SOX5 is located on chromosome 12p12.1. It encodes multiple protein isoforms, the most abundant of which is 763 amino-acid long. The SOX5 protein belongs to the family of SOX transcription factors. These factors are encoded by 20 different genes in humans. Their common feature is a high-mobility-group (HMG) DNA-binding domain at least 50% similar to that of the family founder, SRY (encoded by the Sex-determining Region on the Y chromosome).
Lamb-Shaffer syndrome was initially described in patients with chromosomal deletions (ranging from a few kb to several Mb) encompassing parts or all exons of SOX5. Later on, heterozygous point variants causing a loss of function were reported to lead to the same clinical syndrome.
Pathogenic point variants include nonsense variants, variants altering consensus splice sites, and small nucleotide insertions or deletions leading to a frameshift. They are found throughout the coding sequence. Missense variants, usually clustered in the highly conserved HMG domain, are also a frequent pathogenic variant class. These missense variants typically abolish the DNA-binding ability of the SOX5 protein and thereby preclude transcriptional activity.
Most pathogenic variants and deletions were found to have occurred de novo in affected individuals. In a few cases, patients inherited the mutation from a parent presenting no or mild signs of the syndrome. Parental mosaicism is relatively frequent in Lamb-Shaffer syndrome (10-15% of families) and has to be taken in account for genetic counselling.
The identification of pathogenic SOX5 variants and diagnosis of Lamb-Shaffer syndrome require sequencing of the SOX5 gene, usually by next-generation sequencing (NGS; i.e., panel testing, exome, or genome). Sanger sequencing is also possible when the syndrome is strongly suspected. If no pathogenic variants are identified, the possibility of microdeletions altering the gene should be considered and tested using either microarrays or copy-number assessment using NGS or genome data. Pathogenicity of novel missense variants may require the use of in silico tools and segregation in additional family members. In some cases, functional studies may be required to build evidence that a detected variant is deleterious. For example, specific assays are available to test the impact of SOX5 variants on the transcriptional activity in vitro and can be used to assess variant pathogenicity. Whether the phenotype of the individual is consistent with Lamb-Schaffer syndrome should also be considered.
SOX5