THE PREVALENCE OF FRAGILE X SYNDROME IN INDIVIDUALS WITH AUTISM SPECTRUM DISORDER: GENETIC INSIGHTS AND DIAGNOSTIC CHALLENGES

Öz

Objective: Fragile X Syndrome (FXS) is a complex neurodevel opmental condition characterised by delayed language develop ment, dysmorphic features, and impaired cognitive development. FXS, which results from CGG repeat expansion in the FMR1 gene, is the most commonly identified genetic cause of autism. Accu rate diagnosis of FXS is crucial for effective management and treatment. This study aimed to evaluate the prevalence of FXS in individuals with Autism Spectrum Disorder (ASD). Material and Methods: We conducted a retrospective study involv ing 50 patients. Comprehensive fragment analysis of the FMR1 gene was performed, with repeat sequences classified according to the stringent guidelines established by American College of Medical Genetics and Genomics (ACMG), Clinical Molecular Genetics Society (CMGS) ve European Society of Human Genetics (ESHG). Results: FXS was identified in three individuals (6%) within the study cohort. This finding aligns with previous reports indicating prevalence rates between 2% and 8% among ASD populations, thereby confirming the significance of our results. Conclusion: The overlapping symptoms of FXS and idiopathic autism present diagnostic challenges, highlighting the importance of identifying FXS to implement targeted therapies. Family history is critical in identifying at risk individuals, as FXS can lead to varied manifestations in family members, including ataxia and early menopause. Although this study provides valuable insights, the limited sample size underscores the need for larger scale research. Advanced genetic investigations and comprehensive panels could further aid in identifying additional causes of autism. This study emphasises the significance of genetic testing for FXS in the context of autism, aiming to enhance interventions and provide accurate recurrence risk counseling for families affected by this prevalent condition.

Anahtar Kelimeler

• Fragile X Syndrome
• autism spectrum disorder
• FMR1 gene
• fragment analysis

OTİZM SPEKTRUM BOZUKLUĞU OLAN BİREYLERDE FRAGİLE X SENDROMU PREVALANSI: GENETİK BULGULAR VE TANISAL ZORLUKLAR

Öz

Amaç: Fragile X sendromu (FXS), gecikmiş dil gelişimi, dismorfik özellikler ve zihinsel gelişimin bozulması ile karakterize karmaşık bir nörogelişimsel durumdur. FMR1 genindeki CGG tekrar genişlemesi sonucu ortaya çıkan FXS, otizmin en sık belirlenen genetik nedenidir. FXS’ nin doğru tanısı, etkili yönetim ve tedavi için büyük önem taşımaktadır. Bu çalışma, otizmli bireylerde FXS prevalansını değerlendirmeyi amaçlamaktadır. Gereç ve Yöntemler: Bu çalışmada 50 hasta üzerinde yapılan fragman analizi ile FMR1 genindeki CGG tekrar uzunlukları değerlendirildi. Elde edilen sonuçlar, tekrarlayan bölgelerin American College of Medical Genetics and Genomics (ACMG), Clinical Mole cular Genetics Society (CMGS) ve European Society of Human Genetics (ESHG) kılavuzlarına uygun olarak sınıflandırılmasıyla yorumlandı. Bulgular: Literatürde yer alan destekleyici çalışmalar da FXS ile otizm arasındaki bağlantıyı vurgulamaktadır. Çalışma kohortunda üç bireyde (%6) FXS tespit edilmiştir. Bu bulgu, otizm spektrum bozukluğu popülasyonlarında %2 ile %8 arasında değişen prevalans oranlarını bildiren önceki çalışmalarla uyumlu olup, elde edilen sonuçların önemini doğrulamaktadır. Sonuç: FXS ile idiopatik otizmin örtüşen semptomları tanısal zorluklar yaratmakta olup, hedefe yönelik tedavilerin uygulanabilmesi için FXS’ nin belirlenmesi büyük önem taşımaktadır. Aile öyküsü, risk altındaki bireylerin tanımlanmasında kritik bir rol oynamaktadır. FXS, aile bireylerinde ataksi ve erken menopoz gibi farklı klinik belirtilere yol açabilmektedir. Otizmin genetik etiyolojisinin belirlenmesinde altın standart tekniklerden FMR1 fragman analizi ile FXS ekartasyonu sonrası kapsamlı genetik paneller, otizmin ek nedenlerinin belirlenmesine katkı sağlamaktadır. Bu çalışma, otizm bağlamında FXS için genetik testlerin önemini vurgulamakta, müdahaleleri iyileştirmeyi ve etkilenen ailelere doğru tekrar risk danışmanlığı sağlamayı hedeflemektedir.

