The p.Ile202Thr Substitution in TUBB2B Can Be Associated with Syndromic Presentation of Congenital Fibrosis of the Extraocular Muscles

<b>Background</b>: Dominantly acting variants in <i>TUBB2B</i> have primarily been associated with cortical dysplasia complex with other brain malformations 7 (CDCBM7), a disorder in which cortical brain abnormalities are typically linked to developmental delay/intellectual disability (DD/ID) and seizures. While the majority of <i>TUBB2B</i> pathogenic variants have been linked to isolated CDCBM7, only one family with CDCBM7 and congenital fibrosis of the extraocular muscles (CFEOM) has been reported so far. We describe a second individual with a severe phenotype of CFEOM combined with CDCBM7 carrying a pathogenic <i>TUBB2B</i> missense variant previously reported in two individuals with isolated CDCBM7. <b>Methods</b>: A trio-based WGS analysis was performed. The structural impact of the identified substitution was assessed by using the UCSF Chimera (v.1.17.3) software and PyMOL docking plugin DockingPie tool. <b>Results</b>: WGS analysis identified a de novo missense <i>TUBB2B</i> variant (p.Ile202Thr, NM_178012.5), previously associated with isolated CDCBM7. Structural analysis and docking simulations revealed that Ile202 contributes to establishing a proper hydrophobic environment required to stabilize GTP/GDP in the β-tubulin pocket. p.Ile202Thr was predicted to disrupt these interactions. <b>Conclusions</b>: Our findings broaden the mutational spectrum of <i>TUBB2B</i>-related CFEOM, targeting a different functional domain of the protein, and further document the occurrence of phenotypic heterogeneity. We also highlight the limitations of exome sequencing in accurately mapping <i>TUBB2B</i> coding exons due to its high sequence homology with <i>TUBB2A</i> and suggest targeted or genome analyses when clinical suspicion is strong.