Phenotypic heterogeneity associated with KIF21A: Two new cases and review of the literature.
Phenotypic heterogeneity associated with KIF21A: Two new cases and review of the literature.
复制标题
与 KIF21A 相关的表型异质性：两个新病例和文献综述。
DOI：
10.1002/ajmg.a.63455
复制
发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Kernohan,KristinD
中科院分区：
文献类型：
--
作者：
Bhola,PriyaT;Mishra,Radha;Posey,JenniferE;Hamilton,LeslieE;Graham,GailE;Punetha,Jaya;Care4RareCanadaConsortium;Lupski,JamesR;Boycott,KymM;D'Amours,Damien;Kernohan,KristinD
我们对与罕见疾病临床谱系相关的遗传和表型异质性的理解继续扩大。彻底的表型描述和模型生物体功能研究是剖析疾病过程生物学的宝贵工具。众所周知，动蛋白基因与特定的疾病表型有关，包括KIF21A在内的一组动蛋白基因与多种疾病有关。在这里，我们报告了两名通过外显子测序鉴定出KIF21A变异的患者；一名患者具有双等位基因变异，支持一种新的KIF21A相关综合征的隐性遗传，这是该疾病的第二次报告，另一名患者具有杂合的从头开始变异等位基因，代表迄今描述的疾病的表型扩展。我们提供了这两个家族的详细表型信息，包括KIF21A双等位基因变异相关的神经轴索营养不良的新的神经病理学发现。此外，我们还研究了酿酒酵母中的显性变异体，以评估变异体的致病性，发现该变异体似乎损害了蛋白质的功能。KIF21A相关疾病有越来越多的证据表明表型异质性；需要进一步的患者和等位基因系列的研究来定义表型谱，并进一步探索这些疾病的分子病因学。
Our understanding of genetic and phenotypic heterogeneity associated with the clinical spectrum of rare diseases continues to expand. Thorough phenotypic descriptions and model organism functional studies are valuable tools in dissecting the biology of the disease process. Kinesin genes are well known to be associated with specific disease phenotypes and a subset of kinesin genes, includingKIF21A, have been associated with more than one disease. Here we report two patients withKIF21Avariants identified by exome sequencing; one with biallelic variants, supporting a novelKIF21Arelated syndrome with recessive inheritance and the second report of this condition, and another with a heterozygous de novo variant allele representing a phenotypic expansion of the condition described to date. We provide detailed phenotypic information on both families, including a novel neuropathology finding of neuroaxonal dystrophy associated with biallelic variants inKIF21A. Additionally, we studied the dominant variant inSaccharomyces cerevisiaeto assess variant pathogenicity and found that this variant appears to impair protein function.KIF21Aassociated disease has mounting evidence for phenotypic heterogeneity; further patients and study of an allelic series are required to define the phenotypic spectrum and further explore the molecular etiology for each of these conditions.