OCA2基因c.1441G>A(p.Ala481Thr)位点变异的生育遗传咨询探讨

Reproductive genetic counseling for gene OCA2 c.1441G>A(p.Ala481Thr)variant

目的对OCA2基因c.1441G>A(p.Ala481Thr)位点变异白化病家系的遗传咨询和生育指导。方法丈夫,26岁,轻度白化病表现,毛发偏黄,皮肤白皙,视力正常,无白化病相关系统受累表现。妻子,27岁,G_(0)P_(0),身体良好。夫妇属非近亲婚配。现备孕咨询,评估生育白化病患儿风险。遗传咨询后,建议其进行遗传性白化病相关基因的测序检测。以“OCA2基因,c.1441G>A位点”为检索词,检索Pubmed、OMIM、Clinvar数据库、中国知网、万方数据库(建库至2023年10月),选取OCA2基因c.1441G>A(p.Ala481Thr)变异相关的白化病病例相关资料文献。结果结果显示,丈夫OCA2基因存在2个变异,分别为NM_000275.3:c.182G>A(p.Trp61*)和NM_000275.3:c.1426A>G(p.Asn476Asp),妻子OCA2基因有1个杂合变异,为NM_000275.3:c.1441G>A(p.Ala481Thr)。Sanger溯源验证,丈夫所携无义变异c.182G>A(p.Trp61*)来源其母亲,所携错义变异c.1426A>G(p.Asn476Asp)变异来源其父亲。妻子所携错义变异c.1441G>A(p.Ala481Thr)并非来源其父亲,其母亲信息不详。使用数据库搜索c.1441G>A变异的表型效应,得知c.1441G>A(p.Ala481Thr)属于一种亚等效变异,Ala481Thr在黑色素形成中有70%的野生型功能,纯合子无表现,表型正常。据c.1441G>A的亚等效作用,遗传咨询后,夫妇知情同意选择自然怀孕方式。随访这对夫妇怀孕并分娩1表型正常女儿。经测序验证,女儿遗传了父亲c.1426A>G(p.Asn476Asp)变异和母亲正常OCA2基因。结论报道一例白化病OCA2基因c.1441G>A变异相关的生育遗传咨询案例,复习文献,总结c.1441G>A(p.Ala481Thr)白化病的亚等效作用所产生的表型特异性,帮助临床医生正确认识合理运用恰当的遗传学检测手段和深刻理解临床决策前充分遗传咨询的重要性,从而提高对该类变异的遗传咨询能力,有效地避免了过度医疗。

Objective To provide genetic counseling and reproductive guidance for albinism families with OCA2 c.1441G>A(p.Ala481Thr).Methods The 26 years old husband had only mild albinism phenotype of yellow hair and fair skin,but without other albinism-related.The 27 years old wife in good health condition had no history of pregnancy.The couple is a non-consanguineous marriage.They had reproductive need for pregnancy counseling to assess the risk of albinism offspring.After genetic counseling,they conducted gene sequencing for inherited albinism.“OCA2 c.1441G>A”as the search term in Pubmed,OMIM,Clinvar database,CNKI,Wan Fang database(established until October 2023)was searched.A complete literature of albinism cases with OCA2 c.1441G>A(p.Ala481Thr)variant was selected.Results It was showed that the husband had two mutations in OCA2 gene,including NM_000275.3:c.182G>A(p.Trp61*)和NM_000275.3:c.1426A>G(p.Asn476Asp),and the wife had one heterogenic mutation in OCA2 gene NM_000275.3:c.1441G>A(p.Ala481Thr).Sanger sequencing verification showed that the nonsense variant c.182G>A(p.Trp61*)of the husband was from his mother,and the missense variant c.1426A>G(p.Asn476Asp)was from his father.The missense variant c.1441G>A(p.Ala481Thr)of the wife did not originate from her father,and the information of her mother is unknown.The phenotypic effect of c.1441G>A variant was searched in the corresponding database.The variant c.1441G>A(p.Ala481Thr)was not classical pathogenic variant,but a sub-equivalent variant.Ala481 Thr had 70%wild-type allele function in melanin formation but no albinism phenotypic effect when in,therefore,the homozygote phenotype was completely normal.According to the sub-equivalent effect of c.1441G>A,the couple choose the natural pregnancy way.Finally,the couple gave birth to a daughter with normal phenotype inherited the variant of c.1426A>G(P.SN476asp)from father and the normal OCA2 gene from mother after gene sequencing verification.Conclusion One case of reproductive genetic counseling for one couple with the husband carrying OCA2 c.1441G>A mutation associated with albinism was reported,literatures were reviewed,and phenotypic specificity resulting from sub-equivalent effect of c.1441G>A associated albinism were summarized.This finding aims to help clinicians correctly understand the importance of rational use of appropriate genetic testing techniques and deeply understand the adequate genetic counseling before clinical decision-making,so as to improve genetic counseling ability for such variants and effectively avoid excessive medical treatment.