Nörogelişimsel Bozukluklar ve Doğuştan Anomalileri Olan Pediatrik Hastalarda Kromozomal Mikrodizin Analizi: Aday Bir KYNU Lokusunu Vurgulayan İki Merkezli Bir Çalışma

Öz

Kromozomal mikroarray analizi (CMA), nörogelişimsel bozukluklar ve konjenital anomalileri olan çocuklarda ilk basamak tanı aracıdır; ancak anlamı belirsiz varyantların (VUS) yorumlanması zorluk oluşturmaya devam etmektedir. Bu çalışma, konjenital anomali ve/veya dismorfik özellikleri olan pediatrik hastalarda kopya sayısı varyantı (CNV) spektrumunu tanımlamayı ve segregasyon analizi ile ayrıntılı fenotip-genotip korelasyonu yoluyla VUS yorumlamasına odaklanmayı amaçlamıştır. 2021-2022 yılları arasında iki üçüncü basamak genetik kliniğine yönlendirilen, anormal CMA sonucu olan 28 pediatrik hastayı retrospektif olarak değerlendirdik. Başvuru endikasyonları arasında nörogelişimsel gecikme, zihinsel yetersizlik, dismorfizm ve/veya konjenital anomaliler yer almaktaydı. CNV'ler 2020 ACMG/ClinGen kriterlerine göre sınıflandırıldı. On üç ailede 15 CNV için ebeveyn segregasyon analizi yapıldı ve CNV kırılma noktalarının neden olduğu gen bozulmalarına özel olarak dikkat edildi. Kohort, yaş ortalaması 5.28±4.39 yıl olan 16 erkek ve 12 kadından oluşmaktaydı. On dördü delesyon ve yirmisi duplikasyon olmak üzere 34 CNV tanımlandı; yedisi patojenik/olası patojenik, 27'si ise VUS olarak sınıflandırıldı. Segregasyon analizinde beş de novo, altı maternal ve dört paternal varyant saptandı. VACTERL-benzeri bulguları olan bir hastada, KYNU geninin intron 12'sinde bozulmaya neden olan 2q22.2 kazanımı tespit edildi. Üç hastada ek karyotip anormallikleri görüldü ve bu durum CMA'nın tamamlayıcı rolünü vurgulamaktadır. Bir hastada ayrıca HTT ve ADD1 genlerini bozan de novo 4p16.3 duplikasyonu belirlendi. Bulgularımız, özellikle VUS ve nadir intrajenik bozulmalar olmak üzere CNV'lerin yorumlanmasında ayrıntılı fenotipleme, kırılma noktası analizi ve segregasyon çalışmalarının önemini ortaya koymaktadır. Genomik bulguların klinik özellikler ve kalıtım modelleriyle bütünleştirilmesi, fenotip-genotip korelasyonunu iyileştirebilir ve aday lokusların belirlenmesine katkı sağlayabilir.

Anahtar Kelimeler

• CMA
• CNV'ler
• VUS
• Nörogelişimsel Bozukluklar
• KYNU Geni
• VACTERL birlikteliği
• VACTERL birlikteliği

Destekleyen Kurum

Bu çalışma, kamu, ticari veya kar amacı gütmeyen sektörlerdeki herhangi bir fon kuruluşundan özel bir hibe almamıştır.

Etik Beyan

Bu çalışma, Ümraniye Eğitim ve Araştırma Hastanesi etik kurulu tarafından onaylanmıştır (karar numarası: 2023/222023618). Bu makalenin yayınlanması ve bu vakalara ilişkin görüntülerin ve diğer klinik bilgilerin akademik amaçlarla raporlanması için tüm hastaların ebeveynlerinden yazılı bilgilendirilmiş onam alınmıştır. Tüm işlemler Helsinki Bildirgesi'ne uygun olarak gerçekleştirilmiştir.

Teşekkür

Klinik değerlendirmede verdikleri yardımlar için hastalarımızın ailelerine en içten şükranlarımızı sunuyoruz.

Chromosomal Microarray Analysis in Pediatric Patients with Neurodevelopmental Disorders and Congenital Anomalies: A Two-Center Experience

Öz

Chromosomal microarray analysis (CMA) is a first-tier diagnostic tool for children with neurodevelopmental disorders and congenital anomalies; however, interpretation of variants of uncertain significance (VUS) remains challenging. This study aimed to characterize the copy number variant (CNV) spectrum in pediatric patients with congenital anomalies and/or dysmorphic features, focusing on VUS interpretation through segregation analysis and detailed phenotype–genotype correlation. We retrospectively evaluated 28 pediatric patients with abnormal CMA results referred to two tertiary genetics clinics between 2021 and 2022. Indications included neurodevelopmental delay, intellectual disability, dysmorphism, and/or congenital anomalies. CNVs were classified according to 2020 ACMG/ClinGen standards. Parental segregation analysis was performed for 15 CNVs in 13 families, with particular attention to gene disruption caused by CNV breakpoints. The cohort included 16 males and 12 females, with a mean age of 5.28±4.39 years. Thirty-four CNVs were identified, including 14 deletions and 20 duplications; seven were pathogenic/likely pathogenic and 27 were VUS. Segregation analysis identified five de novo, six maternal, and four paternal variants. A 2q22.2 gain disrupting KYNU at intron 12 was identified in a patient with VACTERL-like features. Three patients had additional karyotypic abnormalities, highlighting the complementary role of CMA. A de novo 4p16.3 duplication disrupting both HTT and ADD1 was also identified. Our findings highlight the importance of detailed phenotyping, breakpoint analysis, and segregation studies in interpreting CNVs, particularly VUS and rare intragenic disruptions. Integrating genomic findings with clinical features and inheritance patterns may improve phenotype–genotype correlation and support the identification of candidate loci.

Anahtar Kelimeler

• CMA
• CNVs
• VUS
• Neurodevelopmental Disorders
• KYNU Gene
• VACTERL associatio

Destekleyen Kurum

This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Etik Beyan

This study was approved by the ethics committee of Ümraniye Education and Researge Hospital (decision number: 2023/222023618). Written informed consents were obtained from the parents of all patients for publication of this manuscript, and for images and other clinical information relating to these cases to be reported for academic purpose. All procedures were performed in accordance with the Declaration of Helsinki.

Teşekkür

We express our sincere gratitude to the families of our patients for their help in clinical assessment.

Kaynakça

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