Early-onset Parkinson's disease in a patient with a rare homozygous pathogenic GBA1 variant and no Gaucher disease symptoms.

IF 1.6 4区 医学 Q3 CLINICAL NEUROLOGY
Juliana Cordovil Cotrin, Rafael Mina Piergiorge, Andressa Pereira Gonçalves, Mariana Spitz, Alexandra Lehmkuhl Gerber, Ana Paula de Campos Guimarães, Ana Tereza Ribeiro Vasconcelos, Cíntia Barros Santos-Rebouças
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引用次数: 0

Abstract

Parkinson's disease (PD) is a multifaceted neurodegenerative disorder with both non-motor and motor symptoms. Variants in the glucosylceramidase beta 1 (GBA1) gene are the strongest genetic risk factor for PD, while homozygous or compound heterozygous variants in this gene classically cause Gaucher disease (GD). This study presents an early-onset PD patient with a homozygous GBA1 deletion. Whole-exome sequencing (WES) was performed, and the identified variant was validated via Sanger sequencing. The variant was classified according to ACMG guidelines and ClinGen updates. The patient, a Brazilian female of mixed ethnicity, exhibited the full spectrum of classical motor and non-motor PD symptoms without evident hallmarks of GD. The identified homozygous GBA1 variant (NM_000157.4:c.222_224del; p.T75del; rs761621516) has a very low global allele frequency (0.00003284) and is associated with reduced enzymatic activity. This variant exhibits a founder effect among individuals of African descent. This case highlights an intricate genotype-phenotype landscape for GBA1 variants, underscoring the role of homozygous GBA1 variants in PD pathogenesis.

1例罕见纯合致病性GBA1变异患者的早发性帕金森病,无戈谢病症状
帕金森病(PD)是一种多方面的神经退行性疾病,具有非运动和运动症状。糖基神经酰胺酶β 1 (GBA1)基因的变异是PD最强的遗传危险因素,而该基因的纯合或复合杂合变异通常会导致戈谢病(GD)。本研究报告了一例GBA1纯合子缺失的早发性PD患者。进行全外显子组测序(WES),并通过Sanger测序对鉴定的变异进行验证。该变体根据ACMG指南和ClinGen更新进行分类。患者为巴西混血女性,表现出全谱的经典运动和非运动PD症状,没有明显的GD特征。鉴定出的GBA1纯合子变异(NM_000157.4:c.222_224del;p.T75del;Rs761621516)具有非常低的全球等位基因频率(0.00003284),并且与酶活性降低有关。这种变异在非洲人后裔中表现出创始人效应。该病例突出了GBA1变异复杂的基因型-表型格局,强调了纯合子GBA1变异在PD发病机制中的作用。
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来源期刊
Neurogenetics
Neurogenetics 医学-临床神经学
CiteScore
3.90
自引率
0.00%
发文量
24
审稿时长
6 months
期刊介绍: Neurogenetics publishes findings that contribute to a better understanding of the genetic basis of normal and abnormal function of the nervous system. Neurogenetic disorders are the main focus of the journal. Neurogenetics therefore includes findings in humans and other organisms that help understand neurological disease mechanisms and publishes papers from many different fields such as biophysics, cell biology, human genetics, neuroanatomy, neurochemistry, neurology, neuropathology, neurosurgery and psychiatry. All papers submitted to Neurogenetics should be of sufficient immediate importance to justify urgent publication. They should present new scientific results. Data merely confirming previously published findings are not acceptable.
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