İzole katarakt tanılı çocuk olgularda tüm ekzom sekanslama yöntemiyle mutasyon taranması
Küçük Resim Yok
Dosyalar
Tarih
2021
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Ege Üniversitesi, Tıp Fakültesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Konjenital katarakt, çocukluk çağı körlüklerin önlenebilir nedenlerinden biridir. Çocuklukta körlüğün yaklaşık 1/10'inin nedeni konjenital katarakttır. Konjenital kataraktların (KK) kliniği ve genetiği heterojen olup, farklı sınıflandırmaları vardır. Bu sınıflandırmalar etiyoloji, oluşum dönemleri, morfolojileri ve oluş nedenlerine göre yapılmaktadır. Etiyolojisine göre: idiyopatik ve herediter, oluşma dönemlerine göre: konjenital, infantil ve juvenil, morfolojilerine göre: total ve kısmi, oluş nedenlerine göre: primer ve sekonder olarak alt gruplarda sınıflandırılmıştır. Kataraktların yaklaşık 1/3'i genetik geçişli olup, en sık OD (otozomal dominant) olmak üzere, OR (otozomal resesif) ve X'-e bağlı kalıtılabilmektedir. Amaç: Bu çalışmada, bilinen bir metabolik hastalık ve genetik sendrom ile ilişkilendirilmeyen KK tanılı hastalarda yeni nesil dizi (YND) inceleme yöntemi ile etiyoloji tanımlama amaçlanmıştır. Gereç ve Yöntem: Aralık 2019-Şubat 2021 tarihleri arasında, Ege Üniversitesi Çocuk Genetik Hastalıkları ve Çocuk Metabolizma bölümlerinden takipli olan, 0-18 yaş arasında bilinen bir metabolik hastalık ve genetik sendrom ile ilişkilendirilmeyen, sağlıklı, ek göz anomalisi olmayan ve izole KK tanılı 11 hasta çalışmaya dahil edildi. Bu veriler esasında olgu rapor formu oluşturuldu. Hastalardan YND inceleme için kan örneği alındı. Bulgular: Çalışmamızda bilinen metabolik hastalıklar ve genetik sendromlar ile ilişkilendirilmeyen sağlıklı, izole 11 konjenital katarakt tanılı hasta yer almaktadır. On bir hastanın 8'inin anne ve babası arasında akrabalık vardı. Akraba evliliğinden olan hastaların 4'ünda ve akraba evliliğinden olmayan iki hastada (%54,5) izole KK ile ilişkili olan 4 tanımlanmamış, bir tanımlanmış olmak üzere toplam 5 farklı gende mutasyon bulundu. Aynı zamanda akraba evliliğinden olan bir hastamızda ise kataraktı Warburg Micro sendromu ile ilişkili olan RAB3GAP1 geninde mutasyon saptandı. Bir hastamızda ise katarakt ameliyatı sonrası posterior kapsuler opaklaşma oluşumunda yer aldığı bilinen CTBP2 gen mutasyonu saptandı. Üç hastamızda izole katarakt ile ilişkili olabilecek patojenik gen mutasyonu görülmedi. İzole katarakt ile ilişkili sonuçlara bakıldığında, 6 hastanın birinde (%16,7) izole kataraktın oluşumunda en sık yer alan, kristalin grubundan olan CRYGD geninde mutasyon bulundu. Geriye kalan 5 hastada nadir izole KK'a neden olan gen mutasyonları bulundu ki, bunlar: iki hastada (%33,3) transkripsiyon faktör gen mutasyonu olan HSF4 (Heat Shock Factor 4) gen mutasyonu, bir hastada (%16,7) FYCO1 (FYVE and coiled coil domain containing 1), bir hastada (%16,7) VIM (Vimentin) ve son bir hastamızda da (%14,3) WFS1 (Wolfram syndrome 1) geniyle ilişkili olan nadir KK gen mutasyonlarıydı. Mutasyonlar: CRYGD geninde c.463C>T, HSF4 geninde c.965dup, VIM geninde c.1360G>A, FYCO1 geninde c.3330C>A, WFS1 geninde c.1294C>G şeklindeydi. Hastalarımızda ek göz anomalisi yoktu. İzole KK tanısı alan 10 hastanın 9'unda (%90) bilateral, birinde (%10) unilateral katarakt vardı. Hastaların 10'unda (%90) nükleer, birinde (%10) ise polar tip katarakt saptandı. Çalışmamızda izole KK ile ilişkili olan ve daha önce tanımlanmayan 4 gen mutasyonu saptandı. Warburg Mikro sendromu ile ilişkili olan RAB3GAP1 gen mutasyonu da daha önce tanımlanmamış olup, yeni bir mutasyon olarak değerlendirildi. Sonuç: YND inceleme yönteminin KK gibi genetik heterojen hastalıkların etiyolojisini tanımlamakta önemli bir yöntem olduğu görülmektedir.
