SAS is caused by alterations of SATB2 that can include single nucleotide variants (loss-of-function as well as missense), intragenic deletions and duplications, contiguous deletions, and translocations with secondary gene disruption. Truncating mutations (nonsense, frameshift, splice site) are responsible for approximately 40% of cases followed by missense (25%), large contiguous deletions (19%), and intragenic exonic deletions (12%).
While haploinsufficiency of SATB2 seems the most likely mechanism of disease, a dominant negative effect has been suggested as a possible explanation in some cases.