AUTS2 disruption underlies radioulnar synostosis and skeletal dysmorphogenesis: evidence from four unrelated cases

While AUTS2 is recognised as a pivotal neurodevelopmental gene, its role in skeletal morphogenesis has remained unexplored. We investigated the contribution of AUTS2 to radioulnar synostosis (RUS) and associated skeletal dysplasias through integrated molecular and phenotypic analyses of unrelated probands.

Comprehensive genetic profiling was performed on patients with RUS, including G-banding karyotyping, translocation breakpoint mapping via low-coverage whole-genome sequencing with PCR/Sanger validation, CNV detection using SNP array (Infinium OmniZhongHua-8) and qPCR, and exome sequencing followed by orthogonal Sanger confirmation.

Four novel pathogenic AUTS2 variants were identified from four unrelated patients: a balanced translocation [46,XY,t(7;21)(q11.22;q21.1)] disrupting intron 5 (hg19:chr7:71,845,797); a heterozygous 2.99 Mb deletion (hg19:7q11.22[67,488,531-70,480,818]) spanning AUTS2 and flanking loci; and two de novo frameshift insertions (c.47_48insG; c.864_865insGGACTGTTGCAAAGAGCCA). All variants impaired the full-length AUTS2 transcript. Affected individuals exhibited RUS accompanied by additional skeletal anomalies (micrognathia, short stature, dysplasia of hip joint, tight heel cords) and other AUTS2 syndrome features. Notably, phenotypic overlap with Tsukahara syndrome (OMIM 603438) was observed, suggesting potential diagnostic continuity between these entities.

This study establishes AUTS2 as a critical regulator of skeletal development, with molecular disruptions directly linked to RUS pathogenesis and broader skeletal dysmorphogenesis.