Congenital cataracts are one of the preventable causes of childhood blindness. Approximately 1/10 of childhood blindness is caused by congenital cataracts. The clinic and genetics of congenital cataracts are heterogeneous and have different classifications. These classifications are made according to etiology, formation periods, morphologies and types of occurrence; according to its etiology: idiopathic and hereditary, according to the period of occurrence: congenital, infantile and juvenile, according to morphology: total and partial, according to the types of occurrence: primary and secondary. Approximately 1/3 of cataracts are inherited autosomal dominant (AD) which is the most common inheritence pattern, and followed by autosomal recessive (OR) and X-linked inheritence. Objective: This study aimed to define the etiology of congenital cataract (CC) in patients which is not associated with a known metabolic disease and genetic syndrome, by using the whole exome sequencing (WES). Materials and Methods: Between December 2019 and February 2021, patients between the ages of 0-18, who were not associated with a known metabolic disease or genetic syndrome, who had no additional eye anomalies and who were diagnosed with isolated congenital cataract, were included in this study at Ege University Pediatric Genetic Diseases and Pediatric Metabolism Departments. Based on these data, a case report form was created and filled out. Blood was drawn from the 11 patient for WES examination and the results were discussed in the light of mutation types. Results: Our study included 11 healthy, isolated patients with a diagnosis of congenital cataract that were not associated with known metabolic diseases and genetic syndromes. Eight of the eleven patients had consanguinity between their parents. Mutations were found in 4 of the consanguineous and two patients (54.5%) who were not consanguineous, in a total of 5 different genes, 4 of which were unidentified and one identified, which were associated with isolated CC. At the same time, a mutation in the RAB3GAP1 gene, which is associated with cataract and Warburg Micro syndrome, was detected in one of our patients who were consanguineous. A CTBP2 gene mutation, which is known to be involved in the formation of posterior capsular opacification after cataract surgery, was detected in one of our patients. No pathogenic gene mutations that could be associated with isolated cataracts were observed in our three patients. Considering the results related to isolated cataract, one of 6 patients (16.7%) found a mutation in the CRYGD gene, which is the crystalline group most frequently involved in the formation of isolated cataracts. In the remaining 5 patients, gene mutations causing rare isolated CC were found: HSF4 (Heat Shock Factor 4) gene mutation with transcription factor gene mutation in two patients (33.3%), FYCO1 in one patient (16.7%). Rare CC gene mutations were associated with (FYVE and coiled coil domain containing 1), VIM (Vimentin) in one patient (16.7%) and WFS1 (Wolfram syndrome 1) gene in a last patient (14.3%). Mutations: c.463C>T in CRYGD gene, c.965dup in HSF4 gene, c.1360G>A in VIM gene, c.3330C>A in FYCO1 gene, c.1294C>G in WFS1 gene. There was no additional eye anomaly in our patients. Nine (90%) of 10 patients diagnosed with isolated CC had bilateral cataracts and one (10%) had unilateral cataracts. Nuclear cataract was detected in 10 (90%) and polar type cataracts in one (10%) of the patients. In our study, 4 gene mutations that were associated with isolated CC and were not identified before were found. The RAB3GAP1 gene mutation associated with Warburg Micro syndrome has not been defined before and was considered as a new mutation. Conclusion: Whole exome sequencing seems to be an important method in defining the etiology of genetic heterogeneous diseases such as isolated congenital cataract.
