RADİYAL IŞIN DEFEKTLERİNİN KLİNİK SINIFLANDIRMASI VE ETYOPATOGENEZİNİN ARAŞTIRILMASI

Year 2018, Volume: 81 Issue: 4, 127 - 138, 01.12.2018

Şahin Avcı , Güven Toksoy Gülenadam Bağırova Umut Altunoğlu Birsen Karaman Seher Başaran Hülya Kayserili Z. Oya Uyguner

Abstract

DOI: 10.26650/IUITFD.427250

Amaç: Radiyal ışın defektleri (RID)
1/30.000 prevalansı ile üst ekstremitenin en sık gözlenen konjenital
anomalisidir. Olguların yaklaşık %30’unda RID izole olarak, %70’inde ek
anomaliler veya sendromlar ile birlikte gözlenir. Bu nedenle, olgularda tanının
kesinleşmesi, izlemi, ailelere özgün genetik danışma verilmesi ve sonraki
gebeliklerinde prenatal tanı seçeneğinin sunulabilmesi için önemlidir. Bu
çalışma ile RID olgularının ayırıcı tanısında yol gösterici olması, moleküler
tanıya katkı sağlaması amacıyla yeni nesil dizileme (YND) gen-paneli
oluşturuldu ve panelin moleküler tanıdaki etkinliği araştırıldı.

Gereç ve Yöntem:  Bu çalışmada, 2004-2014 yılları arasında
kliniğimizde RID bulgusu ile değerlendirilen 37 aileden 48 etkilenmiş olgunun
klinik, moleküler ve sitogenetik bulguları değerlendirildi. Karyotipi normal
saptanan ve moleküler tanısı olmayan 31 ailenin indeks olgusunda 14 farklı
fenotip ile ilişkili 43 gen, RID için tasarladığımız hedefe yönelik YND paneli
ile dizilendi.

Bulgular: Sitogenetik analiz ile bir olguda
trizomi 18 ve diğer bir olguda ise ailevi t(2;12)(q31;q24.3) translokasyonu
saptandı. Dört ailede ilişkili genlerdeki (SF3B4, SALL4, TBX5, FANCA)
mutasyonlar çalışma öncesinde moleküler analizlerle belirlenmişti. Tanısı
olmayan 31 indeks olgunun 5’inde (%16), 4 farklı gende (FANCA, NIPBL, ESCO2,
BRIP1) 6 farklı mutasyon saptandı.

Sonuç: RID nedeniyle değerlendirilen 37
ailenin 2’sinde (%5.4) kromozom anomalisi ve 9’unda (%24.3) 7 farklı gende 9
farklı mutasyon saptandı. Bulgularımız, RID olgularında özgün tasarlanan yeni
nesil dizileme panelimizin moleküler tanıya önemli oranda katkı sağladığını; RID’ın
etyopatogenezinde kromozom anomalilerinin de yer aldığını, ayırıcı tanıda yer
alması ve RID-panel çalışmasından önce kromozom anomalilerinin dışlanması
gerektiğini gösterdi.

Keywords

Fanconi anemisi, radial ışın defektleri, yeni nesil dizileme

CLINICAL CLASSIFICATION OF RADIAL RAY DEFECTS AND RESEARCH INTO ETIOPATHOGENESIS

Abstract

DOI: 10.26650/IUITFD.427250

Objective: Radial ray defects (RRDs) are
the most common congenital abnormality of the upper extremities, with a
prevalence of 1:30,000. 70% of RRDs are syndromic or accompanied by additional
malformations, whereas 30% are in isolated form. Definitive diagnosis is
critical for follow-up and provides an opportunity for prenatal diagnosis. The
aim of this study was to provide a guide for the differential diagnosis of
patients with RRD via contributing to their molecular diagnosis by constructing
a next-generation sequencing (NGS) gene-panel test.

Materials and Methods: 48 probands from 37
families, referred for genetic consultation due to RRD, between the years of
2004–2014, were evaluated by cytogenetic and molecular tools following clinical
examinations. 31 probands, with normal karyotype, were screened for 43 RRD
associated genes of 14 syndromes by using in-house-designed targeted NGS
gene-panel.

Results: Chromosomal abnormalities [a
trisomy 18 and a familial reciprocal translocation t(2;12)(q31;q24.3)] in two
families and mutations in related genes (SF3B4, SALL4, TBX5, FANCA) in four
families were known before the initiation of this study. In remaining 31
probands, five families identified to have six different mutations in four
different genes (FANCA, NIPBL, ESCO2, BRIP1).

Conclusion: Chromosomal abnormalities in
two of the 37 families (5.4%) and gene mutations in nine of the 37 families
(24.3%) were identified. Our study demonstrated that an in-house-designed
targeted NGS containing 43 genes made considerable contribution to the
diagnosis of RRD. Moreover, chromosomal abnormalities must always be considered
in the differential diagnosis and excluded before gene-panel screening.

Keywords

Fanconi anemia, next-generation sequencing, radial ray defects

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