Tüm Ekzom Dizilemesi, Joubert ile İlişkili Bozuklukları Olan Türk Ailelerinde Yeni Mutasyonları Ortaya Koydu

Yıl 2026, Cilt: 48 Sayı: 2, 210 - 219, 11.02.2026

Onur Emre Onat , Umut Arda Bayraktar , Yusuf Bayraktar

https://izlik.org/JA23UN23AF

Öz

Joubert sendromu (JS) ve ilişkili bozukluklar, beyin MRI’sında karakteristik “azı dişi belirtisi” ile tanımlanan, serebellar vermis ve beyin sapının anormal gelişimini yansıtan nadir nörogelişimsel durumlardır. Klinik tablo oldukça değişkendir; hipotoni, ataksi, gelişimsel gecikme ve anormal göz hareketlerinden retinayı, böbrekleri ve karaciğeri etkileyen çoklu organ tutulumuna kadar geniş bir yelpazede görülebilir. Bu çeşitlilik genetik düzeyde de yansımaktadır. Günümüze kadar OMIM’de JS ile resmi olarak ilişkilendirilmiş 39 gen tanımlanmış olup, literatürde en az 22 ek aday gen daha önerilmiştir. Genotip-fenotip ilişkileri dikkatlice değerlendirildiğinde, etkilenen bireylerin yaklaşık %80’inde moleküler tanıya ulaşılabilmektedir. Bu takip çalışmasında, üç akraba evliliği olan Türk ailesinde JS’nin genetik temelini araştırmak için tüm ekzom dizilemesi (WES) uyguladık. Her aileden yalnızca bir etkilenmiş bireyin dizilenmesiyle, beklenen kalıtım modeliyle uyumlu, nadir ve protein yapısını değiştiren varyantlara öncelik verdik. Aile 1’de, probandın retina distrofisiyle uyumlu olarak INPP5E geninde homozigot bir missens mutasyon (c.1204A>G; p.K402E; JBTS1) belirledik. Aile 2’de, TMEM67 geninde iki yeni bileşik heterozigot missens varyantı (c.1526T>C; p.F509S ve c.2639C>A; p.S880Y; JBTS6) saptadık; bu varyantlar etkilenmiş bireydeki karaciğer ve böbrek tutulumu ile uyumludur ve ne ClinVar’da ne de popülasyon veri tabanlarında bildirilmiştir. Aile 3’te bilinen JSRD genlerinde patojenik veya olası patojenik bir varyant saptanmadı; bu durum, bu soy ağacının daha önce tanımlanmamış bir JS ilişkili genin belirlenmesine katkı sağlayabileceğini düşündürmektedir. Genel olarak bulgularımız, WES’in JS gibi genetik açıdan heterojen bozukluklarda hızlı ve maliyet-etkin bir tanı aracı olarak etkinliğini vurgulamakta ve akrabalık oranlarının yüksek olduğu popülasyonlarda özellikle değerli olduğunu ortaya koymaktadır.

Anahtar Kelimeler

Joubert sendromu , tüm ekzom dizilemesi , siliyopatiler , genetik heterojenite , moleküler tanı

Whole Exome Sequencing Identified Novel Mutations in Turkish Families with Joubert-related Disorders

https://izlik.org/JA23UN23AF

Öz

Joubert syndrome (JS) and related disorders are rare neurodevelopmental conditions defined by the characteristic “molar tooth sign” on brain MRI, which reflects abnormal development of the cerebellar vermis and brainstem. The clinical picture is highly variable, ranging from hypotonia, ataxia, developmental delay, and abnormal eye movements to multiorgan involvement affecting the retina, kidneys, and liver. This diversity is mirrored at the genetic level. To date, 39 genes have been formally associated with JS in OMIM, and at least 22 additional candidates have been proposed in the literature. When genotype-phenotype correlations are carefully assessed, a molecular diagnosis can be reached in up to 80% of affected individuals. In this follow-up study, we applied whole-exome sequencing (WES) to investigate the genetic basis of JS in three consanguineous Turkish families. Sequencing a single affected member from each family, we prioritized rare, protein-altering variants that were compatible with the expected inheritance model. In Family 1, we identified a homozygous missense mutation in INPP5E (c.1204A>G; p.K402E; JBTS1), consistent with the proband’s retinal dystrophy. In Family 2, we detected two novel compound heterozygous missense variants in TMEM67 (c.1526T>C; p.F509S and c.2639C>A; p.S880Y; JBTS6), which align with the hepatic and renal involvement seen in the affected individual; neither variant has been reported in ClinVar or population databases. No pathogenic or likely pathogenic variants were found in known JSRD genes in Family 3, raising the possibility that this pedigree may contribute to the identification of a previously unrecognized JS-associated gene. Taken together, our findings highlight the effectiveness of WES as a rapid, cost-efficient diagnostic tool for genetically heterogeneous disorders like JS, and underscore its particular value in populations with high rates of consanguinity.

