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Background and Objectives: Clark-Baraitser syndrome is characterized by intellectual disability with or without autism spectrum disorders, speech delay, motor delay, behavioral abnormalities, and facial dysmorphism. It is caused by a heterozygous pathogenic variant in the thyroid hormone receptor interactor 12 ( TRIP12 ) gene. However, loss of function and haploinsufficiency are the pathogenic mechanisms behind the TRIP12 -related disorder., Methods: We conducted an exome sequencing analysis for 2 unrelated patients with moderate intellectual disability, speech delay, and motor delay., Results: We identified 2 de novo TRIP12 mutations in these 2 patients. One patient had a frameshift duplication, whereas the other had a synonymous variant. Both patients presented with common features of the syndrome, but clinical heterogeneity has been also observed between them. For the synonymous variant, reverse transcription PCR in RNA extracted from leukocytes demonstrated the presence of a truncated messenger RNA (mRNA) transcript that skipped exon 12. This transcript escapes degradation at the mRNA level. To assess the effect of the synonymous substitute on TRIP12 proteolytic activity, the expression of 9 known responsive genes at the mRNA level was measured, of which 3 genes were upregulated at least 2-fold in the patient., Discussion: We reported 2 patients with Clark-Baraitser syndrome caused by novel synonymous and frameshift variants in the TRIP12 gene, and our study expands the mutation spectrum of the TRIP12 gene. This study will help to improve our understanding of variable phenotypic presentations in TRIP12 -related disorders., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)