SHANK3 haploinsufficiency: a “common” but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders

  • Catalina Betancur1, 2, 3Email author and

    Affiliated with

    • Joseph D Buxbaum4

      Affiliated with

      Molecular Autism20134:17

      DOI: 10.1186/2040-2392-4-17

      Received: 24 May 2013

      Accepted: 29 May 2013

      Published: 11 June 2013


      Autism spectrum disorders (ASD) are etiologically heterogeneous, with hundreds of rare, highly penetrant mutations and genomic imbalances involved, each contributing to a very small fraction of cases. In this issue of Molecular Autism, Soorya and colleagues evaluated 32 patients with Phelan-McDermid syndrome, caused by either deletion of 22q13.33 or SHANK3 mutations, using gold-standard diagnostic assessments and showed that 84% met criteria for ASD, including 75% meeting criteria for autism. This study and prior studies demonstrate that this syndrome appears to be one of the more penetrant causes of ASD. In this companion review, we show that in samples ascertained for ASD, SHANK3 haploinsufficiency is one of the more prevalent monogenic causes of ASD, explaining at least 0.5% of cases. We note that SHANK3 haploinsufficiency remains underdiagnosed in ASD and developmental delay, although with the increasingly widespread use of chromosomal microarray analysis and targeted sequencing of SHANK3, the number of cases is bound to rise.



      Autism spectrum disorders

      Autism spectrum disorders (ASD) are highly genetic disorders, and current estimates indicate that there could be over 1,000 genes that contribute to ASD risk [1]. Very few genes are therefore likely to contribute to more than 1% of ASD, and mutations of FMR1 (the gene disrupted in Fragile X syndrome) and MECP2 (the gene disrupted in Rett syndrome), considered among the most common causes of ASD, explain 2% and 0.5% of ASD, respectively. Here we show that loss of a functional copy of SHANK3 is among the more prevalent rare causes of ASD.

      SHANK3 codes for a scaffolding protein that lies at the core of the postsynaptic density in glutamatergic synapses. 22q13.3 deletions and mutations that lead to a loss of a functional copy of SHANK3 cause Phelan-McDermid syndrome, characterized by moderate to profound intellectual disability, severely delayed or absent speech, hypotonia, and ASD or ASD traits [2, 3]. Dysmorphic features are usually mild and include dysplastic nails, large or prominent ears, long eyelashes, wide nasal bridge, bulbous nose and sacral dimple. Decreased perspiration, mouthing or chewing non-food items, and decreased perception of pain are frequently noted. Other features include seizures, brain, renal and cardiac malformations, motor deficits, gastroesophageal reflux, lymphedema, and immune defects. Because of its nonspecific clinical presentation, the diagnosis requires molecular genetic testing to identify SHANK3 deletions (the preferred method being chromosome microarray analysis) or mutations.

      In this issue, Soorya and colleagues evaluated ASD in a sample of 32 patients with SHANK3 haploinsufficiency using standard diagnostic tests — the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule — and showed that 84% (27/32) met criteria for ASD, including 75% (24/32) meeting criteria for autism. These findings indicate that Phelan-McDermid syndrome is one of the more highly penetrant causes of autism [4].

      We can get a reasonably accurate estimate of the frequency of SHANK3 deletions and mutations in ASD through the review of recent studies in ASD that made use of either chromosome microarray or targeted resequencing of SHANK3. A survey of all relevant studies, including negative studies, indicates that at least 0.5% of subjects with ASD have haploinsufficiency at the SHANK3 locus. Table 1 shows 14 genome-wide microrray studies in ASD that would reliably detect larger dosage imbalance at SHANK3. These studies included 7,887 affected individuals, and collectively identified 13 deletions (0.16%). This frequency is likely underestimated because, in many of these studies, efforts were made at the recruiting sites to exclude cases with severe intellectual disability or syndromic autism (that is, those with dysmorphic features or other congenital anomalies). In addition, many of the patient samples had been prescreened for cytogenetic abnormalities and microdeletion/microduplication syndromes. Furthermore, although we tried to exclude studies that had clearly overlapping samples, there are probable sample overlaps among the remaining studies (overlapping ASD cases without a deletion would lead to apparently decreased rates of the deletion). Moreover, because Phelan-McDermid syndrome is a mostly sporadic disorder (the deletion is de novo in 80% of cases, while in 20% it results from familial balanced translocations or other chromosome rearrangements), screening ASD samples with an overrepresentation of multiplex families will necessarily result in a lower yield. Finally, it should be noted that most of the microarray analyses reviewed here would have missed small deletions involving only SHANK3.
      Table 1

