Germline variant 의 해석은 인간 유전체 내의 변이를 분석하고 해석하는 과정으로, 유전적 질환의 원인을 파악하거나 우리의 생물학적 특성을 이해하는 데 중요한 정보를 제공합니다. Germline variant는 개인이 출생 시 물려받은 유전자 변이로, 혈액이나 조직 등에서 모두 동일하게 나타납니다. 그러나 이러한 변이는 개인별로 다르며, 질병 발생 가능성 등에 대한 예측을 위해 정확한 해석이 필요합니다. 따라서, 이번 글에서는 ACMG guideline 2015와 clingen specification을 참고하여 germline variant의 해석에 대해 다루어 보겠습니다.
Germline variant classification
Variant classification은 germline variant를 분류하는 데 사용되며, 분류는 다음과 같이 5단계로 구성됩니다.
Benign (양성)
질병과 관련이 없으며, 일반적으로 흔히 발견되는 변이입니다.
Likely Benign (잠재적으로 양성)
질병과 관련이 없을 가능성이 높지만, 추가적인 연구가 필요할 수 있습니다.
Variant of Uncertain Significance (VUS) (의미 불명확한 변이)
변이의 의미와 질병과의 연관성을 확인할 수 없으며, 이러한 경우에는 추가 연구가 필요합니다.
Likely Pathogenic (잠재적으로 병원성)
질병과 연관이 있을 가능성이 높지만, 추가적인 연구가 필요할 수 있습니다.
Pathogenic (병원성)
질병과 강한 연관성이 있으며, 환자와 가족들에게 질병을 유발할 수 있습니다.
이러한 분류는 ACMG guideline 2015에서 제시되었으며, 많은 임상 현장 및 연구에서 사용되고 있습니다.
ACMG guideline 2015의 분류 기준
2015년에 나온 ACMG guideline은 Germline variant 해석에 있어서 중요한 기준들을 제시하였습니다.
Population data, computational prediction data, functional data, segregation data, de novo data, allelic data들을 어떻게 적용하여 germline variant를 해석하여야 하는지에 대한 전반적인 기준들을 제시하였습니다. Benign의 경우에는 stand-alone, strong, supporting의 3가지 evidence level로, pathogenic variant의 경우에는 very strong, strong, moderate, supporting evidence까지 줄 수 있습니다.
ACMG guideline 2015는 28개의 기준을 사용하여 germline variant를 분류합니다. 이 중 대부분의 기준은 변이가 병원성인지 여부를 결정하는 데 사용됩니다. ACMG guideline 2015의 분류 기준 중 가장 중요한 기준 몇 가지를 구체적으로 다루어 보겠습니다.
PVS1 (Pathogenic Very Strong 1)
가장 중요한 기준입니다. PVS1 null 변이란, nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multiexon deletion과 같은 유전자 변이들을 말합니다. 이러한 변이들은 일반적으로 유전자 기능을 파괴하여 전사되지 않거나, nonsense-mediated decay (NMD) 등의 메커니즘으로 유전자 생성물을 완전히 없앨 수 있습니다. 하지만, 이러한 null 변이를 pathogenic variant로 분류하는 것은 주의가 필요합니다.
먼저, 해당 변이가 해당 질병의 유전 패턴과 일치하는지 확인해야 합니다. 예를 들어, 일부 유전자에서는 heterozygous missense 변이만이 질병을 일으키며, null 변이는 유전자의 heterozygous 상태에서는 오히려 benign할 수 있습니다. 이러한 경우에는 해당 null 변이가 pathogenic variant가 될 수 없습니다.
또한, 이전 연구에서 이미 병원성으로 확인된 특정 지점 이후에 위치한 null 변이는, 해당 위치 이전의 null 변이와는 다른 효과를 나타낼 수 있으므로 주의가 필요합니다. 예를 들어, 마지막 엑손이나 마지막에서 두 번째 엑손에서의 null 변이는 NMD를 피할 가능성이 높아서, 해당 위치 이전에 위치한 null 변이와는 다른 효과를 나타낼 수 있습니다.
또한, splice-site 변이의 경우 null 효과를 나타낼 가능성이 높지만, RNA 분석이나 단백질 분석과 같은 기술로 이를 확인해야 합니다. 또한, in-frame deletion/insertion도 주의해야 합니다. in-frame변이가 생겨도 단백질의 중요한 부분이 유지되고 있을 경우에는, mild 또는 neutral한 영향만을 미칠 수 있습니다.
