한국인 신경섬유종증 1형 환자에서 관찰된 NF1 유전자 변이 분포
NF1 Variant Spectrum in Korean Patients with Neurofibromatosis Type 1 Disorder
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배경: 신경섬유종증 1형(NF1)은 가장 높은 빈도로 발생하는 상염색체 우성 유전질환의 하나로, NF1 유전자에 다양한 질병연관변이가 발생하는 것으로 보고되었다. 본 연구는 한국인 NF1 환자에서 NF1 유전자 변이의 빈도와 특성을 확인하고자 수행되었다. 방법: 본 연구에는 서울성모병원에 의뢰된 NF1 유전자 검사 462 건이 포함되었다. NF1 유전자 변이는 messenger RNA (mRNA) 및 일부 genomic DNA 직접염기서열분석법과 multiplex ligation-dependent probe amplification (MLPA) 방법으로 분석하였다. 결과: 전체 462명 중 303명(65.6%)의 환자에서 231종류의 변이를 검출하였다. 217종류의 변이를 질병연관변이로 보고하였고, 이 중 106개(48.4%)의 변이는 이전 보고가 없는 새로운 변이였다. 가장 많은 환자들에게서 검출된 변이는 절단형 돌연변이로, 177명의 환 자에서 135종류의 변이를 검출하였다. 짜깁기 변이는 42명의 환자 에서 39종류, 과오변이는 44명의 환자에서 36종류가 검출되었다. MLPA에서만 확인되었던 엑손 단위 이상의 큰 결실은 25명의 환자 에서 8종류가 관찰되었다. mRNA 분석에서 4건의 aberrant transcript를 발견하였다. NF1 유전자의 변이 검출 률은 NIH 진단기준 충족 수에 따라 유의하게 높았다. 결론: 본 연구에서는 한국인 NF1 환자가 지닌 다양한 종류의 변이 를 검출하였다. 이러한 다양한 스펙트럼의 변이를 검출하기 위해 서 mRNA 및 gDNA에 대한 염기서열분석과 MLPA 검사를 통합적 으로 수행하여야 하며 새로 검출한 변이를 규명하기 위해 추가적 평가가 필요할 것으로 생각된다.
Abstract
Background: Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans, and many different variants in the NF1 gene have been observed. The aim of this study was to investigate the genetic variant spectrum of NF1 patients in Korea. Methods: A total of 462 cases were enrolled for NF1 analysis at Seoul St. Mary’s Hospital. NF1 was analyzed through Sanger sequencing of messenger RNA (mRNA) and genomic DNA (gDNA), and/or multiplex ligation-dependent probe amplification (MLPA) analysis. Results: We identified 231 types of NF1 variants in 303 out of the 462 patients (65.6%). Of these, 217 variants were classified as pathogenic or likely pathogenic, and 48.4% (N=106) of these were novel changes. Truncating variants encompassing frameshift and nonsense variants were most commonly observed (135 types of variants in 177 patients), followed by splicing defect variants (39 types in 42 patients) and missense variants (36 types in 44 patients). There were 8 distinctive large deletions in 25 patients, detected via MLPA analysis. Interestingly, 4 cases showed aberrant transcripts that were identified through mRNA Sanger sequencing. The frequency of NF1 mutation detected was significantly higher according to the number of satisfying National Institutes of Health (NIH) diagnostic criteria. Conclusions: This study revealed a wide spectrum of NF1 variants in Korean NF1 patients. A comprehensive analytical strategy that combines mRNA and gDNA analyses and MLPA is required to detect sequence variants. Additionally, it is important to define the effect of newly detected variants on the clinical course.
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