Indeed, some manifestation frequently observed in PMS, such as renal abnormalities and lymphedema, are not linked to SHANK3 haploinsufficiency, but depend on other 22q13 deleted genes, which play a role in shaping the PMS phenotype in each patient [15, 31, 32], The relevance of other genes in addition to SHANK3 is further underscored by the existence of a phenotype consistent with PMS in individuals carrying interstitial 22q13 deletions that preserve SHANK3, leading to distinguish between PMS-SHANK3 related and PMS-SHANK3 unrelated forms [33]. This evidence concerns the gene SHANK3 and lymphedema.