      22q13.3 deletions involving SHANK3 identified through microarray analyses in autism spectrum disorder samples



      22q13.3 deletions

      Sebat et al.[5]


      1 de novo

      Moessner et al. [6]


      2 de novoa

      Weiss et al. [7]

      299 b


      van der Zwaag et al.[8]



      Guilmatre et al.[9]


      2 de novo

      Qiao et al.[10]



      Schaefer et al.[11]



      Pinto et al.[12] + Autism Genome Project (manuscript in preparation)


      3 de novoc

      Shen et al.[13]



      Rosenfeld et al.[14]


      4 (2 de novo, 2 unknown)

      Bremer et al.[15]


      1 de novo

      Sanders et al.[16]



      Wisniowiecka-Kowalnik et al.[17]



      Girirajan et al.[18]





      13 (0.16%)

      a Family 3524, with two affected siblings with an apparent de novo SHANK3 deletion, was part of another cohort and was thus not included here. In addition, this family’s deletion was previously reported in Sebat et al. [5].

      b 299 patients from deCODE (Iceland); subjects from AGRE and Boston Children’s Hospital overlap other studies and were not included here.

      c One family (2072) was already reported in Sebat et al. [5] (89-3524-100) and Moessner et al. [6] (3524), and was not included here.

      There have been five studies in ASD that have examined SHANK3 for mutations, using targeted resequencing (Table 2 and Figure 1). These studies identified five de novo deleterious mutations in 1,614 subjects with ASD (0.31%). The combined rate of deletions and mutations in ASD is therefore 0.5%, making haploinsufficiency at the SHANK3 locus one of the more common monogenic causes of ASD. Studies in intellectual disability and developmental delay confirm this rate of SHANK3 haploinsufficiency in these disorders as well [1921].
      Table 2

      De novo SHANK3 mutations identified through large-scale screening of autism spectrum disorder samples







      Durand et al. [2]





      exon 21

      Moessner et al.[6]





      exon 8

      Gauthier et al. [22]




      (splice site deletion)

      intron 19

      Schaaf et al. [23]




      Boccuto et al. [24]





      exon 4



      exon 21



      5 (0.31%)


      a Genomic locations are based on GRCh37 (hg 19). bSHANK3 reference sequence NM_033517.1 (mRNA) and NP_277052.1 (protein).
      Figure 1

      De novo SHANK3 mutations identified through large-scale surveys in autism spectrum disorders. See Table 2 for references.

      In conclusion, recent studies of patients with ASD indicate that SHANK3 haploinsufficiency is found in approximately 0.5% of individuals with ASD. In addition, Soorya and colleagues and prior publications indicate that a very high proportion of individuals with SHANK3 haploinsufficiency have ASD.

      Chromosome microarray analysis is still not routinely carried out for individuals with unexplained developmental delay or ASD, in spite of recommendations from several expert societies. In addition, SHANK3 is one of the most GC-rich genes in the genome, and targeted resequencing requires considerable optimization to reliably sequence this gene. As a result, few clinical laboratories screen SHANK3 routinely. Furthermore, whole exome sequencing does a very poor job of adequately covering SHANK3 because of the GC content. Thus, both clinical and research studies will need to continue to use chromosome microarray analyses and Sanger methods to query this important gene, until better whole-exome or whole-genome sequencing protocols are developed. For all these reasons, Phelan-McDermid syndrome remains undiagnosed in many individuals, denying them and their families any benefits that derive from an etiological diagnosis. As Phelan-McDermid syndrome continues to be studied we will understand more about this disorder, including natural history and therapies that are most beneficial for this group of individuals.



      We thank the families affected by Phelan-McDermid syndrome for their participation in our respective research studies and for their ongoing support.

