The most common form of PMS is caused by a de novo chromosomal deletion but one of the parents may also be a carrier.

The 22q13.3 deletion syndrome (Phelan-McDermid syndrome) usually results from deletions of 100 kb to 9 Mb involving the distal long arm of chromosome 22. Almost all of these deletions include the SHANK3 gene that encodes a scaffold protein in the postsynaptic densities of excitatory synapses, linking membrane receptors to the actin cytoskeleton. This syndrome is characterized by neurological deficits, which include overall developmental delay, moderate to severe intellectual impairment, severe speech delay or absence, and neonatal hypotonia.