuşma güçlüğü, hiperaktivite ve gelişme geriliği gibi şikayetleri bulunan veya frajil X fenotipi gösteren 107 hastada fragile X yaygınlığını belirlemek için sitogenetik ve moleküler taramalar yapıldı. 107 hastanın sadece 26’sı moleküler olarak değerlendirildi. Bulgular: Sitogenetik olarak incelenen 107 olgunun 8’inde frajil X pozitif hücrelere rastlandı. Buna göre erkek olguların % 4.7’sinde, kadın olguların ise % 2.8’inde frajil X pozitif hücrelere rastlandı. 14 olguda (%13.1) ise otozomal frajil bölgelere rastlandı. Bir olgunun 9. kromozomunda perisentrik inversiyona rastlandı. Moleküler analizi yapılan 26 olgunun tamamının CGG tekrar sayısı artışı bakımından normal oldukları tespit edildi. Sonuç: Frajil X sendromunun tanısında kromozom analizi ve moleküler yöntem birlikte kullanılmalıdır. Frajil X pozitif bireylerin bulunduğu ailelerin tüm bireylerinin hem sitogenetik ve hem de moleküler olarak taranmalarında fayda görülmektedir. Hastalara ve hasta ailelerine genetik danışmanlık verilmesinde yarar görülmektedir.

Keywords

Frajil X sendromu, FMR1 geni, sitogenetik ve moleküler taramalar

References

• Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S,et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 1991; 67: 1047-1058.
• Martin JB, Bell J. A pedigree of mental defect showing sex-linkage. J Neurol Psychitr. 1943; 61: 54- 157.
• Lubs HA. A marker X chromosome. Am J Hum Genet. 1969; 21: 231-244.
• Gustavson KH, Blomquist HK, Holmgren G. Prevalence of the fragile X syndrome in mentally retarded boys in a Swedish county. Am J Med Genet. 1986; 23: 581-7.
• Carpenter NJ, Leichtman LG, Say B. Fragile Xlinked mental retardation. A survey of 65 patients with mental retardation of unknown origin. Am J Dis Child. 1982; 136: 392–8.
• İskenius UF, Felsch G, Schirren C, Schwinger E.
• Screening for fra (X) (q) in a population of mentally retarded males. Hum Genet. 1983; 63: 3-157.
• Demirhan O, Taştemir D, Somer DR, Firat S, Avcı A.
• A Cytogenetic Study in 120 Turkish Children with Intellectual Disability and Characteristics of Fragile X Syndrome. Yonsei Med J. 2003; 44: 583 -592.
• Hofstee YO, Arinomi T, Hamaguchi H. Comparison between the cytogenetic test for fragile X and the molecular analysis of the FMR1 gene in Japanese mentally retarded individuals. Am J Med Genet. 1994; 51: 466-470.
• Tunçbilek E, Alikaşifoğlu M, Boduroğlu K, Aktaş D,
• Anar B. Frequency of fragile X syndrome among Turkish patients with mental retardation of unknown etiology. Am J Med Genet. 1999; 84: 202-3.
• Bilgen T, Keser I, Mihci E., Haspolat S, Tacoy S., Luleci G. Molecular analysis of fragile X syndrome in Antalya Province. Indian J Med Sci. 2005; 59(4): 150-155.
• Uyguner ZO, Wollnik B, Kayserili H, Tükel T, Basaran S, Apak MY. Establishment Of A Nonradioactive Molecular Diagnosis Of Fragile-X Syndrome. Turk J Med Sci. 2000; 30: 253–260.
• 1Shaffer LG, Slovak ML, Campbell LJ. An International System for Human Cytogenetic Nomenclature. Published in collaboration with Cytogenetic and Genome Research, 2009.
• Webb T. The epidemiology of the fragile X syndrome. In: Davies KE, (ed). The fragile X syndrome. Oxford: Oxford University Pres, 1989.
• Sherman SL. Epidemiology. In: Hagerman RJ, Cronister AC, (eds). Fragile X syndrome: Diagnosis, treatment, and research. Baltimore: The Johns Hopkins University Pres, 1996.
• Turner G, Webb T, Wake S, Robinson H. Prevalence of Fragile X syndrome. Am J Med Genet. 1996; 64: 196-197.
• Proops R, Mae M, Jacobs PA. A study of mental retardation in children in the island of Hawaii. Clin Genet. 1983; 23: 81-96.
• Iqbal MA, Sakati N, Nester M, Ozand P. Cytogenetic Diagnosis of Fragile X Syndrome: Study of 305 Suspected Cases In Saudi Arabia. Ann Saudi Med. 2000; 20: 3-4.
• Mannens M, Slater RM, Heyting C, Bliek J, De Kraker J, Coad N, et al. Molecular nature of genetic changes resulting in loss of heterozygosity of chromosome 11 in Wilms' tumours. Hum Genet. 1988; 81: 41-48.
• Faradz SMH, Buckley M, Tang L, Leigh D, Holden JJA. Molecular screening for fragile X syndrome among Indonesian children with developmental disability. Am J Med Genet. 1999; 83: 350-351.
• Keser I, Lüleci G, Aklan M. The results of molecular and cytogenetıc analysıs in 6 famılıes wıth Fragıle - X syndrome in Turkey. Marmara Medical Journal. 2000; 13(1): 7-10.
• Curry CJ, Stevenson RE, Aughton D, Byrne J, Carey JC, Cassidy S, et al. Evaluation of mental retardation: Recommendations of a consensus conference. American College of Medical Genetics. Am J Med Genet. 1997; 72: 468-477.
• Liu YC, Lee ML, Chen CP, Lee CC, Lin SJ, Chao MC, et al. Inversion and enlargement of the heterochromatin region of chromosome no. 9 among Taiwanese. Tzu Chin Med J. 1997; 9(3): 159–167.
• Kunughi H, Lee KB, Nanko S. Cytogenetic findings in 250 schizophrenics: evidence confirming an excess of the X chromosome aneuploidies and pericentric inversion of chromosome 9. Schizophr Res. 1999; 40: 43– 47.
• Demirhan O, Taştemir D. Chromosome aberrations in a schizophrenia population. Schizophr Res. 2003; 65: 1–7.