SPONDİLOEPİ (META) FİZYAL DİSPLAZİ ÖN TANILI BEŞ TÜRK ERKEK HASTADAKİ GENETİK ETYOLOJİNİN ARAŞTIRILMASI
Abstract
AMAÇ: İskelet displazisi orantısız boy kısalığı ve çeşitli ortopedik komplikasyonlarla karakterize kompleks bir hastalık grubudur. X'e Bağlı Spondiloepifizyal Displazi Tarda, progresif spondiloepi(meta)fizyal displazi ve prematür osteoartritin eşlik ettiği X'e bağlı kalıtsal bir iskelet displazisidir. Trafficking protein particle complex 2 (TRAPPC2) geni bu hastalıkla ilişkilendirilmiştir. Progresif psödoromatoid displazi (PPRD), dirsek eklemlerinde genişleme ve artrit benzeri bulgular ile karakterize bir hastalıktır. Otozomal resesif kalıtımlı bir iskelet displazisi subgrubu olan bu hastalığa ise 6q21 kromozomal lokasyonunda bulunan celluler communication network factor 6 (CCN6) genindeki mutasyonlar neden olur. Bu çalışma ile X'e bağlı ya da otozomal resesif kalıtım paterni düşünülen, yıllardır tanı almamış beş erkek bireye tanı koyarak, olası tedavileri belirlemek ve prenatal preimplantasyon genetik test olanağı sunmak amaçlandı.
GEREÇ VE YÖNTEM: Bu çalışmaya, X'e bağlı veya otozomal resesif kalıtımlı iskelet displazisi olan beş erkek kardeş dahil edildi. Dört hastaya Whole Ekzom Sekanslama (WES) yapıldı. Bir hasta ve aynı aileden dört sağlıklı bireye ise Sanger sekanslama yapıldı.
BULGULAR: Etkilenen tüm kardeşlerde CCN6 geninde homozigot c.210C>A (p.Cys70Ter) ve c.302G>A (p.Gly101Glu) mutasyonları bulundu. Böylece, X'e bağlı resesif kalıtım paterni olma olasılığına rağmen WES sonrası otozomal resesif PPRD tanısı koyuldu.
SONUÇ: Bu çalışma normalde bir çocukluk çağı hastalığı olan Progresif psödoromatoid displazisi tanısı alan ortalama yaşı 54.6 olan en yaşlı hastaları sunmaktadır. p.Cys70Ter değişikliği Türk hastalarda en sık görülen patojenik varyanttır. Bu çalışma, Progresif psödoromatoid displazinin ortalama yaşam süresi üzerinde anlamlı bir etkisinin olmadığını göstermesi açısından da önemlidir. Aynı zamanda bu çalışma, bu hastalığın seyrini ve yaşam boyu eşlik edebilecek klinik bulguları göstermesi açısından da önemlidir.
Supporting Institution
Manisa Celal Bayar Üniversitesi Rektörlüğü Bilimsel Araştırma Projeleri Koordinasyon Birimi
Project Number
2017-075
References
- 1. Xia XY, Yu J, Li WW,et al. A novel nonsense mutation in the sedlin gene (SED L) causes severe spondyloepiphyseal dysplasia tarda in a five-generation Chinese pedigree. Genetics and Molecular Research. 2014;13:3362-70.
- 2. Fiedler J, Merrer ML, Mortier G, Heuertz S, Faivre L, Brenner RE. X‐linked spondyloepiphyseal dysplasia tarda: Novel and recurrent mutations in 13 European families. Human mutation. 2004;24(1):103.
- 3. Shaw MA, Brunetti‐Pierri N, Kadasi L, et al. Identification of three novel SEDL mutations, including mutation in the rare, non‐canonical splice site of exon 4. Clinical genetics. 2003;64(3):235-42.
- 4. Gedeon AK, Tiller GE, Le Merrer M, et al. The molecular basis of X-linked spondyloepiphyseal dysplasia tarda. The American Journal of Human Genetics. 2001;68(6):1386-97.
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- 6. Rai E, Mahajan A, Kumar P, et al. Whole exome screening identifies novel and recurrent WISP3 mutations causing progressive pseudorheumatoid dysplasia in Jammu and Kashmir-India. Scientific Reports. 2016;6:27684.
- 7. El-Shanti HE, Omari HZ, Qubain HI. Progressive pseudorheumatoid dysplasia: report of a family and review. Journal of Medical Genetics. 1997;34(7):559-63.
- 8. Yin L, Mao Y, Zhou Y, et al. A retrospective study of nine patients with progressive pseudorheumatoid dysplasia: to explore early diagnosis and further treatment. Clin Rheumatol. 2022;41(3):877-8.
- 9. Tran MN, Kleer CG. Matricellular CCN6 (WISP3) protein: a tumor suppressor for mammary metaplastic carcinomas. Journal of cell communication and signaling. 2018;12:13-9.