Anahtar Kelimeler

• Fragile X sendromu
• otizm spektrum bozukluğu
• FMR1 geni
• fragman analizi

Kaynakça

1. Harris SW, Hessl D, Goodlin-Jones B, Ferranti J, Bacalman S, Barbato I, et al. Autism profiles of males with fragile X syndrome. In: MacLean WE Jr, Abbeduto L, editors. Am J Ment Retard2008;113(6):427-38. google scholar
2. Hnoonual A, Plong-On O, Worachotekamjorn J, Charalsawadi C, Limprasert P. Clinical and molecular characteristics of FMR1 microdeletion in patient with fragile X syndrome and review of the literature. Clin Chim Acta 2024;553:117728. google scholar
3. Hunter J, Rivero-Arias O, Angelov A, Kim E, Fotheringham I, Leal J. Epidemiology of fragile X syndrome: A systematic review and meta-analysis. Am J Med Genet A 2014;164(7):1648-58. google scholar
4. Hagerman R. Consideration of connective tissue dysfunction in the AleX syndrome. Am J Med Genet 1984;17(1):111-21. google scholar
5. Chatterji S, Pachter L. Reference based annotation with GeneMapper. Genome Biol 2006;7(4):R29. google scholar
6. Schaefer GB, Mendelsohn NJ. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15(5):399-407. google scholar
7. Hunter JE, Berry-Kravis E, Hipp H, Todd PK. FMR1 disorders. In: Adam MP, Feldman J, Mirzaa GM, et al. GeneReviews® Seattle (WA): University of Washington, Seattle; 1993-2025 [updated 2024 May 16; cited 2025]. https://www.ncbi.nlm.nih. gov/books/NBK1384/ google scholar
8. Tassone F, Beilina A, Carosi C, Albertosi S, Bagni C, Li L, et al. Elevated FMR1 mRNA in premutation carriers is due to increased transcription. RNA. 2007;13(4):555-62. google scholar

9. Marlborough M, Welham A, Jones C, Reckless S, Moss J. Autism spectrum disorder in females with fragile X syndrome: a systematic review and meta-analysis of prevalence. J Neurodev Disord2021;13(1):28. google scholar
10. Nolin SL, Brown WT, Glicksman A, Houck GE Jr, Gargano AD, Sullivan A, et al. Expansion of the Fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet2003;72(2):454-64. google scholar
11. Bailey DB Jr, Hatton DD, Mesibov G, Ament N, Skinner M. Early development, temperament, and functional impairment in autism and fragile X syndrome. J Autism Dev Disord 2000;30(1):49-59. google scholar
12. Rogers SJ, Hepburn SL, Stackhouse T, Wehner E. The behavioral phenotype in fragile X: symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmental disorders. J Dev Behav Pediatr 2001;22(6):409-17. google scholar
13. Hessl D, Dyer-Friedman J, Glaser B, Wisbeck J, Barajas R, Taylor A, et al. The influence of environmental and genetic factors on behavior problems and autistic symptoms in boys and girls with fragile X syndrome. Pediatrics 2001;108(5):E88. google scholar
14. Granata P, Zito A, Cocciadiferro D, Novelli A, Pessina C, Mazza T, et al. Unveiling genetic insights: Array-CGH and WES discoveries in a cohort of 122 children with essential autism spectrum disorder. BMC Genomics 2024;25(1):1186. google scholar