Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome

Akgun-Dogan, Ozlem; Agaoglu, Nihat Bugra

doi:10.14744/iksstd.2021.08860

Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome

Nihat Buğra AĞAOĞLU, (Ümraniye Eğitim ve Araştırma Hastanesi Tıbbi Genetik Anabilim Dalı, İstanbul, Türkiye)

Özlem AKGÜN DOĞAN (Ümraniye Eğitim ve Araştırma Hastanesi Pediatrik Genetik Bölümü, İstanbul, Türkiye)

İstanbul Kanuni Sultan Süleyman Tıp Dergisi

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Yıl: 2022 Cilt: 14 Sayı: 1 Sayfa Aralığı: 8 - 17 Metin Dili: İngilizce DOI: 10.14744/iksstd.2021.08860 İndeks Tarihi: 26-06-2022

Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome

Öz:

Objective: This study aimed to review the clinical and molecular findings of 12 individuals with Marfan syndrome (MS) to identify novel mutations and associated clinical findings. Method: This study included 12 patients who were diagnosed with MS between January 2018 and January 2021 in a teaching and research hospital in Turkey. The patient files were retrospectively analyzed. A single clinical geneticist evaluated all of the patients. FBN1 sequencing was performed in all patients. Results: There were five male and seven female patients. Four of the patients did not meet the MS clinical diagnostic criteria before the molecular analysis. Most of the patients (67%) were referred due to the aortic dilatation; however, none of the patients had aortic aneurysms/dissections. Skeletal findings and MS-related facial features were present in all of the patients. Ectopia lentis was not detected. Only one patient had a history of pneumothorax. Twelve diverse variants were detected in 12 patients. Of these, ten were classified as pathogenic and two as likely pathogenic, and three were novel and nine were previously reported. There were five nonsense (42%), four frameshift (33%), and three missense (25%) variants. FBN1 variants were distributed within the gene without any hot spots. EGF-like domain was the most commonly affected protein domain. Conclusion: Elucidating the underlying molecular pathology in MS contributes to expanding the phenotype-genotype correlation in the disease and early diagnosis. Our study has broadened the genotypic and phenotypic spectrum of MS in Turkey by describing the clinical findings of 12 patients and reporting three novel variants.

Anahtar Kelime:

Bir Grup Türk Marfan Sendromlu Bireyde Klinik ve Moleküler Bulguların Değerlendirilmesi

Öz:

Amaç: Bu çalışma ile Marfan sendromundaki(MS) fenotipik genotipik spektrumu genişletmek için Marfan Sendromlu bireylerin klinik ve moleküler bulgularının gözden geçirilmesi amaçlandı. Yöntem: Çalışmaya Türkiye'de bir eğitim ve araştırma hastanesinde Ocak 2018- Ocak 2021 tarihleri arasında Marfan Sendromu tanısı konulan toplam 12 hasta dahil edildi. Hasta dosyaları geriye dönük olarak incelendi. Tüm hastalar tek bir klinik genetik uzmanı tarafından değerlendirildi. Tüm hastalarda FBN1 geni dizilendi. Bulgular: Hastaların beşi erkek, yedisi kadındı. Dört hasta moleküler çalışma sonucu olmadan MS klinik tanı kriterlerini karşılamıyordu. Hastaların çoğu (%67) aort dilatasyonu nedeniyle yönlendirilmişti, bununla birlikte hiçbir hastada aort anevrizması/ diseksiyonu saptanmamıştı. Hastaların tümünde iskelet bulguları ve MS ile ilişkili yüz özellikleri mevcuttu. Ektopia lentis tespit edilen hasta yoktu. Pnömotoraks öyküsü sadece bir hastada mevcuttu. On iki hastada 12 farklı varyant tespit edildi. Bunlardan on tanesi patojenik, ikisi muhtemel patojenik olarak sınıflandırıldı; üçü novel varyanttı, dokuzu ise daha önce bildirilmişti. Varyantlardan beşi (%42) nonsense, dördü (%33) frameshift, üçü (%25) ise missense gruptaydı. Saptanan FBN1 varyantları herhangi bir hotspot bölge olmaksızın gen içerisinde dağılmıştı. Protein düzeyinde incelendiğinde EGF-like domain, varyantların en sık etkilediği domaindi.

Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

1. Judge DP, Dietz HC. Marfan's syndrome. Lancet 2005;366:1965–76.
2. Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476–85.
3. Verstraeten A, Alaerts M, Van Laer L, Loeys B. Marfan Syndrome and related disorders: 25 Years of gene discovery. Hum Mutat 2016;37:524–31.
4. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, et al. editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022.
5. Hoffjan S. Genetic dissection of marfan syndrome and related connective tissue disorders: An update 2012. Mol Syndromol 2012;3:47–58.
6. Pereira L, D'Alessio M, Ramirez F, Lynch JR, Sykes B, Pangilinan T, et al. Genomic organization of the sequence coding for fibrillin, the defective gene product in Marfan syndrome. Hum Mol Genet 1993;2:1762.
7. Zeyer KA, Reinhardt DP. Engineered mutations in fibrillin-1 leading to Marfan syndrome act at the protein, cellular and organismal levels.Mutat Res Rev Mutat Res 2015;765:7–18.
8. Reinhardt DP, Keene DR, Corson GM, Pöschl E, Bächinger HP, Gambee JE, et al. Fibrillin-1: Organization in microfibrils and structural properties. J Mol Biol 1996;258:104–16.
9. Granata A, Serrano F, Bernard WG, McNamara M, Low L, Sastry P, et al. An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death. Nat Genet 2017;49:97–109.
10. de Vries BB, Pals G, Odink R, Hamel BC. Homozygosity for a FBN1 missense mutation: Clinical and molecular evidence for recessive Marfan syndrome. Eur J Hum Genet 2007;15:930–5.
11. Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, et al. The human gene mutation database: Towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet 2017;136:665–77.
12. Collod-Beroud G, Le Bourdelles S, Ades L, Ala-Kokko L, Booms P, Boxer M, et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat 2003;22:199–208.
13. Finkbohner R, Johnston D, Crawford ES, Coselli J, Milewicz DM. Marfan syndrome. Long-term survival and complications after aortic aneurysm repair. Circulation 1995;91:728–33.
14. Rao SS, Venuti KD, Dietz HC 3rd, Sponseller PD. Quantifying health status and function in marfan syndrome. J Surg Orthop Adv 2016;25:34–40.
15. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med 2015;17:405–24.
16. Parent JJ, Towbin JA, Jefferies JL. Fibrillin-1 gene mutations in left ventricular non-compaction cardiomyopathy. Pediatr Cardiol 2016;37:1123–6.
17. Arbustini E, Grasso M, Ansaldi S, Malattia C, Pilotto A, Porcu E, et al. Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies. Hum Mutat 2005;26:494.
18. Baetens M, Van Laer L, De Leeneer K, Hellemans J, De Schrijver J, Van De Voorde H, et al. Applying massive parallel sequencing to molecular diagnosis of Marfan and Loeys-Dietz syndromes. Hum Mutat 2011;32:1053–62.
19. Arslan-Kirchner M, Arbustini E, Boileau C, Child A, Collod-Beroud G, De Paepe A, et al. Clinical utility gene card for: Marfan syndrome type 1 and related phenotypes [FBN1]. Eur J Hum Genet 2010;18.
20. Mannucci L, Luciano S, Salehi LB, Gigante L, Conte C, Longo G, et al. Mutation analysis of the FBN1 gene in a cohort of patients with Marfan Syndrome: A 10-year single center experience. Clin Chim Acta 2020;501:154–64.
21. Madar L, Szakszon K, Pfliegler G, Szabó GP, Brúgós B, Ronen N, et al. FBN1 gene mutations in 26 Hungarian patients with suspected Marfan syndrome or related fibrillinopathies. J Biotechnol 2019;301:105–11.
22. Booms P, Cisler J, Mathews KR, Godfrey M, Tiecke F, Kaufmann UC, et al. Novel exon skipping mutation in the fibrillin-1 gene: two 'hot spots' for the neonatal Marfan syndrome. Clin Genet 1999;55:110–7.
23. Maeda J, Kosaki K, Shiono J, Kouno K, Aeba R, Yamagishi H. Variable severity of cardiovascular phenotypes in patients with an early-onset form of Marfan syndrome harboring FBN1 mutations in exons 24-32. Heart Vessels 2016;31:1717–23.
24. Stheneur C, Faivre L, Collod-Béroud G, Gautier E, Binquet C, Bonithon- Kopp C, et al. Prognosis factors in probands with an FBN1 mutation diagnosed before the age of 1 year. Pediatr Res 2011;69:265–70.
25. Loeys B, De Backer J, Van Acker P, Wettinck K, Pals G, Nuytinck L, et al. Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. Hum Mutat 2004;24:140–6.
26. Faivre L, Collod-Beroud G, Adès L, Arbustini E, Child A, Callewaert BL, et al. The new Ghent criteria for Marfan syndrome: What do they change? Clin Genet 2012;81:433–42.
27. Rommel K, Karck M, Haverich A, von Kodolitsch Y, Rybczynski M, Müller G, et al. Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome. Hum Mutat 2005;26:529–39.
28. Baudhuin LM, Kotzer KE, Lagerstedt SA. Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events. Genet Med 2015;17:177–87.
29. Schrijver I, Liu W, Odom R, Brenn T, Oefner P, Furthmayr H, et al. Premature termination mutations in FBN1: Distinct effects on differential allelic expression and on protein and clinical phenotypes. Am J Hum Genet 2002;71:223–37.
30. Comeglio P, Johnson P, Arno G, Brice G, Evans A, Aragon-Martin J, et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: Report of 193 FBN1 mutations. Hum Mutat 2007;28:928.
31. Robinson PN, Godfrey M. The molecular genetics of Marfan syndrome and related microfibrillopathies. J Med Genet 2000;37:9–25.
32. Ittisoponpisan S, Islam SA, Khanna T, Alhuzimi E, David A, Sternberg MJE. Can predicted protein 3D structures provide reliable insights into whether missense variants are disease associated? J Mol Biol 2019;431:2197–212.