- 10. Giusti V, Scotlandi K. CCN proteins in the musculoskeletal system: current understanding and challenges in physiology and pathology. J Cell Commun Signal. 2021;15(4):545-66.
- 11. Van der Auwera GA, Carneiro MO, Hartl C, et al. From FastQ Data to High‐Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline. Current protocols in bioinformatics. 2013;43(11109):11.10.1- 11.10.33
- 12. Li H, Durbin R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics. 2009;25(14):1754-60.
- 13. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic acids Research. 2010;38(16):164.
- 14. Madhuri V, Santhanam M, Rajagopal K, Sugumar LK, Balaji V. WISP3 mutational analysis in Indian patients diagnosed with progressive pseudorheumatoid dysplasia and report of a novel mutation at p. Y198. Bone and Joint Research. 2016;5:301-6.
- 15. Bhavani GS, Shah H, Dalal AB, et al. Novel and recurrent mutations in WISP3 and an atypical phenotype. American Journal of Medical Genetics. 2015;167A(10):2481-4.
- 16. Temiz F, Ozbek MN, Kotan D, et al. A homozygous recurring mutation in WISP3 causing progressive pseudorheumatoid arthropathy. Journal of Pediatric Endocrinology and Metabolism. 2011;24(1-2):105-8.
- 17. Segarra NG, Mittaz L, Campos‐Xavier, et al. The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): a review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals. Am J Med Genet C Semin Med Genet. 2012;160(3):217-29.
- 18. Delague V, Chouery E, Corbani S, et al. Molecular study of WISP3 in nine families originating from the Middle‐East and presenting with progressive pseudorheumatoid dysplasia: Identification of two novel mutations, and description of a founder effect. American Journal of Medical Genetics Part A. 2005;138A(2):118-26.
- 19. Hurvitz JR, Suwairi WM, Van Hul W, et al. Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nature Genetics. 1999;23, 94-8.
- 20. Bhavani GS, Shah H, Shukla A, Dalal A, Girisha KM. Progressive Pseudorheumatoid Dysplasia. Genereviews. September 25, 2015; Last Update: December 23, 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK327267/.
- 21. Ekbote AV, Danda D, Kumar S, Danda S, Madhuri V, Gibikote S. A descriptive analysis of 14 cases of progressive-psuedorheumatoid-arthropathy of childhood from south India: review of literature in comparison with juvenile idiopathic arthritis. Semin Arthritis Rheum. 2013;42(6):582-9.
- 22. Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics. 2010;11:548.
INVESTIGATION OF GENETIC ETIOLOGY IN FIVE TURKISH MALE PATIENTS WITH PRE-DIAGNOSED SPONDYLOEPI (META) PHYSEAL DYSPLASIA
Abstract
OBJECTIVE: Skeletal dysplasias is a complex disease group characterized by disproportionate short stature and various orthopedic complications. X-Linked Spondyloepiphyseal Dysplasia Tarda is an X-linked inherited skeletal dysplasia accompanied by progressive spondyloepi(meta)physeal dysplasia and premature osteoartritis. The gene related to the disorder is trafficking protein particle complex 2 (TRAPPC2). Progressive pseudorheumatoid dysplasia (PPRD) is characterized by enlargement of the elbow joints and arthritis-like findings. It is an autosomal recessive subtype of skeletal dysplasia caused by mutations in cellular communication network factor 6 (CCN6) gene located on chrosomal region 6q21. In this study, it was aimed to diagnose five male individuals with an X-linked or autosomal recessive inheritance pattern, who have not been diagnosed for years, to identify possible treatments and to offer prenatal pmreimplantation genetic testing.
MATERIAL AND METHODS: Five male siblings with skeletal dysplasia with an uncertain inheritance either X-linked or autosomal recessive pattern were included in this study, Whole Exome Sequencing (WES) was applied to the four affected cases. Sanger Sequencing was performed in one affected case and four healthy individuals.
RESULTS: Homozygous c.210C>A (p.Cys70Ter) and homozygous c.302G>A (p.Gly101Glu) mutations in the CCN6 gene were found in all affected siblings. Thus, the final diagnosis after WES was autosomal recessive PPRD despite the possibility of an X-linked recessive pattern.
CONCLUSIONS: This study presents a series of the oldest patients diagnosed with Progressive pseudorheumatoid dysplasia, normally a childhood disease, with an average age of 54.6. The p.Cys70Ter alteration is the most frequent pathogenic variant in Turkish patients. This study is also important in terms of showing that Progressive pseudorheumatoid dysplasia has no significant effect on life expectancy. At the same time, this study shows the progression of this disease and clinical findings that may accompany lifetime.
Project Number
2017-075
References
- 1. Xia XY, Yu J, Li WW,et al. A novel nonsense mutation in the sedlin gene (SED L) causes severe spondyloepiphyseal dysplasia tarda in a five-generation Chinese pedigree. Genetics and Molecular Research. 2014;13:3362-70.