Anahtar Kelimeler

Joubert syndrome , whole-exome sequencing , ciliopathies , genetic heterogeneity , molecular diagnosis

Etik Beyan

The clinical, cytogenetic, and radiological features of these families were previously described in detail by Bayraktar et al.⁹ Written informed consent was obtained from all participating individuals or their legal guardians at the time of the original clinical evaluation, and the study protocol received approval from the Hacettepe University Institutional Review Board. The present work involved additional molecular and genomic analyses performed exclusively on archived peripheral blood samples collected during the initial diagnostic work-up. No new biological samples were collected, and no additional clinical or invasive procedures were conducted for this study.

Teşekkür

We would like to thank the volunteers for participating in the study.

Kaynakça

• 1. Boltshauser E, Isler W. Joubert syndrome: episodic hyperpnea, abnormal eye movements, retardation and ataxia, associated with dysplasia of the cerebellar vermis. Neuropadiatrie. 1977;8(1):57-66.
• 2. Brancati F, Dallapiccola B, Valente EM. Joubert syndrome and related disorders. Orphanet J Rare Dis. 2010;5:20.
• 3. Paprocka J, Jamroz E. Joubert syndrome and related disorders. Neurol Neurochir Pol. 2012;46(4):379-383.
• 4. Bachmann-Gagescu R, Dempsey JC, Bulgheroni S, Chen ML, D’Arrigo S, Glass IA, et al. Healthcare recommendations for Joubert syndrome. Am J Med Genet A. 2020;182(1):229-249.
• 5. Parisi MA, Doherty D, Chance PF, Glass IA. Joubert syndrome (and related disorders) (OMIM 213300). Eur J Hum Genet. 2007;15(5):511-521.
• 6. Glass IA, Dempsey JC, Parisi M, et al. Joubert syndrome. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. 2003 Jul 9 [updated 2025 Mar 13]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1325/
• 7. Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011;12(11):745-755.
• 8. Kars ME, Başak AN, Onat OE, Bilguvar K, Choi J, Itan Y, et al. The genetic structure of the Turkish population reveals high levels of variation and admixture. Proc Natl Acad Sci U S A. 2021;118(36):e2026076118.
• 9. Bayraktar Y, Yonem O, Varlı K, Taylan H, Shorbagi A, Sokmensuer C. Novel variant syndrome associated with congenital hepatic fibrosis. World J Clin Cases. 2015;3(10):904-910.
• 10. Onat OE, Üstünel F. Genome analysis. In: Ranganathan S, Cannataro M, Khan AM, editors. Encyclopedia of Bioinformatics and Computational Biology. 2nd ed. Amsterdam: Elsevier; 2025. p.148-164.
• 11. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754-1760.
• 12. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20(9):1297-1303.
• 13. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559-575.
• 14. Cingolani P, Platts A, Wang LL, Coon M, Nguyen T, Wang L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin). 2012;6(2):80-92.
• 15. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164.
• 16. Liu X, Wu C, Li C, Boerwinkle E. dbNSFP v3.0: a one-stop database of functional predictions and annotations for human nonsynonymous and splice-site SNVs. Hum Mutat. 2016;37(3):235-241.
• 17. Audo I, Bujakowska KM, Léveillard T, Mohand-Saïd S, Lancelot ME, Germain A, et al. Development and application of a next-generation-sequencing approach to detect known and novel gene defects underlying retinal diseases. Orphanet J Rare Dis. 2012;7:8.
• 18. Gana S, Serpieri V, Valente EM. Genotype-phenotype correlates in Joubert syndrome: a review. Am J Med Genet C Semin Med Genet. 2022;190(1):72-88.
• 19. Iannicelli M, Brancati F, Mougou-Zerelli S, Mazzotta A, Thomas S, Elkhartoufi N, et al. Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies. Hum Mutat. 2010;31(5):E1319-E1331.
• 20. Li C, Jensen VL, Park K, Kennedy J, Garcia-Gonzalo FR, Romani M, et al. MKS5 and CEP290 dependent assembly pathway of the ciliary transition zone. PLoS Biol. 2016;14(3):e1002416.
• 21. Coppieters F, Lefever S, Leroy BP, De Baere E. CEP290, a gene with many faces: mutation overview and presentation of CEP290base. Hum Mutat. 2010;31(10):1097-1108.
• 22. Zhang R, Tang J, Li T, Zhou J, Pan W. INPP5E and coordination of signaling networks in cilia. Front Mol Biosci. 2022;9:885592.
• 23. Yinsheng Z, Miyoshi K, Qin Y, Fujiwara Y, Yoshimura T, Katayama T. TMEM67 is required for the gating function of the transition zone that controls entry of membrane-associated proteins ARL13B and INPP5E into primary cilia. Biochem Biophys Res Commun. 2022;636(Pt 1):162-169.
• 24. Özçelik T. Medical genetics and genomic medicine in Turkey: a bright future at a new era in life sciences. Mol Genet Genomic Med. 2017;5(5):466-472. doi:10.1002/mgg3.326.
• 25. Onat OE, Ozcelik T. Genom projects in the world and in Turkey. In: Çağlayan AO, editor. Next-Generation Sequencing and Its Clinical Applications. Ankara: Güneş Kitabevi; 2024. p.493-512.