22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome

Genet Med. 2014 Apr;16(4):318-28. doi: 10.1038/gim.2013.144. Epub 2013 Oct 17.


Purpose: Phelan-McDermid syndrome is a developmental disability syndrome with varying deletions of 22q13 and varying clinical severity. We tested the hypothesis that, in addition to loss of the telomeric gene SHANK3, specific genomic regions within 22q13 are associated with important clinical features.

Methods: We used a customized oligo array comparative genomic hybridization of 22q12.3-terminus to obtain deletion breakpoints in a cohort of 70 patients with terminal 22q13 deletions. We used association and receiver operating characteristic statistical methods in a novel manner and also incorporated protein interaction networks to identify 22q13 genomic locations and genes associated with clinical features.

Results: Specific genomic regions and candidate genes within 22q13.2q13.32 were associated with severity of speech/language delay, neonatal hypotonia, delayed age at walking, hair-pulling behaviors, male genital anomalies, dysplastic toenails, large/fleshy hands, macrocephaly, short and tall stature, facial asymmetry, and atypical reflexes. We also found regions suggestive of a negative association with autism spectrum disorders.

Conclusion: This work advances the field of research beyond the observation of a correlation between deletion size and phenotype and identifies candidate 22q13 loci, and in some cases specific genes, associated with singular clinical features observed in Phelan-McDermid syndrome. Our statistical approach may be useful in genotype-phenotype analyses for other microdeletion or microduplication syndromes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child Development Disorders, Pervasive / genetics*
  • Child Development Disorders, Pervasive / physiopathology
  • Child, Preschool
  • Chromosome Deletion
  • Chromosome Disorders / epidemiology
  • Chromosome Disorders / genetics*
  • Chromosome Disorders / physiopathology*
  • Chromosomes, Human, Pair 22 / genetics*
  • Comparative Genomic Hybridization
  • Developmental Disabilities / genetics*
  • Developmental Disabilities / physiopathology
  • Female
  • Genetic Association Studies
  • Humans
  • Infant
  • Language Development Disorders / genetics*
  • Language Development Disorders / physiopathology
  • Male
  • Nerve Tissue Proteins / genetics*


  • Nerve Tissue Proteins
  • SHANK3 protein, human

Supplementary concepts

  • Telomeric 22q13 Monosomy Syndrome