Abstract：
Griscelli syndrome type 1 (GS1) is a rare inherited autosomal recessive disease caused by a deleterious variant in the MYO5A gene and characterized by general hypopigmentation, neurological symptoms, motor disability, hypotonia, and vision abnormality. Only nine pathogenic variants in the MYO5A gene have been confirmed in association with the GS1. All of the reported pathogenic variants are truncating. Herein, two siblings from a consanguineous Iranian family with abnormal pigmentation and neurological symptoms were referred for genetic counseling. Whole-exome sequencing (WES) revealed a novel homozygous truncating variant c.1633_1634delAA (p.Asn545Glnfs*10) in the MYO5A gene, which was completely co-segregated with the phenotype in all affected and unaffected family members. Computational analysis and protein modeling demonstrated the deleterious effects of this variant on the structure and function of the protein. The variant, according to ACMG guidelines, was classified as pathogenic. Besides the novelty of the identified variant, our patients manifested more severe clinical symptoms and presented distal hyperlaxity in all four limbs, which was a new finding. In conclusion, we expanded the mutational and phenotypic spectrum of the GS1. Moreover, by studying clinical manifestations in all molecularly confirmed reported cases, provided a comprehensive overview of clinical presentation, and attempted to find a genotype-phenotype correlation.
摘要：
Griscelli综合征1型（GS1）是一种罕见的遗传性常染色体隐性遗传疾病，由MYO5A基因的有害变异引起，其特征是一般的色素减退，神经症状,运动障碍,低张力,和视力异常。MYO5A基因中只有9种致病变体已被证实与GS1相关。所有报道的致病变体都是截短的。在这里，来自一个有异常色素沉着和神经系统症状的伊朗近亲家庭的两名兄弟姐妹被转诊接受遗传咨询.全外显子组测序（WES）揭示了一种新的纯合截短变体c.1633_1634delAA（p。Asn545Glnfs*10）在MYO5A基因中，与所有受影响和未受影响的家庭成员的表型完全共隔离。计算分析和蛋白质建模证明了该变体对蛋白质的结构和功能的有害影响。变种,根据ACMG指南,被归类为致病性。除了已识别变体的新颖性，我们的患者表现出更严重的临床症状，并在所有四肢表现出远端过度松弛，这是一个新的发现。总之,我们扩展了GS1的突变和表型谱。此外，通过研究所有分子确诊病例的临床表现，提供了临床表现的全面概述，并试图找到基因型-表型的相关性。
