MOWAT-WİLSON SENDROMU: ONİKİ YENİ OLGUNUN FENOTİPİK VE MOLEKÜLER KARAKTERİZASYONU

Abstract

Amaç: Mowat-Wilson sendromu (MOWS); tanınabilir yüz özellikleri, orta-ağır zihinsel yetersizlik ve korpus kallozum anomalileri, oküler tutulum, genital anomaliler, konjenital kalp defektleri ve Hirschsprung hastalığı gibi multisistemik bulgularla karakterize nadir bir malformasyon sendromudur. Etiyolojide ZEB2 genindeki patojenik varyantlar rol oynamakta olup, neredeyse bütün vakalar sporadik olarak de novo varyantlardan kaynaklanmaktadır. Hastalığın düşük prevalansının yanı sıra etkilenmiş olgularda gözlenen geniş klinik spektrum tanı sürecini zorlaştırabilmektedir. Bu çalışmada yeni bir MOWS kohortu tanımlayarak bu hastalığın klinik ve moleküler spektrumunu genişletmeyi amaçladık. Gereç ve Yöntem: Çalışmaya MOWS klinik tanısı almış 12 olgu dahil edildi. Normal karyotip sonuçlarının elde edilmesinin ardından ZEB2 geni Sanger dizi analizi yöntemiyle incelendi. Bulgular: Doğum ve tekrarlayan klinik değerlendirmelerde alınan antropometrik ölçümlerin ulusal ve MOWS’a özgü büyüme eğrileriyle büyük ölçüde uyumlu olduğu gözlendi. Tüm hastalarda orta ila ağır zihinsel yetersizlik ve karakteristik yüz görünümü mevcuttu. Hastalığın iyi bilinen bulgularına ek olarak; persistan sol süperior vena kava, koanal stenoz, şal skrotum ve atipik oküler anomaliler gibi çok nadir veya daha önce MOWS spektrumunda tanımlanmamış bulgular izlendi. Pigmentasyon bozukluklarının literatür verisine kıyasla belirgin şekilde daha yüksek sıklıkta olduğu gözlendi. İki hastada, CHARGE ve Aicardi sendromları ile örtüşen atipik klinik bulguların varlığı dikkat çekiciydi. Hastalarda, ZEB2 geninde beşi daha önce tanımlanmamış olmak üzere 12 heterozigot varyant tespit edildi. Sonuç: On iki hastanın derin fenotipleme verileri, daha önce MOWS ile klinik ilişkisi net şekilde ortaya konulmamış veya hastalık spektrumunda çok nadir olduğu düşünülen klinik bulguların tanımlanmasını sağladı. Ayrıca, bu çalışma kapsamında ilk kez bildirilen patojenik ZEB2 varyantları ile hastalığın moleküler spektrumu da genişletilmiş oldu.

Keywords

• Mowat-Wilson sendromu
• ZEB2
• zihinsel ye tersizlik
• CHARGE sendromu
• Aicardi sendromu

MOWAT-WILSON SYNDROME: DEEP PHENOTYPING AND MOLECULAR CHARACTERISATION OF TWELVE NEW INDIVIDUALS

Abstract

Objective: Mowat-Wilson syndrome (MOWS) is a rare multisystem malformation syndrome characterised by distinctive facial features, moderate to severe intellectual disability, and variable findings including callosal anomalies, ocular features, genital anomalies, congenital heart defects, and Hirschsprung’s disease. Pathogenic variants in the ZEB2 gene are implicated in the aetiology, with nearly all cases arising sporadically due to de novo variants. In addition to its low prevalence, the broad clinical spectrum observed among patients can make the diagnostic process challenging. This study aims to expand the clinical and molecular spectrum of MOWS by elucidating the characteristics of a new cohort. Material and Methods: Twelve patients with a clinical diagnosis of MOWS were included in the study. Following obtaining normal karyotype results, molecular analysis of ZEB2 was performed using Sanger sequencing. Results: Anthropometric measurements at birth and subsequent visits largely aligned with the national and MOWS growth charts, respectively. All patients exhibited moderate to severe intellectual disability and shared a characteristic facial gestalt. In addition to the well-described features, very rare or previously undescribed abnormalities comprising persistent left superior vena cava, choanal stenosis, shawl scrotum, and ocular anomalies were observed. Skin pigmentation defects were noted at significantly higher frequencies than those previously reported. Two patients displayed atypical features overlapping with CHARGE and Aicardi syndromes. We identified 12 heterozygous variants in ZEB2, five of which were novel. Conclusion: Deep phenotyping data of 12 patients enabled the identification of previously uncertain clinical associations and underrepresented features. The novel pathogenic variants identified here expand the molecular spectrum of ZEB2.

Keywords

• Mowat-Wilson syndrome
• ZEB2
• intellectual disabili ty
• CHARGE syndrome
• Aicardi syndrome

Thanks

We respectfully commemorate Prof. Dr. Murat Derbent, M.D., for his valuable contribution to this study and honor his memory, which remains cherished within the Turkish genetics community. We sincerely thank the families for their participation in this study.

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