Moleküler etiyolojisi aydınlatılamamış Cinsiyet Gelişim Bozukluğu hastalarında Mikroarray Yöntemi ile kopya sayısı değişikliklerinin saptanması ve klinik varyasyonlarla ilişkilendirilmesi
Küçük Resim Yok
Tarih
2022
Yazarlar
Dergi Başlığı
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Cilt Başlığı
Yayıncı
Ege Üniversitesi, Tıp Fakültesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Giriş: Cinsiyet gelişim bozukluğu (CGB); kromozomal, gonadal veya anatomik cinsiyetin anormal olarak gelişimi ile karakterize nadir konjenital bir hastalıktır. Mikroarray (Single nucleotide polymorphism-SNP- array) yöntemi CGB’lerin tanısında, yüksek verimli güçlü bir tam genom tarama imkanı sunmaktadır. Amaç ve Yöntem: Bu çalışmada CGB hastalarında moleküler etiyolojinin aydınlatılmasında mikroarray yöntemi kullanılarak kopya sayısı değişikliklerinin saptanması amaçlanmaktadır. Karyotip analizinde herhangi bir yapısal ya da sayısal anomali saptanmayan, klinik ve laboratuvar bulgular eşliğinde algoritmik yaklaşımla ilişkili moleküler analizleri gerçekleştirilmiş ve herhangi bir patojenik varyant tespit edilmemiş olgularda mikroarray yöntemi ile kopya sayısı değişiklikleri
değerlendirildi. Bulunan değişiklikler ACMG (American College of Medical Genetics and Genomics) 2020 kriterlerine göre skorlandı. Elde edilen skor <0 olan varyantlar öncelikle dışlandı. Skoru 0 ve üstünde saptanan değişiklikler, belirlenen bölgedeki haplo ya da triployetersizlik bildirilen genlerin varlığı, ClinVar ve/veya DECIPHER veritabanlarında yapılan veri girişleri ve bildirilen fenotiplere göre incelendi. Bu veriler ışığında, elde edilen değişiklikler benign, anlamı bilinmeyen veya patojenik olacak şekilde sınıflandırıldı. Bulgular: Cinsiyet gelişim bozukluğu nedeniyle izlenen moleküler genetik etiyolojide patoloji saptanmayan 22 olgu dahil edildi. Olguların 18’i (%81.8) 46,XY ve 4’ü (%18.1) 46,XX CGB olarak sınıflandırıldı. Olguların ortalama yaşı 7.9±4.7 yıldı. Olguların çocuk endokrinoloji kliniğine başvuru yaşı 7.4 ay (en erken:4 günlük, en geç: 15 yaş) idi. Başvuru sırasında olguların 6’sı (%27.2) kız, 16’sı (%72.7) erkek cinsiyette yetiştirilmişti. Başvuru bulguları/yönlendirme nedenleri değerlendirildiğinde; 46,XY CGB grubunda hastaların 2’si (%11.1) inmemiş testis ile beraber hipospadias, 4’ü (%.22.2 ) kuşkulu dış genital yapı, 1’i (%5.5) mikropenis ile beraber hipospadias, 1’i (%5.5) bilateral inmemiş testis, 1’i (% 5.5) tek taraflı inmemiş testis, 8’i (%44.4) izole hipospadias ve 1’i (%5.5) mikropenis ile beraber bilateral inmemiş testis nedeni ile değerlendirildi. Kız cinsiyetinde büyütülmüş 46,XY CGB olgularının başvuru yakınması bir (%4.5) olguda kliteromegali ve bir (%4.5) olguda kasıkta şişlik idi. 46,XX CGB’lerin ise 2’si (%50) kuşkulu dış genital yapı, biri (%25) primer amenore, biri (%25) rastlantısal olarak saptanan Müllerian agenezi nedeniyle başvurdu. Dört (%18.1) olguda anne-baba arasında akrabalık vardı. Beş (%22.7) olguda eşlik eden dismorfik bulgu (mikrognati, polidaktili vb.) mevcuttu. On bir (%50) olguda; doğumsal anomaliler eşlik etmekteydi ve en sık doğumsal anomali (3 olgu, %27) üriner sistem anomalileriydi. Mikroarray analizi ile 22 olgudan 4’ünde hiç varyant saptanmazken, 18 olguda toplam 142 kopya sayısı değişikliği belirlendi. Bunların 114’ü (%80.3) delesyon, 28’i (%19.8) duplikasyondu. Kopya sayısı değişikliği saptanan 18 (%81.8) olgunun varyantları değerlendirildiğinde 5 (%22.7) olguda 13’ü patojenik; 5 (%22.7) olguda 19’u anlamı belirlenemeyen olarak sınıflandırıldı. Patojenik olarak sınıflandırılan varyantlar arasından sadece 1 tanesinde daha önce veri tabanlarında hipospadias ile ilişkili fenotip kaydedilmişken, diğer varyantlarda herhangi bir genital anomali bildirilmemişti. Patojenik ve anlamı bilinmeyen olarak sınıflandırılan varyantların aile segregasyonları ve ileri analizleri planlandı. Sonuç: Karmaşık genetik mekanizmalarla ortaya çıkan CGB’lerin önemli kısmında günümüzde halen genetik tanı konulamamaktadır. CGB’de hızlı ve doğru tanı konulması, cinsiyet seçimi ve olgunun yönetimi açısından önemlidir. CGB olgularında moleküler etiyolojinin aydınlatılmasında tanısal yaklaşım içerisinde seçili olgularda mikroarray analizi yer bulmalıdır. Ayrıca mikroarray analizi CGB etiyolojisinde sorumlu yeni gen bulma çalışmalarında yol gösterici olabilir.
