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Orphanet Journal of Rare Diseases

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Open Access 01-12-2015 | Research

Autism spectrum disorder in Phelan-McDermid syndrome: initial characterization and genotype-phenotype correlations

Authors: Lindsay M. Oberman, Luigi Boccuto, Lauren Cascio, Sara Sarasua, Walter E. Kaufmann

Published in: Orphanet Journal of Rare Diseases | Issue 1/2015

Abstract

Background

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder associated with a terminal deletion affecting chromosome 22 (22q13) that results in the loss of function of the SHANK3 gene. SHANK3 has also been identified in gene-linkage studies to be associated with autism spectrum disorder (ASD). Diagnosis of ASD in individuals with PMS is complicated by the presence of moderate to profound global developmental delay/intellectual disability as well as other co-morbid systemic and neurological symptoms.

Methods

The current study aimed to characterize the symptoms of ASD in patients with PMS and to do a preliminary exploration of genotype-ASD phenotype correlations. We conducted a standardized interview with 40 parents/guardians of children with PMS. Further, we conducted analyses on the relationship between disruption of SHANK3 and adjacent genes on specific characteristic symptoms of ASD in PMS in small subset of the sample.

Results

The majority of PMS participants in our sample displayed persistent deficits in Social communication, but only half met diagnostic criteria under the restricted, repetitive patterns of behavior, interests, or activities domain. Furthermore, logistic regressions indicated that general developmental delay significantly contributed to the ASD diagnosis. The analyses relating the PMS genotype to the behavioral phenotype revealed additional complex relationships with contributions of genes in both deleted and preserved SHANK3 regions to the ASD phenotype and other neurobehavioral impairments.

Conclusions

There appears to be a unique behavioral phenotype associated with ASD in individuals with PMS. There also appears to be contributions of genes in both deleted and preserved SHANK3 regions to the ASD phenotype and other neurobehavioral impairments. Better characterization of the behavioral phenotype using additional standardized assessments and further analyses exploring the relationship between the PMS genotype and behavioral phenotype in a larger sample are warranted.

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Betancur C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 2011;1380:42–77. doi:10.1016/j.brainres.2010.11.078.CrossRefPubMed

Murdoch JD, State MW. Recent developments in the genetics of autism spectrum disorders. Curr Opin Gene Dev. 2013;23(3):310–5. doi:10.1016/j.gde.2013.02.003.CrossRef

Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007;39(1):25–7. doi:10.1038/ng1933.PubMedCentralCrossRefPubMed

Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am J Human Genet. 2007;81(6):1289–97. doi:10.1086/522590.CrossRef

Boccuto L, Lauri M, Sarasua SM, Skinner CD, Buccella D, Dwivedi A, et al. Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders. Eur J Human Genet EJHG. 2013;21(3):310–6. doi:10.1038/ejhg.2012.175.CrossRefPubMed

Sheng M, Kim E. The Shank family of scaffold proteins. J Cell Sci. 2000;113(Pt 11):1851–6.PubMed

Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, et al. Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLoS Genet. 2014;10(9):e1004580. doi:10.1371/journal.pgen.1004580.PubMedCentralCrossRefPubMed

Phelan K, McDermid HE. The 22q13.3 deletion syndrome (phelan-McDermid syndrome). Mol Syndromol. 2012;2(3-5):186–201.PubMedCentralPubMed

Philippe A, Boddaert N, Vaivre-Douret L, Robel L, Danon-Boileau L, Malan V, et al. Neurobehavioral profile and brain imaging study of the 22q13.3 deletion syndrome in childhood. Pediatrics. 2008;122(2):e376–82. doi:10.1542/peds.2007-2584.CrossRefPubMed

10.

Uchino S, Waga C. SHANK3 as an autism spectrum disorder-associated gene. Brain Dev. 2013;35(2):106–10. doi:10.1016/j.braindev.2012.05.013.CrossRefPubMed

11.

Soorya L, Kolevzon A, Zweifach J, Lim T, Dobry Y, Schwartz L, et al. Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Mol Autism. 2013;4(1):18. doi:10.1186/2040-2392-4-18.PubMedCentralCrossRefPubMed

12.

