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
{"title":"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","authors":"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","doi":"10.1111/cge.14770","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Clinical and Neurodevelopmental Characteristics of Paralogous Gain-of-Function Variants at GRIA2 p.Gly792 and GRIA3 p.Gly803.\",\"authors\":\"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\",\"doi\":\"10.1111/cge.14770\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":10354,\"journal\":{\"name\":\"Clinical Genetics\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2025-05-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/cge.14770\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/cge.14770","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
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.
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