Retinitis pigmentosa hastalarının yeni nesil dizileme analizi ile göz ve klinik bulgularının değerlendirilmesi
Date
2023
Authors
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Publisher
Bursa Uludağ Üniversitesi
Abstract
Amaç: Türkiye’nin tüm bölgelerinden kliniğimize başvuran retinitispigmentosa (RP) hastalarında, hastalığın oluşumuna hangi genlerde, hangi tip mutasyonların rol oynadığının yeni nesil dizileme (YND, Next Generation Sequencing, NGS) yöntemi ile belirlenmesi ve bu mutasyonların klinik fenotipe yansımasının incelenmesidir. Gereç ve Yöntem: Kliniğimize başvurarak detaylı fundus muayenesi ileRP tanısı alan ve periferik kandan YND tekniği ile mutasyon analizi yapılan 118hastanın anamnez ve muayene bilgileri retrospektif olarak incelenmiştir. Hastaların hikayesi, özgeçmiş ve soy geçmişleri ile ilgili bilgiler kaydedilmiştir. Genetik analizlerinden kliniği açıklayan patojenik, muhtemel patojenik ve klinik önemi bilinmeyen (VUS) mutasyonlar veri tabanları taranarak Amerika Tıbbi Genetik ve Genomik Derneği'nin (ACMG, 2015) kriterlerine göre belirlenmiştir. Muayene bulgularından en iyi düzeltilmiş görme keskinliği (EİDK), biyomikroskopik muayene ve detaylı fundus muayenesi, göz içi basınç (GİB)ölçümü kaydedilmiştir. Hastaların detaylı optik koherens tomografi (OKT),“Enhanced Depth Imaging-OKT” (EDI-OKT), retina sinir lifi tabakası (RNFL)görüntülemeleri ve varsa elektroretinogram (ERG) bulguları incelenerek; maküla, koroid ve sinir lifi tabakası kalınlığı, epiretinal membran (ERM) ve kistoid maküler ödem (KMÖ) varlığı, elipsoid zon (EZ) uzunluğu kaydedilmiştir. Bulgular: Genel yaş ortalaması 35 olan hastaların (3-77 yaş), 60'ı erkek,58'i kadındı. Toplamda %79,6’lık bir tanı oranıyla 48 gende hastalığa neden olan84 mutasyon belirlendi. Bu mutasyonların 16'sı yeni varyantlardı. En sık görülen iki gen MYO7A ve CDHR1’di. Hastalarda saptanan varyantların 61 tanesi homozigot, 19 tanesi heterozigot, 10 tanesi birleşik heterozigot, 4 tanesi hemizigot kalıtım göstermekteydi. ACMG kriterlerine göre saptanan 84 varyanttan 37’si(%44) patojenikti, 21’i (%25) muhtemelen patojenikti ve 26 tanesi (%31) VUS varyantlardı. Hastalardan 37 tanesi RP’nin eşlik eden sendromik formlarına sahipti. EİDK’nin maküla tutulumu olanlar ve olmayanlar arasında anlamlı farklılık gösterdiği (P<0.001), EZ ile negatif korelasyon gösterdiği (r=-0.684; P<0.001)ancak katarakt (p=0.606) ve yaş (P=0.711) ile anlamlı farklılık göstermediği bulundu. İstatistiksel olarak yaş (P=0.035), semptom başlangıç yaşı (P=0.001) vetünel görme başlangıç yaşı (P=0.01) MYO7A grubunda anlamlı olarak CDHR1grubuna göre daha düşük bulundu. MYO7A grubunda sağ gözde anlamlı olarakCDHR1 grubuna göre KMÖ sıklığı daha yüksek tespit edildi (P=0.021).Sonuç: Moleküler analiz yapılan 118 hastanın 94’ünde (%79,6) kliniği açıklayan ve kalıtım paterni uygun olan mutasyon saptandı. On altı yeni varyant tanımlanarak RP’nin mutasyon spektrumu genişletildi. Literatür ile uyumlu olarak fenotip ve genotip ilişkileri belirlendi. Hastalığın başlama yaşı, maküla tutulumu, aile öyküsü ve eşlik eden sistemik birliktelikleri, refraksiyon ve fundus bulguları; saptanan mutasyonlar ile değerlendirildi. Çalışmamız Türk popülasyonunda RP hastalarında şimdiye kadar yapılmış en geniş çaplı multidisipliner çalışmadır. Elde edilen %79,6’lık tespit oranı, RP hastalarının moleküler tanısı için YND kullanılmasını güçlü bir şekilde desteklemektedir.
