gra2 p.Gly792和gra3 p.Gly803旁系功能获得变异的临床和神经发育特征

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Emilie Sjøstrøm, Dorota Studniarczyk, Xinyao Dou, Rebekka S Dahl, Vincent Cruz, Heng Wang, Sandra Mercier, Wallid Deb, Thomas Besnard, Jennifer Friedman, Miriam Essid, Sana Karoui, Lamia Ben Jemaa, Thouraya Benyounes, Gaetan Lesca, Davide Tonduti, Maria Iascone, Simona Orcesi, Melanie Fradin, Christèle Dubourg, Silvia Napuri, Stuart G Cull-Candy, Ian D Coombs, Mark Farrant, Allan Bayat
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引用次数: 0

摘要

gria相关疾病是由GRIA1、GRIA2、GRIA3或GRIA4中编码α-氨基-3-羟基-5-甲基-4-异恶唑丙酸(AMPA)型谷氨酸受体(ampar)的致病变异引起的。影响AMPAR功能的罕见单等位基因GRIA1-4变异可能导致神经发育障碍。对AMPAR功能的影响可能表现为功能获得(GOF)或功能丧失(LOF)。我们招募了9名不相关的患者,他们要么在GRIA3的p.Gly803位点上有已知的致病GOF变异,要么在GRIA2的邻近位点上有变异(p.Gly792)。具体来说,5名患者携带全新的GRIA3变体(p.Gly803Glu或p.Gly803Val), 1名患者携带母系遗传的GRIA3变体(p.Gly803Ala), 3名患者携带全新的GRIA2变体(p.Gly792Arg, p.Gly792Val或p.Gly792Glu),我们证明这也是GOF。复发症状包括影响运动技能和语言能力的发育迟缓;认知障碍;行为和精神合并症;高张力,脑瘫,非癫痫性肌阵挛,和治疗难治性癫痫。我们还提供有关社交技能、自主水平、生活安排和教育程度的见解。我们比较了与两种旁系GOF GRIA2和GRIA3变异相关的临床特征。我们的研究阐明了与这些变异相关的发育方面、认知能力、癫痫发作概况和行为挑战,并有助于提高我们对这种罕见疾病患者的理解和治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Clinical and Neurodevelopmental Characteristics of Paralogous Gain-of-Function Variants at GRIA2 p.Gly792 and GRIA3 p.Gly803.

GRIA-related disorders arise from disease-causing variants in GRIA1, GRIA2, GRIA3, or GRIA4 that encode α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors (AMPARs). Rare monoallelic GRIA1-4 variants affecting AMPAR function can potentially lead to neurodevelopmental disorders. The impact on AMPAR function may manifest as either gain-of-function (GOF) or loss-of-function (LOF). We recruited nine unrelated patients with either known disease-causing GOF variants in GRIA3 at position p.Gly803 or variants at the paralogous position in GRIA2 (p.Gly792). Specifically, five patients carried a de novo GRIA3 variant (p.Gly803Glu or p.Gly803Val), one carried a maternally inherited GRIA3 variant (p.Gly803Ala) and three carried de novo GRIA2 variants (p.Gly792Arg, p.Gly792Val, or p.Gly792Glu) which we demonstrate are also GOF. Recurrent symptoms included developmental delay affecting both motor skills and language abilities; cognitive impairment; behavioral and psychiatric comorbidities; hypertonia, cerebral palsy, non-epileptic myoclonus, and treatment-resistant epilepsy. We also provide insights into social skills, levels of autonomy, living arrangements, and educational attainment. We compared the clinical features associated with the two paralogous GOF GRIA2 and GRIA3 variants. Our study elucidates the developmental aspects, cognitive abilities, seizure profiles, and behavioral challenges associated with these variants and contributes to advancing our understanding and treatment of patients affected by this rare condition.

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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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