Spinal Musküler Atrofi Açısından Değerlendirilen Hastalarda Tanısal Netleştirme ve Keşifsel SMN Dışı Genetik Bulgular: Retrospektif Tanımlayıcı Gözlemsel Bir Çalışma

Abstract

Spinal musküler atrofi (SMA), SMN1 genindeki bialelik patojenik varyantların neden olduğu nöromüsküler bir hastalıktır. Yenidoğan taramasının (NBS) yaygınlaşmasıyla birlikte, moleküler sonuçların doğru yorumlanması tanı ve klinik yönetim açısından büyük önem kazanmıştır. Bu çalışmada, kesinleşmiş veya şüpheli SMA nedeniyle değerlendirilen hastaların klinik ve genetik bulgularının tanımlanması, mevcut tüm ekzom dizileme (WES) raporlarında saptanan SMN dışı varyantların incelenmesi ve SMA taraması, raporların yorumlanması ve sonuçların iletilmesiyle ilişkili farklı tanısal netleştirme sorunlarının ortaya konulması amaçlandı. Bu retrospektif, tanımlayıcı ve gözlemsel çalışmaya, Ocak 2023 ile Aralık 2025 tarihleri arasında çocuk immünolojisi bölümümüzde SMA ile ilişkili nedenlerle değerlendirilen ardışık 10 hastanın tamamı dahil edildi. Üçü kesinleşmiş SMA tanılı ve biri tanısal netleştirme amacıyla yönlendirilmiş olmak üzere dört hastanın WES raporlarına ulaşıldı. Analizler tanımlayıcı olarak gerçekleştirildi; eksik bilgiler “mevcut değil” şeklinde kaydedildi ve gruplar arası veya genotip-fenotip karşılaştırması yapılmadı. Yedi hastada kesinleşmiş SMA tanısı bulunmaktaydı (altı tip 1 ve bir tip 3). Üç hasta ise farklı tanısal netleştirme sorunları nedeniyle yönlendirilmişti: tarama ve doğrulayıcı moleküler testler arasında uyumsuzluk (P8), rapor yorumlama veya genetik danışmanlık hatası (P9) ve taşıyıcılık durumu ile SMA tanısı arasındaki ayrımın iletilmesine ilişkin tanısal iletişim hatası (P10). İki hastada heterozigot DNAH1 ve DNAH12 varyantları saptandı. Bu bulgular olası değiştirici etkiler açısından keşifsel nitelikte değerlendirildi; ancak fonksiyonel, segregasyonla ilişkili veya nedenselliği destekleyen herhangi bir kanıt mevcut değildi. Söz konusu yorumlama ve iletişim sorunları gereksiz izlem ve bildirilen psikososyal yük ile ilişkiliydi. Ayrıntılı tedavi öykülerinin mevcut olmaması nedeniyle, kesinleşmiş olgular arasındaki fenotipik farklılıklar SMN2 kopya sayısı veya keşifsel SMN dışı varyantlarla ilişkili olarak yorumlanamadı. SMN dışı bulgular, kanıtlanmış SMA değiştiricileri olarak değil, hipotez oluşturucu bulgular olarak değerlendirilmelidir. NBS ve doğrulayıcı testlerin doğru yorumlanması ve uygun genetik danışmanlık sağlanması, tanısal belirsizliğin ve buna bağlı yükün azaltılması açısından önemlidir.

Keywords

• Spinal Müsküler Atrofi
• Genetik Testler
• Ekzom Dizileme
• Yenidoğan Taraması
• Genetik Danışmanlık

Diagnostic Clarification and Exploratory Non-SMN Genetic Findings in Patients Evaluated for Spinal Muscular Atrophy: A Retrospective Descriptive Observational Study

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by biallelic pathogenic variants in SMN1. As newborn screening (NBS) expands, accurate interpretation of molecular results is essential for diagnosis and management. This study aimed to describe clinical and genetic findings in patients evaluated for confirmed or suspected SMA, explore non-SMN variants identified in available whole-exome sequencing (WES) reports, and characterize distinct diagnostic-clarification problems related to SMA screening, report interpretation, and communication. This retrospective descriptive observational study included all 10 consecutive patients evaluated for SMA-related concerns in our pediatric immunology department between January 2023 and December 2025. WES reports were available for four patients, including three with confirmed SMA and one referred for diagnostic clarification. Analyses were descriptive; missing information was recorded as not available, and no between-group or genotype–phenotype comparisons were performed. Seven patients had confirmed SMA (six type 1 and one type 3), while three were referred for distinct diagnostic-clarification concerns: screening and confirmatory molecular discordance (P8), report interpretation or counseling error (P9), and diagnostic communication error regarding carrier status versus SMA (P10). Heterozygous DNAH1 and DNAH12 variants were identified in two patients. These findings were considered exploratory candidate modifiers; however, no functional, segregation, or causal evidence was available. These interpretation and communication problems were associated with unnecessary follow-up and reported psychosocial burden. Phenotypic differences among confirmed cases could not be interpreted in relation to SMN2 copy number or exploratory non-SMN variants because detailed treatment histories were unavailable. Non-SMN findings should be interpreted as hypothesis-generating rather than as established SMA modifiers. Accurate interpretation of NBS and confirmatory testing, together with appropriate genetic counseling, is essential to reduce diagnostic uncertainty and related burden.

Keywords

• Spinal Muscular Atrophy (SMA)
• ; Genetic Testing
• Exome sequencing
• Neonatal Screening
• Genetic Counseling

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