Introduction: Disorders of Sex Development (DSD); It is a rare congenital disease characterized by abnormal development of chromosomal, gonadal or anatomical sex. Microarray (SNP array) method offers a powerful full genome scanning opportunity in the diagnosis of DSDs. Aim and Method: In this study, it is aimed to determine the copy number variations by using the microarray method to elucidate the molecular etiology in DSD patients. Copy number variations were evaluated with the microarray method in cases where no structural or numerical anomalies were detected in the karyotype analysis, molecular analyzes related to the algorithmic approach were performed in the presence of clinical and laboratory findings, and no pathogenic variant was detected. The variants found were scored according to the ACMG 2020 criteria. Variants with the resulting score <0 were first excluded. Changes with a score of 0 and above, the presence of genes with reported haplo or triploinsufficiency in the determined region, data entries made in the ClinVar and/or DECIPHER databases, and reported phenotypes were examined. In the light of these data, the obtained changes were classified as benign, obscure or pathogenic. Results: Twenty-two cases with no pathology in the molecular genetic etiology, who were followed up due to sexual developmental disorder, were included. Eighteen (81.8%) of the cases were classified as 46,XY and 4 (18.1%) as 46,XX DSD. The mean age of the cases was 7.9±4.7 years. The age of admission to the pediatric endocrinology clinic was 7.4 months (earliest: 4 days, latest: 15 years). At the time of admission, 6 (27.2%) of the cases were female and 16 (72.7%) were male. When the application findings / reasons for referral are evaluated; In 46,XY DSD group, 2 (11.1%) patients had hypospadias with undescended testis, 4 (22.2%) had suspicious external genitalia, 1 (5.5%) had hypospadias with micropenis, 1 (5.5%) ) were evaluated for bilateral undescended testis, 1 (5.5%) unilateral undescended testis, 8 (44.4%) isolated hypospadias, and 1 (5.5%) bilateral undescended testis with micropenis. The presenting complaint of 46,XY DSD cases enlarged in female gender was cliteromegaly in one (4.5%) case and swelling in the groin in one (4.5%) case. Of 46,XX DSDs, 2 (50%) admitted with suspicious external genitalia, one (25%) primary amenorrhea, and one (25%) coincidentally found Müllerian agenesis. There was consanguinity between the parents in four (18.1%) cases. Concomitant dysmorphic findings (micrognathia, polydactyly, etc.) were present in five (22.7%) cases. In 11 (50%) cases; congenital anomalies were accompanied and the most common congenital anomalies (3 cases, 27%) were urinary system anomalies. While no variant was detected in 4 out of 22 cases with microarray analysis, a total of 142 copy number changes were detected in 18 cases. Of these, 114 (80.3%) were deletions and 28 (19.8%) were duplications. When variants of 18 (81.8%) cases with copy number changes were evaluated 13 out of 5 (22.7%) cases are pathogenic; 19 out of 5 (22.7%) cases were classified as undetermined. While only 1 of the variants classified as pathogenic had a hypospadias-related phenotype previously recorded in databases, no genital anomalies were reported in other variants. Family segregations and further analyzes of variants classified as pathogenic and of unknown significance were planned. Conclusion: Today, genetic diagnosis cannot be made in the majority of DSDs that occur with complex genetic mechanisms. Rapid and accurate diagnosis in DSD is important in terms of gender selection and management of the case. Microarray analysis should be included in selected cases within the diagnostic approach to elucidate the molecular etiology of DSD cases. In addition, microarray analysis can guide studies to find new genes responsible for the etiology of DSD.
