Genotype-phenotype correlation in Phelan-McDermid syndrome: A comprehensive review of chromosome 22q13 deleted genes

Am J Med Genet A. 2021 Jul;185(7):2211-2233. doi: 10.1002/ajmg.a.62222. Epub 2021 May 5.


Phelan-McDermid syndrome (PMS, OMIM #606232), also known as chromosome 22q13 deletion syndrome, is a rare genetic disorder characterized by intellectual disability, hypotonia, delayed or absent speech, motor impairment, autism spectrum disorder, behavioral anomalies, and minor aspecific dysmorphic features. Haploinsufficiency of SHANK3, due to intragenic deletions or point mutations, is sufficient to cause many neurobehavioral features of PMS. However, several additional genes located within larger 22q13 deletions can contribute to the great interindividual variability observed in the PMS phenotype. This review summarizes the phenotypic contributions predicted for 213 genes distributed along the largest 22q13.2-q13.33 terminal deletion detected in our sample of 63 PMS patients by array-CGH analysis, spanning 9.08 Mb. Genes have been grouped into four categories: (1) genes causing human diseases with an autosomal dominant mechanism, or (2) with an autosomal recessive mechanism; (3) morphogenetically relevant genes, either involved in human diseases with additive co-dominant, polygenic, and/or multifactorial mechanisms, or implicated in animal models but not yet documented in human pathology; (4) protein coding genes either functionally nonrelevant, with unknown function, or pathogenic through mechanisms other than haploinsufficiency; piRNAs, noncoding RNAs, miRNAs, novel transcripts and pseudogenes. Our aim is to understand genotype-phenotype correlations in PMS patients and to provide clinicians with a conceptual framework to promote evidence-based genetic work-ups, clinical assessments, and therapeutic interventions.

Keywords: Phelan-McDermid syndrome; SHANK3; autism; chromosome 22q13.3 deletion syndrome.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Chromosome Deletion
  • Chromosome Disorders / genetics*
  • Chromosome Disorders / pathology
  • Chromosomes, Human, Pair 22 / genetics*
  • Genetic Association Studies*
  • Haploinsufficiency / genetics
  • Humans
  • MicroRNAs / genetics
  • Point Mutation / genetics


  • MicroRNAs

Supplementary concepts

  • Telomeric 22q13 Monosomy Syndrome