APA	Agaoglu N, Akgun-Dogan O (2022). Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome. , 8 - 17. 10.14744/iksstd.2021.08860
Chicago	Agaoglu Nihat Bugra,Akgun-Dogan Ozlem Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome. (2022): 8 - 17. 10.14744/iksstd.2021.08860
MLA	Agaoglu Nihat Bugra,Akgun-Dogan Ozlem Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome. , 2022, ss.8 - 17. 10.14744/iksstd.2021.08860
AMA	Agaoglu N,Akgun-Dogan O Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome. . 2022; 8 - 17. 10.14744/iksstd.2021.08860
Vancouver	Agaoglu N,Akgun-Dogan O Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome. . 2022; 8 - 17. 10.14744/iksstd.2021.08860
IEEE	Agaoglu N,Akgun-Dogan O "Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome." , ss.8 - 17, 2022. 10.14744/iksstd.2021.08860
ISNAD	Agaoglu, Nihat Bugra - Akgun-Dogan, Ozlem. "Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome". (2022), 8-17. https://doi.org/10.14744/iksstd.2021.08860

APA	Agaoglu N, Akgun-Dogan O (2022). Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome. İstanbul Kanuni Sultan Süleyman Tıp Dergisi, 14(1), 8 - 17. 10.14744/iksstd.2021.08860
Chicago	Agaoglu Nihat Bugra,Akgun-Dogan Ozlem Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome. İstanbul Kanuni Sultan Süleyman Tıp Dergisi 14, no.1 (2022): 8 - 17. 10.14744/iksstd.2021.08860
MLA	Agaoglu Nihat Bugra,Akgun-Dogan Ozlem Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome. İstanbul Kanuni Sultan Süleyman Tıp Dergisi, vol.14, no.1, 2022, ss.8 - 17. 10.14744/iksstd.2021.08860
AMA	Agaoglu N,Akgun-Dogan O Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome. İstanbul Kanuni Sultan Süleyman Tıp Dergisi. 2022; 14(1): 8 - 17. 10.14744/iksstd.2021.08860
Vancouver	Agaoglu N,Akgun-Dogan O Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome. İstanbul Kanuni Sultan Süleyman Tıp Dergisi. 2022; 14(1): 8 - 17. 10.14744/iksstd.2021.08860
IEEE	Agaoglu N,Akgun-Dogan O "Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome." İstanbul Kanuni Sultan Süleyman Tıp Dergisi, 14, ss.8 - 17, 2022. 10.14744/iksstd.2021.08860
ISNAD	Agaoglu, Nihat Bugra - Akgun-Dogan, Ozlem. "Evaluation of Clinical and Molecular Findings in a Group of Turkish Individuals with Marfan Syndrome". İstanbul Kanuni Sultan Süleyman Tıp Dergisi 14/1 (2022), 8-17. https://doi.org/10.14744/iksstd.2021.08860