SOX5 variants were first reported in relation to autosomal dominant Lamb-Shaffer syndrome in 2012 (Lamb et al., PMID:22290657). SOX5 encodes a SRY-related HMG-box transcription factor involved in the regulation of embryonic development, chondrogenesis, and nervous system development. Lamb-Shaffer syndrome is characterized by developmental delay/intellectual disability, autism spectrum disorder, hypotonia, skeletal defects, dysmorphic facial features including frontal bossing, facial asymmetry, strabismus, depressed nasal bridge, bulbous nasal tip and crowded teeth.
At least 10 unique heterozygous variants (large deletions, translocations, truncating and missense) have been reported in 10 probands in 5 publications (PMIDs:22290657, 29477873, 31578471, 33296143, 234938568) included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Two subjects from Lamb et al (PMID:22290657) and one from Lee et al (PMID:23498568) included in the curation were unable to be entered for scoring due the limitations of the gene curation interface. Details of these subjects are as follows: Lamb et al reported Subject 2, a 4 year old female with a 137 kb de novo intragenic SOX5 deletion and global developmental delay (2 points) and Subject 6, a 4 year old male with a 133 kb intragenic SOX5 deletion and global developmental delay, strabismus, and frontal bossing (1.5 points). These variants were identified via oligonucleotide-based aCGH. Lee et al reported a 32 month-old male with a 53 kb de novo SOX5 deletion identified by chromosomal microarray and intellectual disability, speech delay and frontal bossing (2 points). Inclusion of these three individuals contributed 5.5 points to this curation.
This gene-disease relationship is also supported by experimental evidence. Dy et al (PMID:18543318) generated a conditional null mouse model that demonstrated generalized chrondrodysplasia. The skeletal defects present in this model are similar to those observed in individuals with Lamb-Shaffer syndrome. Due to a lack of a neurodevelopmental phenotype in this model, the score has been downgraded.
In summary, SOX5 is definitively associated with autosomal dominant Lamb-Shaffer syndrome. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on 01/27/2022 (SOP version 8).
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