마지막으로, null 변이가 발견된 엑손이 해당 질병과 관련된 다른 pathogenic variant가 없는 경우, 해당 엑손이 대체로 spliced out될 가능성이 있으므로 주의가 필요합니다. 특히, 예방적인 검사에서 예기치 않게 발견된 null 변이인 경우, 해당 변이가 질병을 유발할 가능성이 낮을 수 있으므로, 주의가 필요합니다.
참고로, canonical ±1 or 2 splice sites란, 유전자의 전사 과정 중 중요한 역할을 하는 스플라이스 사이트(splice site) 중에서도 특히 중요한 위치를 가리킵니다. 스플라이스 사이트는 유전자의 전사 과정에서 엑손(exon)과 인트론(intron)을 연결해주는 영역으로, 이 영역에서 인트론이 제거되고 엑손이 이어지는 과정이 진행됩니다.
canonical ±1 or 2 splice sites는 인트론과 엑손 사이의 경계 부근에 위치한 스플라이스 사이트 중에서도, 특히 중요한 스플라이스 사이트를 가리킵니다. “canonical”이란 용어는 표준적인 스플라이스 사이트를 의미하며, “+1″과 “+2″는 인트론과 엑손 경계에서 첫 번째와 두 번째 염기를 가리킵니다. 마찬가지로, “-1″과 “-2″는 엑손과 인트론 경계에서 엑손 끝에서 첫 번째와 두 번째 염기를 가리킵니다.
canonical ±1 or 2 splice sites는 스플라이스 사이트 중에서도 가장 중요한 위치에 속하기 때문에, 이 영역에 발생하는 변이는 전사 과정에서 이상을 일으켜 유전적 질환의 원인이 될 수 있습니다. 예를 들어, 스플라이스 사이트 변이로 인해 전사 과정에서 인트론 제거가 제대로 이루어지지 않아 엑손이 제거되거나, 엑손이 이어지지 않아 이상한 단백질이 생성되는 경우가 있습니다. 이러한 이유로, canonical ±1 or 2 splice sites에서 발생하는 변이는 질병의 유전적 원인으로 분류될 수 있습니다.
PS3 BS3
Functional study와 관련한 분류 기준입니다. 잘 설계된 functional study에 의해 유전자에 damaging effect의 증거가 있을 경우 PS3으로, 증거가 없을 경우에는 BS3으로 분류합니다. Functional study는 유전자 또는 단백질 기능에 미치는 변이의 영향을 예측하는데 유용한 도구입니다. 그러나, 모든 기능적 연구가 유전자 또는 단백질 기능에 미치는 영향을 예측하는데 효과적이지는 않습니다. 예를 들어, 특정 효소 활성화 실험은 대사 경로에서 missense 변이가 효소 기능에 미치는 영향을 평가하는 데 효과적인 방법입니다. 그러나 다른 기능적 실험들은 단백질 기능에 대한 변이의 영향을 덜 정확하게 예측할 수도 있습니다.
따라서 기능적 연구의 타당성을 평가할 때에는, 기능적 실험이 생물학적 환경을 얼마나 정확하게 반영하는지 고려해야 합니다. 예를 들어, 환자나 동물 모델로부터 생겨난 조직을 직접 사용하여 효소 활성을 평가하는 것은, in vitro에서 단백질을 발현하는 것보다 더 강력한 증거가 될 수 있습니다. 또한, 어떤 실험이 단백질의 전체 생물학적 기능을 반영하는지, 단지 일부 기능만을 반영하는지 고려해야 합니다.
PS4 PM2 BA1 BS1 BS2
해당 variant의 frequency와 인구 집단에서의 빈도와 비교하여 evidence를 부여하는 기준들입니다.
이를 위해서는 1000 Genome Project, gnomAD 등의 population database에서 해당 변이의 인구집단에서의 빈도를 검색하는 것이 유용합니다.
일반적으로, 대조군에서 해당 변이의 allele frequency가 희귀 Mendelian 장애에 대한 예상 수준보다 높은 경우, 이는 희귀 Mendelian 장애에 대한 Benign 해석(BS1)을 지지하는 강력한 증거가 됩니다. 이것이 5% 이상이면, 단독으로도 Benign 지지 증거(BA1)로 간주됩니다. 조사대상 질병이 어린 시기에 완전히 penetrant한데도 불구하고, 건강한 성인에서 해당 변이를 관찰할 경우 이는 양성적 해석에 강력한 증거가 됩니다(BS2). 만약 해당 변이가 데이터베이스에 존재하지 않는 경우, 데이터베이스에서 변이 사이트를 정확하게 검출할 수 있는지 확인해야 합니다. 일반 인구집단 또는 control cohort (1,000명 이상)에서 변이가 없거나, recessive 질환이라면 기대되는 carrier 빈도 이하이고, 환자와 일치하는 인종 집단이라면 이것은 병원성의 moderate evidence (PM2)로 간주될 수 있습니다.