- 2. Fiedler J, Merrer ML, Mortier G, Heuertz S, Faivre L, Brenner RE. X‐linked spondyloepiphyseal dysplasia tarda: Novel and recurrent mutations in 13 European families. Human mutation. 2004;24(1):103.
- 3. Shaw MA, Brunetti‐Pierri N, Kadasi L, et al. Identification of three novel SEDL mutations, including mutation in the rare, non‐canonical splice site of exon 4. Clinical genetics. 2003;64(3):235-42.
- 4. Gedeon AK, Tiller GE, Le Merrer M, et al. The molecular basis of X-linked spondyloepiphyseal dysplasia tarda. The American Journal of Human Genetics. 2001;68(6):1386-97.
- 5. Uludağ Alkaya D, Kasapçopur Ö, Bursalı A, et al. Specific early signs and long-term follow-up findings of Progressive Pseudorheumatoid Dysplasia (PPRD) in the Turkish cohort. Rheumatology (Oxford). 2021;17:926.
- 6. Rai E, Mahajan A, Kumar P, et al. Whole exome screening identifies novel and recurrent WISP3 mutations causing progressive pseudorheumatoid dysplasia in Jammu and Kashmir-India. Scientific Reports. 2016;6:27684.
- 7. El-Shanti HE, Omari HZ, Qubain HI. Progressive pseudorheumatoid dysplasia: report of a family and review. Journal of Medical Genetics. 1997;34(7):559-63.
- 8. Yin L, Mao Y, Zhou Y, et al. A retrospective study of nine patients with progressive pseudorheumatoid dysplasia: to explore early diagnosis and further treatment. Clin Rheumatol. 2022;41(3):877-8.
- 9. Tran MN, Kleer CG. Matricellular CCN6 (WISP3) protein: a tumor suppressor for mammary metaplastic carcinomas. Journal of cell communication and signaling. 2018;12:13-9.
- 10. Giusti V, Scotlandi K. CCN proteins in the musculoskeletal system: current understanding and challenges in physiology and pathology. J Cell Commun Signal. 2021;15(4):545-66.
- 11. Van der Auwera GA, Carneiro MO, Hartl C, et al. From FastQ Data to High‐Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline. Current protocols in bioinformatics. 2013;43(11109):11.10.1- 11.10.33
- 12. Li H, Durbin R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics. 2009;25(14):1754-60.
- 13. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic acids Research. 2010;38(16):164.
- 14. Madhuri V, Santhanam M, Rajagopal K, Sugumar LK, Balaji V. WISP3 mutational analysis in Indian patients diagnosed with progressive pseudorheumatoid dysplasia and report of a novel mutation at p. Y198. Bone and Joint Research. 2016;5:301-6.
- 15. Bhavani GS, Shah H, Dalal AB, et al. Novel and recurrent mutations in WISP3 and an atypical phenotype. American Journal of Medical Genetics. 2015;167A(10):2481-4.
- 16. Temiz F, Ozbek MN, Kotan D, et al. A homozygous recurring mutation in WISP3 causing progressive pseudorheumatoid arthropathy. Journal of Pediatric Endocrinology and Metabolism. 2011;24(1-2):105-8.
- 17. Segarra NG, Mittaz L, Campos‐Xavier, et al. The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): a review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals. Am J Med Genet C Semin Med Genet. 2012;160(3):217-29.
- 18. Delague V, Chouery E, Corbani S, et al. Molecular study of WISP3 in nine families originating from the Middle‐East and presenting with progressive pseudorheumatoid dysplasia: Identification of two novel mutations, and description of a founder effect. American Journal of Medical Genetics Part A. 2005;138A(2):118-26.
- 19. Hurvitz JR, Suwairi WM, Van Hul W, et al. Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nature Genetics. 1999;23, 94-8.
- 20. Bhavani GS, Shah H, Shukla A, Dalal A, Girisha KM. Progressive Pseudorheumatoid Dysplasia. Genereviews. September 25, 2015; Last Update: December 23, 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK327267/.
- 21. Ekbote AV, Danda D, Kumar S, Danda S, Madhuri V, Gibikote S. A descriptive analysis of 14 cases of progressive-psuedorheumatoid-arthropathy of childhood from south India: review of literature in comparison with juvenile idiopathic arthritis. Semin Arthritis Rheum. 2013;42(6):582-9.
- 22. Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics. 2010;11:548.
Details
| Primary Language | English |
|---|---|
| Subjects | Clinical Sciences |
| Journal Section | Articles |
| Authors | |
| Project Number | 2017-075 |
| Publication Date | April 5, 2023 |
| Acceptance Date | June 16, 2022 |
| Published in Issue | Year 2023 Volume: 24 Issue: 2 |
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