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Case Report: A Novel De Novo Missense Mutation of the GRIA2 Gene in a Chinese Case of Neurodevelopmental Disorder With Language Impairment.

ABSTRACT: Introduction: Neurodevelopmental disorders with language impairment and behavioral abnormalities (NEDLIB) are a disease caused by heterozygous variants in the glutamate ionotropic receptor AMPA type subunit 2 (GRIA2) gene, which manifest as impaired mental development or developmental delay, behavioral abnormalities including autistic characteristics, and language disorders. Currently, only a few mutations in the GRIA2 gene have been discovered. Methods: A GRIA2 variation was detected in a patient by whole-exome sequencing, and the site was validated by Sanger sequencing from the family. Results: We report a Chinese case of NEDLIB in a girl with language impairment and developmental delay through whole-exome sequencing (WES). Genetic analysis showed that there was a de novo missense mutation, c.1934T > G (p.Leu645Arg), in the GRIA2 gene (NM_001083619.1), which has never been reported before. Conclusion: Our case shows the potential diagnostic role of WES in NEDLIB, expands the GRIA2 gene mutation spectrum, and further deepens the understanding of NEDLIB. Deepening the study of the genetic and clinical heterogeneity, treatment, and prognosis of the disease is still our future challenge and focus.

SUBMITTER: Zhou B

PROVIDER: S-EPMC8655903 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Histone deacetylase 3 (HDAC3) is a crucial epigenetic modulator essential for various developmental and physiological functions. Although its dysfunction is increasingly recognized in abnormal phenotypes, to our knowledge, there have been no established reports of human diseases directly linked to HDAC3 dysfunction. Using trio exome sequencing and extensive phenotypic analysis, we correlated heterozygous de novo variants in HDAC3 with a neurodevelopmental disorder having variable clinical presentations, frequently associated with intellectual disability, developmental delay, epilepsy, and musculoskeletal abnormalities. In a cohort of six individuals, we identified missense variants in HDAC3 (c.277G>A [p.Asp93Asn], c.328G>A [p.Ala110Thr], c.601C>T [p.Pro201Ser], c. 797T>C [p.Leu266Ser], c.799G>A [p.Gly267Ser], and c.1075C>T [p.Arg359Cys]), all located in evolutionarily conserved sites and confirmed as de novo. Experimental studies identified defective deacetylation activity in the p.Asp93Asn, p.Pro201Ser, p.Leu266Ser, and p.Gly267Ser variants, positioned near the enzymatic pocket. In addition, proteomic analysis employing co-immunoprecipitation revealed that the disrupted interactions with molecules involved in the CoREST and NCoR complexes, particularly in the p.Ala110Thr variant, consist of a central pathogenic mechanism. Moreover, immunofluorescence analysis showed diminished nuclear to cytoplasmic fluorescence ratio in the p.Ala110Thr, p.Gly267Ser, and p.Arg359Cys variants, indicating impaired nuclear localization. Taken together, our study highlights that de novo missense variants in HDAC3 are associated with a broad spectrum of neurodevelopmental disorders, which emphasizes the complex role of HDAC3 in histone deacetylase activity, multi-protein complex interactions, and nuclear localization for proper physiological functions. These insights open new avenues for understanding the molecular mechanisms of HDAC3-related disorders and may inform future therapeutic strategies.

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Case Report: A Novel De Novo Missense Mutation of the GRIA2 Gene in a Chinese Case of Neurodevelopmental Disorder With Language Impairment.

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