이런 식으로 해당 변이에 대해 어떤 기준을 줄 수 있는지 최종적으로 분석하여, 다음의 표에 의하여 evidence의 갯수에 따라 Pathogenic, Likely pathogenic, Benign, Likely benign, Uncertain significance의 5가지로 해당 변이를 분류할 수 있습니다.
Clingen Expert Panel Specification
ACMG 가이드라인에 의해 변이들이 분류되지만, 각각의 질환에 대한 변이 해석은 clingen 워킹그룹의 가이드라인에 보다 구체적으로 제시되어 있습니다.
Clingen Expert Panel Specification은 유전체 염기서열 변이를 분석하여 유전질환을 진단하거나 그 위험성을 평가하는 데 사용되는 국제적인 가이드라인입니다. Clingen specification은 유전체 의학 분야에서 유전자 변이의 임상적 의미를 결정하는 데 중요한 역할을 합니다.
Clingen specification은 다양한 분야의 전문가들이 참여하여 유전체 의학에서 사용되는 유전자 변이 분석의 품질과 일관성을 향상시키기 위해 개발되었습니다. 이러한 가이드라인은 의료 전문가들이 유전체 분석 결과를 더 잘 이해하고 해석할 수 있도록 지원합니다.
Clingen에서는 현재까지 22개의 expert panel specification을 release하였습니다.
Clingen specification과 ACMG guideline 모두 유전체 분석 결과를 해석하는 데 사용되는 가이드라인입니다. 그러나 이들은 목적과 사용 방식, 그리고 해당 분야에서의 역할 등에서 차이가 있습니다.
ACMG guideline은 유전병에 대한 유전체 분석 결과를 해석하고 분류하는 데 사용됩니다. 이는 수많은 다양한 상황에서 적용될 수 있으며, 특정 돌연변이에 대한 병원성 평가를 결정하기 위한 28가지의 기준을 제공합니다. 이러한 기준은 판단을 내리기 위한 엄격한 프로세스를 강조하고, 시험 결과의 상황과 함께 고려해야 할 다양한 인자를 고려합니다.
반면에 Clingen specification은 ACMG guideline에 의거하여 수립된 규격이며, ACMG guideline에서 제공하는 28가지 기준 중에서 몇 가지를 구체화하고 보완하는 역할을 합니다. Clingen specification은 유전체 분석 결과의 각 항목에 대한 해석 방법을 제공하며, 기존의 ACMG guideline보다 더 세부적인 정보를 제공합니다. Clingen specification은 ACMG guideline에서 언급되지 않은 상황에 대한 추가 지침도 제공하므로, ACMG guideline과 Clingen specification을 함께 사용하여 더 완벽한 해석을 할 수 있습니다.
또한, Clingen specification은 분석을 수행하는 병원이나 연구실에서 사용하는 데 초점을 맞추고 있습니다. 따라서 Clingen specification은 현장 의료진이나 유전체 분석 연구자들이 일상적으로 사용할 수 있도록 설계되었습니다.
ACMG guideline과 Clingen specification은 모두 유전체 분석 결과를 해석하는 데 중요한 역할을 합니다. 하지만 ACMG guideline은 기준이 되는 프로세스를 제공하는 반면, Clingen specification은 이를 세부화하고 보완하여 보다 정확한 해석을 제공합니다.
Germline variant 해석의 중요성과 미래
Germline variant의 해석은 유전적 질환의 원인을 파악하는 데 중요한 정보를 제공하며, 이를 위해 ACMG guideline 2015와 clingen specification 등의 지침을 참고하여 variant classification과 분류 기준을 확인하고 정확한 해석이 필요합니다. 이를 통해 유전적 질환의 예측과 예방, 진단, 치료, 상담 등의 분야에서 많은 발전이 이루어지고 있습니다. 따라서, ACMG guideline 2015와 clingen specification을 함께 활용하여 variant를 정확하게 분류하고 유전적 질환의 원인을 파악하는 것이 중요합니다. 이를 통해 개인 맞춤형 치료 등의 의학적인 발전에 이바지할 수 있을 것입니다.
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