SHANK3 and Phelan-McDermid syndrome: In this study we assessed genome-wide DNA methylation profiles in a cohort of individuals with PHMDS, including individuals with large (2 to 5.8 Mb) 22q13.3 deletions, with small deletions (< 1 Mb) or with intragenic variants in SHANK3. Given the molecular and phenotypic complexity of this disease, we hypothesized a differentiating DNA methylation epi-signature that would enable assessment of variants of unknown clinical significance, such as smaller deletions at 22q13 or SHANK3 variants, as well as diagnosis of ambiguous clinical cases.