与轻度神经发育障碍相关的遗传性致病变异体
Inherited Pathogenic Variant Associated With a Mild Neurodevelopmental Disorder.
作者信息
Hildebrand Michael S, Braden Ruth O, Lauretta Mariana L, Kaspi Antony, Leventer Richard J, Anderson Melinda, Goel Himanshu, Bahlo Melanie, Scheffer Ingrid E, Amor David J, Janowski Robert, Niessing Dierk, Morgan Angela T
机构信息
From the Epilepsy Research Centre (M.S.H., I.E.S.), Department of Medicine, The University of Melbourne, Austin Health, Heidelberg; Neuroscience Group (M.S.H., R.J.L., I.E.S.); Speech and Language (R.O.B., M.L., A.T.M.), Murdoch Children's Research Institute, Royal Children's Hospital, Parkville; Department of Audiology and Speech Pathology (R.O.B., M.L., A.T.M.), The University of Melbourne, Carlton; Population Health and Immunity Division (A.K., M.B.), The Walter and Eliza Hall Institute of Medical Research; Department of Medical Biology (A.K., M.B.), The University of Melbourne; Department of Paediatrics (R.J.L., I.E.S., D.J.A.), The University of Melbourne; Department of Neurology (M.S.H., R.J.L., I.E.S., D.J.A.), Royal Children's Hospital, Parkville; PURA Foundation Australia Ltd (M.A.), Plenty, Victoria; Hunter Genetics (H.G.), John Hunter Hospital, New Lambton Heights, New South Wales; The Florey Institute (I.E.S.); Neurodisability and Rehabilitation Group (D.J.A.), Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia; and Institute of Structural Biology (R.J., D.N.), Helmholtz Zentrum Muenchen-German Research Centre for Environmental Health, Neuherberg, Germany.
出版信息
Neurol Genet. 2024 Aug 6;10(5):e200181. doi: 10.1212/NXG.0000000000200181. eCollection 2024 Oct.
OBJECTIVES
Purine-rich element-binding protein alpha (PURA) regulates gene expression and is ubiquitously expressed with an enrichment in neural tissues. Pathogenic variants in cause the neurodevelopmental disorder PURA syndrome that has a variable phenotype but typically comprises moderate-to-severe global developmental delay, intellectual disability, early-onset hypotonia and hypothermia, epilepsy, feeding difficulties, movement disorders, and subtle facial dysmorphism. Speech is reportedly absent in most, but the specific linguistic phenotype is not well described.
METHODS
We used genome sequencing to identify a pathogenic gene variant as part of a study of children ascertained for severe primary speech disorder in the absence of moderate or severe ID.
RESULTS
The novel c.296G>T (p.Arg99Leu) pathogenic missense variant segregated in the female proband and her affected mother. The proband had dysarthria; phonological disorder; and severe receptive and expressive language impairment, borderline intellect, attention difficulties, oropharyngeal dysmotility, and dysmorphic facial features. Her mother had dysarthria, moderate receptive language impairment, and borderline intellect. Both the proband and her mother completed mainstream schooling with classroom support.
DISCUSSION
This is the first inherited pathogenic germline variant in over 600 unrelated families documented on ClinVar or reported in the literature. testing should be considered in families with primary speech disorder and borderline intellectual disability, given the specific genetic counseling implications.
目的
富含嘌呤元件结合蛋白α（PURA）调节基因表达，在神经组织中普遍表达且表达量丰富。PURA基因的致病性变异会导致神经发育障碍PURA综合征，该综合征具有可变的表型，但通常包括中度至重度的全面发育迟缓、智力残疾、早发性肌张力减退和体温过低、癫痫、喂养困难、运动障碍以及轻微的面部畸形。据报道，大多数患者无言语能力，但具体的语言表型尚未得到充分描述。
方法
作为一项针对无中度或重度智力残疾的严重原发性言语障碍儿童的研究的一部分，我们使用基因组测序来鉴定致病基因变异。
结果
新发现的c.296G>T（p.Arg99Leu）致病性错义变异在女性先证者及其患病母亲中分离。先证者患有构音障碍、音韵障碍以及严重的接受性和表达性语言障碍、边缘智力、注意力困难、口咽运动障碍和面部畸形特征。她的母亲患有构音障碍、中度接受性语言障碍和边缘智力。先证者及其母亲在课堂支持下完成了主流学校教育。
讨论
这是ClinVar记录的600多个无关家庭中或文献报道的首个遗传性PURA致病种系变异。鉴于特定的遗传咨询意义，对于患有原发性言语障碍和边缘智力残疾的家庭，应考虑进行PURA检测。
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