J Med Genet 48:761-766 doi:10.1136/jmedgenet-2011-100225
  • Genotype-phenotype correlations
  • Original article

Association between deletion size and important phenotypes expands the genomic region of interest in Phelan–McDermid syndrome (22q13 deletion syndrome)

  1. Julianne S Collins1,2
  1. 1Greenwood Genetic Center, Greenwood, South Carolina, USA
  2. 2Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, USA
  3. 3Hayward Genetics Center, Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, USA
  1. Correspondence to Sara M Sarasua, Office of Bioinformatics and Epidemiology, Greenwood Genetic Center, 101 Gregor Mendel Circle, Greenwood, South Carolina, 29646, USA; smsaras{at}
  1. Contributors SMS developed the analytic approach, performed statistical analysis, wrote the paper and is guarantor. RCR, KP and BRD designed the study, collected the data and revised the manuscript. RCR performed physical examinations. BRD designed the microarray. AD performed the microarray analyses and revised the manuscript. CFC and JDR assisted with statistical analysis and revised the paper. LB assisted with data collection and coding, assisted with interpretation of results and revised the paper. JSC guided data coding and analysis, guided writing of the paper and revised the paper.

  • Received 27 May 2011
  • Revised 18 August 2011
  • Accepted 6 September 2011
  • Published Online First 7 October 2011


Background The clinical features of Phelan–McDermid syndrome (also known as 22q13 deletion syndrome) are highly variable and include hypotonia, speech and other developmental delays, autistic traits and mildly dysmorphic features. Patient deletion sizes are also highly variable, prompting this genotype–phenotype association study.

Methods Terminal deletion breakpoints were identified for 71 individuals in a patient cohort using a custom-designed high-resolution oligonucleotide array comparative genomic hybridisation platform with a resolution of 100 bp.

Results Patient deletion sizes were highly variable, ranging from 0.22 to 9.22 Mb, and no common breakpoint was observed. SHANK3, the major candidate gene for the neurologic features of the syndrome, was deleted in all cases. Sixteen features (neonatal hypotonia, neonatal hyporeflexia, neonatal feeding problems, speech/language delay, delayed age at crawling, delayed age at walking, severity of developmental delay, male genital anomalies, dysplastic toenails, large or fleshy hands, macrocephaly, tall stature, facial asymmetry, full brow, atypical reflexes and dolichocephaly) were found to be significantly associated with larger deletion sizes, suggesting the role of additional genes or regulatory regions proximal to SHANK3. Individuals with autism spectrum disorders (ASDs) were found to have smaller deletion sizes (median deletion size of 3.39 Mb) than those without ASDs (median deletion size 6.03 Mb, p=0.0144). This may reflect the difficulty in diagnosing ASDs in individuals with severe developmental delay.

Conclusions This genotype–phenotype analysis explains some of the phenotypic variability in the syndrome and identifies new genomic regions with a high likelihood for causing important developmental phenotypes such as speech delay.


  • Funding Support for this study was provided by the Greenwood Genetic Center, the Phelan–McDermid Syndrome Foundation (SMS), the Genetics Endowment of South Carolina, the South Carolina Birth Defects Foundation and the South Carolina Department of Disabilities and Special Needs.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval The study was conducted with the approval of the Institutional Review Board of Self Regional Healthcare (Greenwood, South Carolina).

  • Provenance and peer review Not commissioned; externally peer reviewed.