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

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

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

Kaynakça

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