Introduction: Disorders of Sex Development (DSD); It is a rare congenital disease characterized by abnormal development of chromosomal, gonadal or anatomical sex. Microarray (SNP array) method offers a powerful full genome scanning opportunity in the diagnosis of DSDs. Aim and Method: In this study, it is aimed to determine the copy number variations by using the microarray method to elucidate the molecular etiology in DSD patients. Copy number variations were evaluated with the microarray method in cases where no structural or numerical anomalies were detected in the karyotype analysis, molecular analyzes related to the algorithmic approach were performed in the presence of clinical and laboratory findings, and no pathogenic variant was detected. The variants found were scored according to the ACMG 2020 criteria. Variants with the resulting score <0 were first excluded. Changes with a score of 0 and above, the presence of genes with reported haplo or triploinsufficiency in the determined region, data entries made in the ClinVar and/or DECIPHER databases, and reported phenotypes were examined. In the light of these data, the obtained changes were classified as benign, obscure or pathogenic. Results: Twenty-two cases with no pathology in the molecular genetic etiology, who were followed up due to sexual developmental disorder, were included. Eighteen (81.8%) of the cases were classified as 46,XY and 4 (18.1%) as 46,XX DSD. The mean age of the cases was 7.9±4.7 years. The age of admission to the pediatric endocrinology clinic was 7.4 months (earliest: 4 days, latest: 15 years). At the time of admission, 6 (27.2%) of the cases were female and 16 (72.7%) were male. When the application findings / reasons for referral are evaluated; In 46,XY DSD group, 2 (11.1%) patients had hypospadias with undescended testis, 4 (22.2%) had suspicious external genitalia, 1 (5.5%) had hypospadias with micropenis, 1 (5.5%) ) were evaluated for bilateral undescended testis, 1 (5.5%) unilateral undescended testis, 8 (44.4%) isolated hypospadias, and 1 (5.5%) bilateral undescended testis with micropenis. The presenting complaint of 46,XY DSD cases enlarged in female gender was cliteromegaly in one (4.5%) case and swelling in the groin in one (4.5%) case. Of 46,XX DSDs, 2 (50%) admitted with suspicious external genitalia, one (25%) primary amenorrhea, and one (25%) coincidentally found Müllerian agenesis. There was consanguinity between the parents in four (18.1%) cases. Concomitant dysmorphic findings (micrognathia, polydactyly, etc.) were present in five (22.7%) cases. In 11 (50%) cases; congenital anomalies were accompanied and the most common congenital anomalies (3 cases, 27%) were urinary system anomalies. While no variant was detected in 4 out of 22 cases with microarray analysis, a total of 142 copy number changes were detected in 18 cases. Of these, 114 (80.3%) were deletions and 28 (19.8%) were duplications. When variants of 18 (81.8%) cases with copy number changes were evaluated 13 out of 5 (22.7%) cases are pathogenic; 19 out of 5 (22.7%) cases were classified as undetermined. While only 1 of the variants classified as pathogenic had a hypospadias-related phenotype previously recorded in databases, no genital anomalies were reported in other variants. Family segregations and further analyzes of variants classified as pathogenic and of unknown significance were planned. Conclusion: Today, genetic diagnosis cannot be made in the majority of DSDs that occur with complex genetic mechanisms. Rapid and accurate diagnosis in DSD is important in terms of gender selection and management of the case. Microarray analysis should be included in selected cases within the diagnostic approach to elucidate the molecular etiology of DSD cases. In addition, microarray analysis can guide studies to find new genes responsible for the etiology of DSD.
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