PCCA和PCCB基因变异导致的丙酸血症3家系遗传学分析

Genetic analysis of 3 families with propionic acidemia caused by PCCA and PCCB gene variations

目的:探讨丙酸血症(PA)家系的临床特征及基因变异,明确其遗传病因。方法:收集3个PA患者家系的临床资料,对患者进行全外显子测序,对患者及其父母就候选变异行Sanger测序验证。ACMG评估变异基因的致病性。结果:患者1表现为以扩张型心肌病为首发症状的晚发型PA,患儿2和3分别表现为以喂养困难和“反应差、喂养困难、嗜睡”为首发症状的早发型PA。Sanger测序验证结果显示:患者1 PCCB基因c.647T>C及c.184-2A>G复合杂合变异,其中c.647T>C为新发变异,来源于其母亲,c.184-2A>G来源于其父亲;患儿2 PCCB基因c.838dup及c.1357dup复合杂合变异,c.838dup来源于其父亲,c.1357dup来源于其母亲;患儿3 PCCA基因c.1288C>T及外显子8~19缺失复合杂合变异,c.1288C>T来源于其父亲,外显子8~19缺失为新发变异。结论:PCCB基因c.647T>C及c.184-2A>G复合杂合变异、c.838dup及c.1357dup复合杂合变异、PCCA基因c.1288C>T及外显子8~19缺失复合杂合变异分别是3个家系患PA的遗传学病因。

Aim:To investigate the clinical characteristics and gene variations of propionic acidemia(PA)families and clarify its genetic etiology.Method:Clinical data from 3 PA families were collected,and whole exome sequencing was performed.Sanger sequencing was used to validate the candidate variants in patients and their parents.The pathogenicity of the variant genes was assessed according to ACMG guidelines.Result:Patient 1 presented with late-onset PA with dilated cardiomyopathy as the initial symptom,while patients 2 and 3 exhibited early-onset PA with feeding difficulties,and poor responsiveness,feeding difficulties and lethargy as their initial symptoms,respectively.Sanger sequencing results revealed compound heterozygous mutations in the PCCB gene of patient 1:c.647T>C and c.184-2A>G,with c.647T>C being a novel mutation inherited from the mother and c.184-2A>G from the father;patient 2 had compound heterozygous mutations in the PCCB gene:c.838dup and c.1357dup,with c.838dup from the father and c.1357dup from the mother;patient 3 had compound heterozygous mutations in the PCCA gene:c.1288C>T and a deletion of exons 8-19,with c.1288C>T from the father and the deletion of exons 8-19 being a novel mutation.Conclusion:The compound heterozygous variants c.647T>C and c.184-2A>G in the PCCB gene,c.838dup and c.1357dup in the PCCB gene,and c.1288C>T and the deletion of exons 8-19 in the PCCA gene are the genetic causes of PA in the 3 families,respectively.