Objective: The aim of this study is to determine the mutations involved in the development of retinitis pigmentosa (RP) in patients from all regions of Turkey who presented to our clinic, using next-generation sequencing (NGS) and to investigate the clinical implications of these mutations. Materials and Methods: Anamnesis and examination data of 118 patients diagnosed with RP by detailed fundus examination and peripheral blood mutation analysis using NGS were retrospectively analyzed. Information on the patients history, personal and family background was recorded. Pathogenic, likely pathogenic, and variants of uncertain significance (VUS) that explain the clinical findings were determined according to The American College of Medical Genetics and Genomics (ACMG, 2015) criteria by screening databases. Best-corrected visual acuity (BCVA), biomicroscopic examination, detailed fundus examination, and intraocular pressure (IOP) measurements were recorded. Detailed optical coherence tomography (OCT), Enhanced Depth Imaging-OCT (EDI-OCT), retinal nerve fiber layer (RNFL) imaging, and if available, electroretinogram (ERG) findings were examined and macular, choroidal, nerve fiber layer thickness, presence of epiretinal membrane (ERM) and cystoid macular edema (CME), ellipsoid zone (EZ) length were recorded. Results: The average age of the patients (aged 3-77) was 35, with 60 males and 58 females. A total of 84 mutations causing the disease in 48 genes were identified with a diagnostic rate of 79.6%. Sixteen of these mutations were novel variants. The two most common genes were MYO7A and CDHR1. Sixty-one of the identified variants were homozygous, 19 were heterozygous, 10 were compound heterozygous, and four were hemizygous inheritance. According to the ACMG criteria, 37 of the 84 variants (44%) were pathogenic, 21 (25%) were likely pathogenic, and 26 (31%) were VUS. Thirty-seven patients had syndromic forms accompanying RP. It was found that BCVA showed significant difference between those with and without macular involvement (P<0.001) and had a negative correlation with EZ (r=-0.684; P<0.001), but no significant difference with cataract (p=0.606) and age (P=0.711) was found. Statistically, age (P=0.035), symptom onset age (P=0.001), and tunnel vision onset age (P=0.01) were significantly lower in the MYO7A group compared to the CDHR1 group. The frequency of CME in the right eye was significantly higher in the MYO7A group compared to the CDHR1 group (P=0.021). Conclusion: Mutations explaining the clinical findings and with a consistent inheritance pattern were identified in 94 of the 118 patients (79.6%) who underwent molecular analysis. Sixteen new variants were identified, expanding the mutation spectrum of RP. Genotype-phenotype relationships were determined in accordance with the literature. The age of disease onset, macular involvement, family history, accompanying systemic comorbidities, refraction, and fundus findings were evaluated in relation to the identified mutations. Our study is the most comprehensive multidisciplinary study conducted on RP patients in the Turkish population to date. The obtained detection rate of 79.6% strongly supports the use of NGS for the molecular diagnosis of RP patients.
Objective: The aim of this study is to determine the mutations involved in the development of retinitis pigmentosa (RP) in patients from all regions of Turkey who presented to our clinic, using next-generation sequencing (NGS) and to investigate the clinical implications of these mutations. Materials and Methods: Anamnesis and examination data of 118 patients diagnosed with RP by detailed fundus examination and peripheral blood mutation analysis using NGS were retrospectively analyzed. Information on the patients history, personal and family background was recorded. Pathogenic, likely pathogenic, and variants of uncertain significance (VUS) that explain the clinical findings were determined according to The American College of Medical Genetics and Genomics (ACMG, 2015) criteria by screening databases. Best-corrected visual acuity (BCVA), biomicroscopic examination, detailed fundus examination, and intraocular pressure (IOP) measurements were recorded. Detailed optical coherence tomography (OCT), Enhanced Depth Imaging-OCT (EDI-OCT), retinal nerve fiber layer (RNFL) imaging, and if available, electroretinogram (ERG) findings were examined and macular, choroidal, nerve fiber layer thickness, presence of epiretinal membrane (ERM) and cystoid macular edema (CME), ellipsoid zone (EZ) length were recorded. Results: The average age of the patients (aged 3-77) was 35, with 60 males and 58 females. A total of 84 mutations causing the disease in 48 genes were identified with a diagnostic rate of 79.6%. Sixteen of these mutations were novel variants. The two most common genes were MYO7A and CDHR1. Sixty-one of the identified variants were homozygous, 19 were heterozygous, 10 were compound heterozygous, and four were hemizygous inheritance. According to the ACMG criteria, 37 of the 84 variants (44%) were pathogenic, 21 (25%) were likely pathogenic, and 26 (31%) were VUS. Thirty-seven patients had syndromic forms accompanying RP. It was found that BCVA showed significant difference between those with and without macular involvement (P<0.001) and had a negative correlation with EZ (r=-0.684; P<0.001), but no significant difference with cataract (p=0.606) and age (P=0.711) was found. Statistically, age (P=0.035), symptom onset age (P=0.001), and tunnel vision onset age (P=0.01) were significantly lower in the MYO7A group compared to the CDHR1 group. The frequency of CME in the right eye was significantly higher in the MYO7A group compared to the CDHR1 group (P=0.021). Conclusion: Mutations explaining the clinical findings and with a consistent inheritance pattern were identified in 94 of the 118 patients (79.6%) who underwent molecular analysis. Sixteen new variants were identified, expanding the mutation spectrum of RP. Genotype-phenotype relationships were determined in accordance with the literature. The age of disease onset, macular involvement, family history, accompanying systemic comorbidities, refraction, and fundus findings were evaluated in relation to the identified mutations. Our study is the most comprehensive multidisciplinary study conducted on RP patients in the Turkish population to date. The obtained detection rate of 79.6% strongly supports the use of NGS for the molecular diagnosis of RP patients.
Description
Keywords
Retinitis pigmentosa, Yeni nesil dizileme, Kalıtım paterni, Varyant tipi, Genotip fenotip korelasyonu, Retinitis pigmentosa, Next-generation sequencing, Inheritance pattern, Variant type, Genotype-phenotype correlation
Citation
Erdem, D. (2023). Retinitis pigmentosa hastalarının yeni nesil dizileme analizi ile göz ve klinik bulgularının değerlendirilmesi. Yayınlanmamış tıpta uzmanlık tezi. Bursa Uludağ Üniversitesi Tıp Fakültesi.