한국인 Birt-Hogg-Dubé 증후군 환자의 분자유전학적 및 임상적 특징
Genetic and Clinical Profiling of Korean Patients with Birt–Hogg–Dubé Syndrome
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초록
Birt-Hogg-Dubé 증후군(BHDS)은 FLCN 유전자의 돌연변이로 인해 발생하는 희귀 상염색체 우성 질환으로, 폐낭종, 기흉, 피부 섬유털집종 및 신장암 증상을 동반한다. 유병률은 10,000,000명당5.67명이며, 현재 한국인 BHDS 환자로 보고된 예는 많지 않다. 이논문에서는 WES (whole-exome sequencing) 및 MLPA (multiplex ligation-dependent probe amplification)를 사용하여 병원성 FLCN 변이가 있는 것으로 확인된 다섯 가족으로부터 9명의 BHDS 환자의 분자유전학적 및 임상적 특성을 검토하였다. 대상 환자군(평균연령 49.2±18.2세, 여성 89%)에서 4개의 병원성 FLCN 유전자 변이가 확인되었는데, 이전에 한국인 BHDS 환자에서는 보고되지 않았던 c.1539-2A>G 변이가 두 가족에서 확인되었다. 일배체형 분석을 통해 해당 두 가족은 공통된 유전적 배경을 공유할 가능성이있음을 알 수 있었다. 폐낭종은 6/7 (86%)의 환자에서 확인되었고, 섬유털집종은 3/8 (38%), 신장암은 2/9 (22%)의 환자에서 확인되어이전의 국내 연구와 유사하였으나, 기흉은 2/9 (22%)의 환자에서확인되어 이전 연구 결과보다 현저히 적었다. 유방암이나 갑상선암등 악성종양도 2/9 (22%)의 환자에서 발견되었다. 본 연구는 한국인 BHDS 환자의 분자유전학적 및 임상적 다양성을 제시하여 한국인 BHDS 환자들의 특성에 대한 이해도를 높여줄 수 있다는 점에서 의의를 가진다.
Abstract
The Birt–Hogg–Dubé syndrome (BHDS) is a rare autosomal dominant disease caused by mutations in the FLCN gene and manifests as pulmonary cysts, pneumothoraces, skin fibrofolliculomas, and renal cancer. Currently, few cases of BHDS have been reported in the Korean population, with a prevalence of 5.67 per 10,000,000. Here, we reviewed the genetic and clinical characteristics of nine patients from five families who were confirmed to carry pathogenic FLCN variants using whole-exome sequencing and multiplex ligation-dependent probe amplification. Among these patients (mean age 49.2±18.2 years; 89% females), four pathogenic FLCN variants were identified, including c.1539-2A>G in two families, which had not been previously reported in Korean patients. Haplotype analysis suggested that these two families shared a common genetic background. We observed pulmonary cysts in 6/7 (86%) patients, fibrofolliculomas in 3/8 (38%), and renal cancer in 2/9 (22%), similar to those in previous Korean studies; however, pneumothorax was identified in 2/9 (22%) patients, indicating a markedly lower rate. Other cancers, such as breast cancer or thyroid carcinoma, were observed in 2/9 (22%) patients. Overall, our study describes the genetic and clinical heterogeneity among Korean patients with BHDS and may help better understand the comprehensive genetic and clinical profiles of BHDS in Korean patients.
참고문헌 (20)
- Menko FH, "Birt-Hogg-Dubé syndrome : diagnosis and management", Lancet Oncol, 10, pp.1199~1206 (2009)
- Schmidt LS, "FLCN : the causative gene for Birt-Hogg-Dubé syndrome", Gene, 640, pp.28~42 (2018)
- Schmidt LS, "Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome", Am J Hum Genet, 76, pp.1023~1033 (2005)
- Gupta N, "Birt-Hogg-Dubé syndrome", Clin Chest Med, 37, pp.475~486 (2016)
- Park HJ, "Birt-Hogg-Dube syndrome prospectively detected by review of chest computed tomography scans", PLoS One, 12, pp.e0170713~ (2017)
- Daccord C, "Birt-Hogg-Dubé syndrome", Eur Respir Rev, 29, pp.200042~ (2020)
- Toro JR, "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome : a new series of 50 families and a review of published reports", J Med Genet, 45, pp.321~331 (2008)
- Kunogi M, "Clinical and genetic spectrum of Birt-Hogg-Dubé syndrome patients in whom pneumothorax and", or multiple lung cysts are the presenting feature, 2010, pp.47, 281~287
- Lee JH, "Birt-Hogg-Dubé syndrome in Korean : clinicoradiologic features and long term follow-up", Korean J Intern Med, 34, pp.830~840 (2019)
- Furuya M, "Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dubé syndrome", Clin Genet, 90, pp.403~412 (2016)
- Sattler EC, "Kidney cancer characteristics and genotype-phenotype-correlations in Birt-Hogg-Dubé syndrome", PLoS One, 13, pp.e0209504~ (2018)
- Chang HC, "Comment on"Birt-Hogg-Dubé syndrome in Korean : clinicoradiologic features and long term follow-up"", Korean J Intern Med, 35, pp.474~475 (2020)
- Lee JH, "Response to comment on"Birt-Hogg-Dubé syndrome in Korean : clinicoradiologic features and long term follow-up"", Korean J Intern Med, 35, pp.476~477 (2020)
- Richards S, "Standards and guidelines for the interpretation of sequence variants : a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology", Genet Med, 17, pp.405~424 (2015)
- "Sequence Variant Interpretation general recommendations for using ACMG/AMP criteria"[URL]
- Abou Tayoun AN, "Recommendations for interpreting the loss of function PVS1 ACMG", AMP variant criterion, 2018, pp.39, 1517~1524
- Harrison SM, "Overview of specifications to the ACMG", AMP variant interpretation guidelines, 2019, pp.103, e93~
- Park HJ, "Outstanding characteristics of Birt-Hogg-Dube syndrome in Korea", Diagnostics(Basel), 13, pp.2047~ (2023)
- Johannesma PC, "Risk of spontaneous pneumothorax due to air travel and diving in patients with Birt-Hogg-Dubé syndrome", Springerplus, 5, pp.1506~ (2016)
- Ray A, "Genetic insight into Birt-Hogg-Dubé syndrome in Indian patients reveals novel mutations at FLCN", Orphanet J Rare Dis, 17, pp.176~ (2022)