SOX5 is a gene located on chromosome 12 that encodes a protein involved in the development of the brain and other organs.
Patients with Lamb-Shaffer syndrome may either have a deletion encompassing the whole gene or parts of the gene, or have point variants that lead to loss of function of the SOX5 protein. These include variants that create stop codons, alter the correct processing (splicing) of the SOX5 RNA, or modify functionally important residues of the SOX5 protein.
These point variants or deletions mainly occur de novo, i.e., are present in the affected patient, but not in their parents. Pathogenic variants and deletions in SOX5 are dominant: one allele with a pathogenic variant /deletion (heterozygous variant) is sufficient to cause Lamb-Shaffer syndrome. Boys and girls are equally affected. Parents carrying a pathogenic SOX5 variant and presenting with a mild form of the disease have been reported to have transmitted the variant to children who presented with a typical form of the disease.
The identification of SOX5 mutations requires sequencing of the SOX5 gene, usually by next-generation sequencing (NGS; i.e., panel testing, exome, or genome). NGS allows to test hundreds or thousands of genes possibly involved in a specific condition (e.g., intellectual disability) or all genes of a genome at the same time. Deletions may be more challenging to identify and require additional genetic analyses such as microarrays or specific analysis of NGS data. Genetic testing of the mutation in parents or other unaffected individuals of the family may be required in some cases to conclude whether the variant may be pathogenic.
SOX5