WDR45 variants as a major cause for a clinically variable intellectual disability syndrome from early infancy in females.

IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Journal of Medical Genetics Pub Date : 2024-11-25 DOI:10.1136/jmg-2024-110068
Chihiro Abe-Hatano, Ken Inoue, Eri Takeshita, Yosuke Kawai, Katsushi Tokunaga, Yu-Ichi Goto
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Abstract

Pathogenic variants of WD repeat domain 45 (WDR45) cause neurodegeneration with brain iron accumulation 5 (NBIA5), which is characterised by progressive neurological regression and brain iron accumulation in adulthood. Early diagnosis of NBIA5 patients is difficult because they often show only a non-specific developmental delay in childhood, but it is essential for lifelong medical management. We investigated 32 females with developmental delays for coding variants of WDR45 using Sanger sequencing. Whole-genome sequencing (WGS) and X chromosome inactivation (XCI) analysis were also performed. We identified two disease-causing variants, one of which was a novel stop-loss variant, c.1051delG p.(Val351CysfsTer60), in a female with severe developmental delay from early infancy with epileptic spasms. The XCI analysis (which we originally developed) suggested a random pattern in white blood cells. WGS did not reveal any other pathogenic variants, including those in two iron transporter genes. Together with our previous findings in the WGS study, WDR45 variants accounted for 12% (6/51) of the females with developmental delay, suggesting that WDR45 is a major gene in females with developmental delay. Pathogenic variants of WDR45 result in various phenotypes that do not necessarily correlate with variant types or XCI skewing patterns.

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WDR45变体是导致女性从婴儿早期开始出现临床变异性智力残疾综合征的主要原因。
WD重复结构域45(WDR45)的致病变体会导致脑铁积聚性神经变性5(NBIA5),其特征是成年后神经系统进行性退化和脑铁积聚。早期诊断 NBIA5 患者非常困难,因为他们在童年时期往往只表现出非特异性的发育迟缓,但这对终生医疗管理至关重要。我们利用桑格测序法对 32 名发育迟缓的女性进行了调查,以寻找 WDR45 的编码变异。同时还进行了全基因组测序(WGS)和X染色体失活(XCI)分析。我们发现了两个致病变体,其中一个是新的止损变体,c.1051delG p.(Val351CysfsTer60), 患有严重发育迟缓并伴有癫痫性痉挛的女性。XCI 分析(我们最初开发的)显示白细胞中存在随机模式。WGS 没有发现任何其他致病变体,包括两个铁转运体基因中的变体。结合我们之前在 WGS 研究中的发现,WDR45 变体占女性发育迟缓患者的 12%(6/51),这表明 WDR45 是女性发育迟缓患者的主要基因。WDR45的致病变异会导致各种表型,而这些表型并不一定与变异类型或XCI倾斜模式相关。
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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
期刊介绍: Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.
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