Sarasua SM, Boccuto L, Sharp JL, Dwivedi A, Chen CF, Rollins JD, et al. Clinical and genomic evaluation of 201 patients with phelan-McDermid syndrome. Hum Genet. 2014;133(7):847–59. doi:10.1007/s00439-014-1423-7.CrossRefPubMed

13.

Lord C, Rutter M, Le Couteur A. Autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord. 1994;24(5):659–85.CrossRefPubMed

14.

Sparrow S, Cicchetti D, Balla D. Vineland adaptive behavior scales: second edition (Vineland II), survey interview form/caregiver rating form. Livonia, MN: Pearson Assessments; 2005.

15.

Sarasua SM, Dwivedi A, Boccuto L, Chen CF, Sharp JL, Rollins JD, et al. 22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome. Genet Med Off J Am College Med Genet. 2014;16(4):318–28. doi:10.1038/gim.2013.144.

16.

Sarasua SM, Dwivedi A, Boccuto L, Rollins JD, Chen CF, Rogers RC, et al. Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome). J Med Genet. 2011;48(11):761–6. doi:10.1136/jmedgenet-2011-100225.CrossRefPubMed

17.

Giza J, Urbanski MJ, Prestori F, Bandyopadhyay B, Yam A, Friedrich V, et al. Behavioral and cerebellar transmission deficits in mice lacking the autism-linked gene islet brain-2. J Neurosci Off J Soc Neurosci. 2010;30(44):14805–16. doi:10.1523/JNEUROSCI.1161-10.2010.CrossRef

18.

Swedo SE, Baird G, Cook Jr EH, Happe FG, Harris JC, Kaufmann WE, et al. Commentary from the DSM-5 workgroup on neurodevelopmental disorders. J Am Acad Child Adolesc Psychiatry. 2012;51(4):347–9. doi:10.1016/j.jaac.2012.02.013.CrossRefPubMed

19.

Baird G, Cook E, Happe F, Harris J, Kaufmann W, King B, et al. Neurodevelopmental disorders. In: Merican psychiatric association. Diagnostic and statistical manual of mental disorders-fifth edition (DSM-5). Washington, D.C: American Psychiatric Publishing; 2013.

20.

Carter JC, Capone GT, Gray RM, Cox CS, Kaufmann WE. Autistic-spectrum disorders in Down syndrome: further delineation and distinction from other behavioral abnormalities. Am J Med Genet Part B Neuropsychiatr Genet Off Publ Int Soc Psychiatr Genet. 2007;144B(1):87–94. doi:10.1002/ajmg.b.30407.CrossRef

21.

Kaufmann WE, Cortell R, Kau AS, Bukelis I, Tierney E, Gray RM, et al. Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors. Am J Med Genet Part A. 2004;129A(3):225–34. doi:10.1002/ajmg.a.30229.CrossRefPubMed

22.

Limperopoulos C, Majnemer A, Steinbach CL, Shevell MI. Equivalence reliability of the Vineland adaptive behavior scale between in-person and telephone administration. Physical Occup Ther Pediatr. 2006;26(1-2):115–27.CrossRef

23.

Ward-King J, Cohen IL, Penning H, Holden JJ. Brief report: telephone administration of the autism diagnostic interview--revised: reliability and suitability for use in research. J Autism Dev Disord. 2010;40(10):1285–90. doi:10.1007/s10803-010-0987-x.CrossRefPubMed

24.

Carpentieri S, Morgan SB. Adaptive and intellectual functioning in autistic and nonautistic retarded children. J Autism Dev Disord. 1996;26(6):611–20.CrossRefPubMed

25.

Perry A, Flanagan HE, Dunn Geier J, Freeman NL. Brief report: the Vineland adaptive behavior scales in young children with autism spectrum disorders at different cognitive levels. J Autism Dev Disord. 2009;39(7):1066–78. doi:10.1007/s10803-009-0704-9.CrossRefPubMed

Title: Autism spectrum disorder in Phelan-McDermid syndrome: initial characterization and genotype-phenotype correlations
Authors: Lindsay M. Oberman
Luigi Boccuto
Lauren Cascio
Sara Sarasua
Walter E. Kaufmann
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Orphanet Journal of Rare Diseases / Issue 1/2015
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-015-0323-9

At a glance: The STEP trials

Springer Medicine

Autism spectrum disorder in Phelan-McDermid syndrome: initial characterization and genotype-phenotype correlations

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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