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Autism spectrum disorders are a group of the most common disorders of neuropsychiatric development, characterized by difficulties in social interaction and adherence to stereotypic behavioral patterns. This group of conditions frequently co-occurs with intellectual disability, epilepsy, attention-deficit hyperactivity disorder, connective tissue disorders and others. Among the most common molecular-genetic causes of autism spectrum disorders are pathogenic variants in the CHD8 gene. CHD8 codes for chromodomain-helicase-DNA-binding protein 8 - a chromatin remodeler that regulates cellular proliferation and brain development in embryogenesis. 6 children and 1 adult (mother of 1 of the children) and were found to have clinically significant variants in CHD8 on whole genome sequencing (3 children and 1 adult had likely pathogenic variants, 3 children– variants of unknown significance). Their phenotype consisted of autism spectrum disorders, developmental delay, ataxia, overgrowth and other signs typically observed in patients with pathogenic variants in CHD8, as well as common comorbidities of autism spectrum disorders, such as attention-deficit hyperactivity disorder and connective tissue disorders. Additionally, 4 patients had hepatomegaly and 2– hyperbilirubinemia (1 had both) - clinical features have not been previously associated with pathogenic variants in CHD8. 2 patients also presented with cardiovascular abnormalities, primarily arrythmias and, in 1 case, cardiomyopathy– also uncharacteristic of patients with pathogenic variants in CHD8. Further research is required to determine the mechanisms underlying the abovementioned clinical features, which are likely carried out through complex interactions between CHD8 and other regulatory proteins. [ABSTRACT FROM AUTHOR]

Context: Pathogenic variants in the TBCE gene, encoding tubulin-specific chaperone E crucial for tubulin folding, are linked to three severe neurodevelopmental disorders: Hypoparathyroidism-retardation-dysmorphism (HRD) syndrome, Kenny-Caffey syndrome type 1, and progressive encephalopathy with amyotrophy and optic atrophy., Objective: We identified patients with a novel, milder TBCE-associated phenotype and aimed to characterize it at the clinical and molecular levels., Materials and Methods: We conducted splicing analysis using deep NGS sequencing of RT-PCR products and detected TBCE through Western blotting. Translation efficiency was measured using a luciferase reporter assay. Overexpression experiments were performed in Hela cells with tubulin staining. Immunofluorescence analysis was used for Golgi complex assessment, while microtubule dynamics were studied post-nocodazole treatment. Electron microscopy facilitated ultrastructural studies., Results: We report seven patients with a novel, milder TBCE phenotype, presenting with amyotrophy, testicular failure, and mild intellectual disability, with or without short stature. All patients were homozygous or compound-heterozygous for the NM_003193.5:c.100+1G>A variant, which causes a splicing alteration and early frameshift. However, we found that the mild phenotype arises due to translation from an alternative open reading frame, producing a partially functional protein. Dermal fibroblasts showed reduced Golgi compactness but normal microtubule dynamics. Electron microscopy revealed varying levels of acto-myosin degradation. The c.100+1G>A variant was found to be 10 times more frequent in Slavic samples than in gnomAD, suggesting underdiagnosis of this phenotype., Conclusion: This study uncovers complex molecular mechanisms contributing to the milder phenotype in patients with the c.100+1G>A variant, providing insights into a new TBCE-related disorder., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Autism spectrum disorders are a group of the most common disorders of neuropsychiatric development, characterized by difficulties in social interaction and adherence to stereotypic behavioral patterns. This group of conditions frequently co-occurs with intellectual disability, epilepsy, attention-deficit hyperactivity disorder, connective tissue disorders and others. Among the most common molecular-genetic causes of autism spectrum disorders are pathogenic variants in the CHD8 gene. CHD8 codes for chromodomain-helicase-DNA-binding protein 8 - a chromatin remodeler that regulates cellular proliferation and brain development in embryogenesis. 6 children and 1 adult (mother of 1 of the children) and were found to have clinically significant variants in CHD8 on whole genome sequencing (3 children and 1 adult had likely pathogenic variants, 3 children- variants of unknown significance). Their phenotype consisted of autism spectrum disorders, developmental delay, ataxia, overgrowth and other signs typically observed in patients with pathogenic variants in CHD8, as well as common comorbidities of autism spectrum disorders, such as attention-deficit hyperactivity disorder and connective tissue disorders. Additionally, 4 patients had hepatomegaly and 2- hyperbilirubinemia (1 had both) - clinical features have not been previously associated with pathogenic variants in CHD8. 2 patients also presented with cardiovascular abnormalities, primarily arrythmias and, in 1 case, cardiomyopathy- also uncharacteristic of patients with pathogenic variants in CHD8. Further research is required to determine the mechanisms underlying the abovementioned clinical features, which are likely carried out through complex interactions between CHD8 and other regulatory proteins., Competing Interests: Declarations. Ethics approval and consent to participate: All results described in the article have been obtained during standard diagnostic procedures provided to patients in our clinic. Consent to participate: All patients (patients’ parents) gave written consent for use of their (their children’s) clinical and genomic data for research and publication. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)