基因型相同而表现型不同的Fabry病一家系报道
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摘要
目的报道一个具有相同α-半乳糖苷酶A突变基因型而临床表现型不同的家系。方法使用二代测序对一个具有多种心律失常的患者进行筛查寻找基因突变,并对家属进一步验证确认。结果该家系中,先证者经历一次心源性休克,且出现多种心律失常,包括室性心动过速、短PR综合征、心房扑动、心房颤动、窦性心动过缓。家族中有1例患者表现为类似的短PR综合征,余患者均有不同的临床表现。DNA测序显示,该家系所有患者皆有α-半乳糖苷酶A错义突变(G43D)。该基因突变既往描述将导致法布里病。结论 GLA基因突变可导致多种临床表型,即使在同一家系相同基因型的条件下,其临床表现的个体差异仍较大。
Objectives To observed the difference on the phenotypes in a family with same α-galactosidase(GLA)mutation. Method DNA sequence was performed to screen the exons of clinical disease-associated genes in the proband,and candidate variants were further validated by direct Sanger sequencing in the family members. Results In this family,the proband experienced an episode of cardiac shock and several types of arrhythmia including ventricular tachycardia,short PR syndrome,atrial fibrillation,atrial flutter and sinus bradycardia. The similar short PR syndrome was found in another family member. All patients show different clinical phenotypes in the family. Genetic analysis revealed a missense mutation(G43D)in all affected family members. This mutation was previous described in patients with Fabry Disease. Conclusions GLA mutations are responsible for a diverse clinical phenotype,even in one family with the same background of gene.
Objectives To observed the difference on the phenotypes in a family with same α-galactosidase(GLA)mutation. Method DNA sequence was performed to screen the exons of clinical disease-associated genes in the proband,and candidate variants were further validated by direct Sanger sequencing in the family members. Results In this family,the proband experienced an episode of cardiac shock and several types of arrhythmia including ventricular tachycardia,short PR syndrome,atrial fibrillation,atrial flutter and sinus bradycardia. The similar short PR syndrome was found in another family member. All patients show different clinical phenotypes in the family. Genetic analysis revealed a missense mutation(G43D)in all affected family members. This mutation was previous described in patients with Fabry Disease. Conclusions GLA mutations are responsible for a diverse clinical phenotype,even in one family with the same background of gene.
引文
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[3] SHEPPARD M N. The heart in Fabry′s disease[J]. Cardiovasc Pathol,2011,20(1):8-14.
[4] ELLIOTT P,BAKER R,PASQUALE F,et al. Prevalence of Anderson-Fabry disease in patients with hypertrophic cardiomyopathy:the European Anderson-Fabry disease survey[J].Heart,2011,97(23):1957-1960.
[5] SACHDEV B, TAKENAKA T, TERAGUCHI H, et al.Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy[J]. Circulation,2002,105(12):1407-1411.
[6] RIERA C,LOIS S,DOMINQUEZ C,et al. Molecular damage in Fabry disease:characterization and prediction of alphagalactosidase A pathological mutations[J]. Proteins,2015,83(1):91-104.
[7] ECHEVARRIA L,BENISTAN K,TOUSSAINT A,et al. Xchromosome inactivation in female patients with Fabry disease[J]. Clin Genet,2016,89(1):44-54.
[8] REDONNET-VERNHET I,PLOOS V A J,JANSEN R P,et al. Uneven X inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the alpha-galactosidase A gene[J]. J Med Genet,1996,33(8):682-688.
[9] KAMPMANN C,WIETHOFF C M,PERROT A,et al. The heart in Anderson Fabry disease[J]. Z Kardiol,2002,91(10):786-795.
[10] POCHIS W T, LITZOW J T, KING B G, et al.Electrophysiologic findings in Fabry′s disease with a short PR interval[J]. Am J Cardiol,1994,74(2):203-204.
[11] BECKER A E,SCHOORL R,BALK A G,et al. Cardiac manifestations of Fabry′s disease. Report of a case with mitral insufficiency and electrocardiographic evidence of myocardial infarction[J]. Am J Cardiol,1975,36(6):829-835.
[12] YOGASUNDARAM H,KIM D,OUDIT O,et al. Clinical features, diagnosis, and management of patients with anderson-fabry cardiomyopathy[J]. Can J Cardiol,2017,33(7):883-897.
[13] LIU Y, WANG F, CHEN X, et al. Fasciculoventricular pathways responsible for ventricular preexcitation in patients with danon disease[J]. Circ Arrhythm Electrophysiol,2018,11(9):e6704.
[2] BRADY R O,GAL A E,BRADLEY R M,et al. Enzymatic defect in Fabry′s disease. Ceramidetrihexosidase deficiency[J].N Engl J Med,1967,276(21):1163-1167.
[3] SHEPPARD M N. The heart in Fabry′s disease[J]. Cardiovasc Pathol,2011,20(1):8-14.
[4] ELLIOTT P,BAKER R,PASQUALE F,et al. Prevalence of Anderson-Fabry disease in patients with hypertrophic cardiomyopathy:the European Anderson-Fabry disease survey[J].Heart,2011,97(23):1957-1960.
[5] SACHDEV B, TAKENAKA T, TERAGUCHI H, et al.Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy[J]. Circulation,2002,105(12):1407-1411.
[6] RIERA C,LOIS S,DOMINQUEZ C,et al. Molecular damage in Fabry disease:characterization and prediction of alphagalactosidase A pathological mutations[J]. Proteins,2015,83(1):91-104.
[7] ECHEVARRIA L,BENISTAN K,TOUSSAINT A,et al. Xchromosome inactivation in female patients with Fabry disease[J]. Clin Genet,2016,89(1):44-54.
[8] REDONNET-VERNHET I,PLOOS V A J,JANSEN R P,et al. Uneven X inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the alpha-galactosidase A gene[J]. J Med Genet,1996,33(8):682-688.
[9] KAMPMANN C,WIETHOFF C M,PERROT A,et al. The heart in Anderson Fabry disease[J]. Z Kardiol,2002,91(10):786-795.
[10] POCHIS W T, LITZOW J T, KING B G, et al.Electrophysiologic findings in Fabry′s disease with a short PR interval[J]. Am J Cardiol,1994,74(2):203-204.
[11] BECKER A E,SCHOORL R,BALK A G,et al. Cardiac manifestations of Fabry′s disease. Report of a case with mitral insufficiency and electrocardiographic evidence of myocardial infarction[J]. Am J Cardiol,1975,36(6):829-835.
[12] YOGASUNDARAM H,KIM D,OUDIT O,et al. Clinical features, diagnosis, and management of patients with anderson-fabry cardiomyopathy[J]. Can J Cardiol,2017,33(7):883-897.
[13] LIU Y, WANG F, CHEN X, et al. Fasciculoventricular pathways responsible for ventricular preexcitation in patients with danon disease[J]. Circ Arrhythm Electrophysiol,2018,11(9):e6704.