ClinGen Guideline을 이용한 LDLR 유전자의 재분석 - 미분류염기변이를 중심으로
Re-evaluation of the LDLR Gene Variants of Uncertain Significance Using ClinGen Guideline
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가족성 고콜레스테롤혈증은 저밀도지단백 콜레스테롤이 지속적으로 상승되어 있는 이상지질혈증으로, 조기 심혈관계 질환 발병의 주요 위험 인자이다. 가족성 고콜레스테롤혈증은 가장 흔한 유전질환 중 하나로 유병률은 약 1:250이며, LDLR 유전자의 이형접합 병인성 변이가 원인의 약 90%를 차지한다. 염기서열분석에서 확인된 변이들은 미국의학유전학회와 분자병리학회(ACMG/AMP)의 지침에 따라 분류되는 반면, 구체적인 질환에 대한 변이 해석은 Clinical Genome Resource (ClinGen) 전문가들의 조정을 거친다. 저자들은 최근 ClinGen에서 발행한 가족성 고콜레스테롤혈증의 변이 해석에 대한 가이드라인을 이용하여, 본원에서 과거 미분류염기변이로 보고했던 변이들을 재분석하였다. 2011년부터 2021년까지 251명의 환자를 대상으로 시행한 LDLR 유전자 검사에서 발견된 66종류의 변이 중, 15명의 환자에서 확인된 13종류의 미분류염기변이가 재분석 대상이었다. 그 결과 두 종류의 과오 변이, c.268G>T (p.D90Y)와 c.694G>T (p.A232S)가 likely pathogenic variant (LPV)로 재분류되었다. ClinGen가이드라인을 활용함으로써 그 당시 LPV로 분류하기에 불충분했던 미분류염기변이에 대한 판독이 적절히 이루어졌다. 가족성 고콜레스테롤혈증의 유전적 원인과 유병률을 감안한다면, 향후 LDLR 유전자에서 발견되는 새로운 변이들은 ClinGen 가이드라인을 근거로 분류해야 할 것이다.
Abstract
Familial hypercholesterolemia (FH) is characterized by elevated LDL cholesterol levels, which is an important risk factor for early-onset cardiovascular disease. FH is one of the common genetic diseases that have a prevalence of approximately 1:250 and is associated with the heterozygous pathogenic variant of the gene encoding for the low-density lipoprotein receptor, LDLR gene (~90%). Variants identified through sequencing analysis are classified according to the American College of Medical Genetics and Association for Molecular Pathology Guideline. However, disease-specific variant curation is performed by the Clinical Genome Resource (ClinGen) Expert Panels. Since a specific ClinGen guideline for FH was recently published, here, we applied this new guideline to re-evaluate and re-classify what was reported as a Variant of Uncertain Significance (VUS) in the LDLR gene. Among 66 different types of LDLR variants from 251 patients during 2011 and 2021, 13 different VUSs reported from 15 patients were re-classified. Among 13 VUSs, two missense variants; c.268G>T (p.D90Y) and c.694G>T (p.A232S), were re-classified to likely pathogenic variants. Using the ClinGen guideline, VUSs previously lacking sufficient evidence to be classified as likely pathogenic have now been appropriately classified. Considering the genetic causes and prevalence of FH, the evaluation and classification of the LDLR gene variants should be updated according to the new ClinGen guideline specific for FH.
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