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Clinical and genomic evaluation of 201 patients with Phelan–McDermid syndrome

Abstract

This study is the first to describe age-related changes in a large cohort of patients with Phelan–McDermid syndrome (PMS), also known as 22q13 deletion syndrome. Over a follow-up period of up to 12 years, physical examinations and structured interviews were conducted for 201 individuals diagnosed with PMS, 120 patients had a focused, high-resolution 22q12q13 array CGH, and 92 patients’ deletions were assessed for parent-of-origin. 22q13 genomic anomalies include terminal deletions of 22q13 (89 %), terminal deletions and interstitial duplications (9 %), and interstitial deletions (2 %). Considering different age groups, in older patients, behavioral problems tended to subside, developmental abilities improved, and some features such as large or fleshy hands, full or puffy eyelids, hypotonia, lax ligaments, and hyperextensible joints were less frequent. However, the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age. Some neurologic and dysmorphic features such as speech and developmental delay and macrocephaly correlated with deletion size. Deletion sizes in more recently diagnosed patients tend to be smaller than those diagnosed a decade earlier. Seventy-three percent of de novo deletions were of paternal origin. Seizures were reported three times more often among patients with a de novo deletion of the maternal rather than paternal chromosome 22. This analysis improves the understanding of the clinical presentation and natural history of PMS and can serve as a reference for the prevalence of clinical features in the syndrome.

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Acknowledgments

We thank the patients and families who participated in this study and made this work possible and the Phelan–McDermid Syndrome Foundation who organized the biannual family conferences where much of the data collection took place. We thank Gail Stapleton and Cindy Skinner who managed data collection at the family conferences. We thank Dr. Amy Lawton-Rauh and Dr. Charles Schwartz for helpful comments on the manuscript. We dedicate this paper to the memory of Julianne S. Collins.

This work was supported, in part, by a fellowship to SMS from the Phelan–McDermid Syndrome Foundation; the Genetics Endowment of South Carolina; and the South Carolina Department of Disabilities and Special Needs.

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The authors declare no conflict of interest.

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Correspondence to Sara M. Sarasua.

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Sarasua, S.M., Boccuto, L., Sharp, J.L. et al. Clinical and genomic evaluation of 201 patients with Phelan–McDermid syndrome. Hum Genet 133, 847–859 (2014). https://doi.org/10.1007/s00439-014-1423-7

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  • DOI: https://doi.org/10.1007/s00439-014-1423-7

Keywords

  • Autism Spectrum Disorder
  • Precocious Puberty
  • Array Comparative Genomic Hybridization
  • 22q13 Deletion
  • Ring Chromosome