Multiexon SOX5 Deletion in a Male with Lamb-Shaffer Syndrome

Goel, H. (2024). Multiexon SOX5 Deletion in a Male with Lamb-Shaffer Syndrome  (Version 1) [DataSet]. GestaltMatcher Database.

We report a 13-year-old male presenting with autism spectrum disorder level 3, moderate intellectual disability, severe language impairment, hypotonia, and facial dysmorphism. Additional features included clumsy gait, constipation, joint laxity, strabismus, myopia, nystagmus, obstructive sleep apnoea, and mild pectus excavatum. Genetic testing identified a heterozygous 131 kb deletion of SOX5 spanning exons 7–15 of the canonical transcript (15 exons total). The deletion was not detected on a 60K microarray due to limited probe coverage but was confirmed by orthogonal sequencing methods. Loss-of-function variants in SOX5 are associated with Lamb-Shaffer syndrome, characterised by developmental delay, language impairment, hypotonia, dysmorphic features, and autism. The original Lamb and Shaffer report described two patients with multi-exon SOX5 deletions involving exons 8–15 and 9–15, similar in size to this case. More recent reports have focused on intragenic loss-of-function variants, with few additional multi-exon deletions affecting the terminal exon. This case highlights the phenotypic overlap with Lamb-Shaffer syndrome and underscores the limitations of lower-resolution arrays for detecting sub-200 kb intragenic deletions. It also expands the spectrum of pathogenic SOX5 deletions, providing further evidence for their role in neurodevelopmental disorders.