P21 Disruption of SPECC1L translation initiation by intragenic deletion: novel pathogenic mechanism in Teebi-Hypertelorism syndrome

Introduction SPECC1L encodes a cytoskeletal-associated protein essential for neural crest cell migration and tissue morphogenesis. SPECC1L pathogenic variants are implicated in variably expressive disorders such as Teebi Hypertelorism Syndrome 1 (TBHS1) and oblique facial clefting. Most TBHS1-associated pathogenic variants cluster in the CCD2 and CHD domains, disrupting interactions with actin filaments and microtubules. Here, we report a novel pathogenic mechanism involving an intragenic deletion that disrupts SPECC1L N-terminal intrinsically disordered region (IDR), sparing the functional domains. Methods An in vitro overexpression assay in HEK293 cells used to assess SPECC1L expression and the deletion functional impact. A literature review was conducted to delineate the variability in SPECC1L-related phenotypes. Results The proband and father had craniofacial dysmorphisms consistent with TBHS1 without congenital anomalies or neurodevelopmental delay. WGS identified a novel heterozygous intragenic SPECC1L exon 3 deletion, encompassing the canonical start codon. Functional assays confirmed translation from a downstream alternative start codon, resulting in stable production of truncated isoforms lacking part of the N-terminal IDR. Conclusion This is the first report of SPECC1L deletion affecting the canonical start codon and N-terminal IDR. The milder phenotype suggests that the N-terminal IDR may affect neural crest development, and its disruption may contribute to developmental defects.