Congenital cataracts are one of the preventable causes of childhood blindness. Approximately 1/10 of childhood blindness is caused by congenital cataracts. The clinic and genetics of congenital cataracts are heterogeneous and have different classifications. These classifications are made according to etiology, formation periods, morphologies and types of occurrence; according to its etiology: idiopathic and hereditary, according to the period of occurrence: congenital, infantile and juvenile, according to morphology: total and partial, according to the types of occurrence: primary and secondary. Approximately 1/3 of cataracts are inherited autosomal dominant (AD) which is the most common inheritence pattern, and followed by autosomal recessive (OR) and X-linked inheritence. Objective: This study aimed to define the etiology of congenital cataract (CC) in patients which is not associated with a known metabolic disease and genetic syndrome, by using the whole exome sequencing (WES). Materials and Methods: Between December 2019 and February 2021, patients between the ages of 0-18, who were not associated with a known metabolic disease or genetic syndrome, who had no additional eye anomalies and who were diagnosed with isolated congenital cataract, were included in this study at Ege University Pediatric Genetic Diseases and Pediatric Metabolism Departments. Based on these data, a case report form was created and filled out. Blood was drawn from the 11 patient for WES examination and the results were discussed in the light of mutation types. Results: Our study included 11 healthy, isolated patients with a diagnosis of congenital cataract that were not associated with known metabolic diseases and genetic syndromes. Eight of the eleven patients had consanguinity between their parents. Mutations were found in 4 of the consanguineous and two patients (54.5%) who were not consanguineous, in a total of 5 different genes, 4 of which were unidentified and one identified, which were associated with isolated CC. At the same time, a mutation in the RAB3GAP1 gene, which is associated with cataract and Warburg Micro syndrome, was detected in one of our patients who were consanguineous. A CTBP2 gene mutation, which is known to be involved in the formation of posterior capsular opacification after cataract surgery, was detected in one of our patients. No pathogenic gene mutations that could be associated with isolated cataracts were observed in our three patients. Considering the results related to isolated cataract, one of 6 patients (16.7%) found a mutation in the CRYGD gene, which is the crystalline group most frequently involved in the formation of isolated cataracts. In the remaining 5 patients, gene mutations causing rare isolated CC were found: HSF4 (Heat Shock Factor 4) gene mutation with transcription factor gene mutation in two patients (33.3%), FYCO1 in one patient (16.7%). Rare CC gene mutations were associated with (FYVE and coiled coil domain containing 1), VIM (Vimentin) in one patient (16.7%) and WFS1 (Wolfram syndrome 1) gene in a last patient (14.3%). Mutations: c.463C>T in CRYGD gene, c.965dup in HSF4 gene, c.1360G>A in VIM gene, c.3330C>A in FYCO1 gene, c.1294C>G in WFS1 gene. There was no additional eye anomaly in our patients. Nine (90%) of 10 patients diagnosed with isolated CC had bilateral cataracts and one (10%) had unilateral cataracts. Nuclear cataract was detected in 10 (90%) and polar type cataracts in one (10%) of the patients. In our study, 4 gene mutations that were associated with isolated CC and were not identified before were found. The RAB3GAP1 gene mutation associated with Warburg Micro syndrome has not been defined before and was considered as a new mutation. Conclusion: Whole exome sequencing seems to be an important method in defining the etiology of genetic heterogeneous diseases such as isolated congenital cataract.
Açıklama
Anahtar Kelimeler
İzole, Konjenital Katarakt, Mutasyon, Yeni Nesil Dizileme, Tüm Ekzom Dizileme, Isolated, Congenital Cataract, Mutation, Next Generation Sequencing, Whole Exome Sequencing