      Authors’ Affiliations

      INSERM U952
      CNRS UMR 7224
      Université Pierre et Marie Curie
      Seaver Autism Center for Research and Treatment, Departments of Psychiatry, Neuroscience, and Genetics and Genomic Sciences,, Friedman Brain Institute, and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai


      1. Betancur C: Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 2011, 1380: 42-77.View ArticlePubMed
      2. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsater H: Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007, 39 (1): 25-27. 10.1038/ng1933.PubMed CentralView ArticlePubMed
      3. Phelan K, McDermid HE: The 22q13.3 deletion syndrome (Phelan-McDermid syndrome). Mol Syndromol. 2012, 2 (3–5): 186-201.PubMed CentralPubMed
      4. Betancur C, Coleman M: Etiological heterogeneity in autism spectrum disorders: role of rare variants. The Neuroscience of Autism Spectrum Disorders. Edited by: Buxbaum JD, Hof PR. 2013, Oxford: Academic, 113-144.View Article
      5. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J: Strong association of de novo copy number mutations with autism. Science. 2007, 316 (5823): 445-449. 10.1126/science.1138659.PubMed CentralView ArticlePubMed
      6. Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, Zwaigenbaum L, Fernandez B, Roberts W, Szatmari P: Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet. 2007, 81 (6): 1289-1297. 10.1086/522590.PubMed CentralView ArticlePubMed
      7. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MA, Green T: Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. 2008, 358 (7): 667-675. 10.1056/NEJMoa075974.View ArticlePubMed
      8. van der Zwaag B, Franke L, Poot M, Hochstenbach R, Spierenburg HA, Vorstman JA, van Daalen E, de Jonge MV, Verbeek NE, Brilstra EH: Gene-network analysis identifies susceptibility genes related to glycobiology in autism. PLoS One. 2009, 4 (5): e5324-10.1371/journal.pone.0005324.PubMed CentralView ArticlePubMed
      9. Guilmatre A, Dubourg C, Mosca AL, Legallic S, Goldenberg A, Drouin-Garraud V, Layet V, Rosier A, Briault S, Bonnet-Brilhault F: Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Arch Gen Psychiatry. 2009, 66 (9): 947-956. 10.1001/archgenpsychiatry.2009.80.PubMed CentralView ArticlePubMed
      10. Qiao Y, Riendeau N, Koochek M, Liu X, Harvard C, Hildebrand MJ, Holden JJ, Rajcan-Separovic E, Lewis ME: Phenomic determinants of genomic variation in autism spectrum disorders. J Med Genet. 2009, 46 (10): 680-688. 10.1136/jmg.2009.066795.View ArticlePubMed
      11. Schaefer GB, Starr L, Pickering D, Skar G, Dehaai K, Sanger WG: Array comparative genomic hybridization findings in a cohort referred for an autism evaluation. J Child Neurol. 2010, 25 (12): 1498-1503. 10.1177/0883073810370479.View ArticlePubMed
      12. Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS: Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010, 466 (7304): 368-372. 10.1038/nature09146.PubMed CentralView ArticlePubMed
      13. Shen Y, Dies KA, Holm IA, Bridgemohan C, Sobeih MM, Caronna EB, Miller KJ, Frazier JA, Silverstein I, Picker J: Clinical genetic testing for patients with autism spectrum disorders. Pediatrics. 2010, 125 (4): e727-e735. 10.1542/peds.2009-1684.PubMed CentralView ArticlePubMed
      14. Rosenfeld JA, Ballif BC, Torchia BS, Sahoo T, Ravnan JB, Schultz R, Lamb A, Bejjani BA, Shaffer LG: Copy number variations associated with autism spectrum disorders contribute to a spectrum of neurodevelopmental disorders. Genet Med. 2010, 12: 694-702. 10.1097/GIM.0b013e3181f0c5f3.View ArticlePubMed
      15. Bremer A, Giacobini M, Eriksson M, Gustavsson P, Nordin V, Fernell E, Gillberg C, Nordgren A, Uppstromer A, Anderlid BM: Copy number variation characteristics in subpopulations of patients with autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet. 2011, 156 (2): 115-124. 10.1002/ajmg.b.31142.View ArticlePubMed
      16. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA: Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011, 70 (5): 863-885. 10.1016/j.neuron.2011.05.002.PubMed CentralView ArticlePubMed
      17. Wisniowiecka-Kowalnik B, Kastory-Bronowska M, Bartnik M, Derwinska K, Dymczak-Domini W, Szumbarska D, Ziemka E, Szczaluba K, Sykulski M, Gambin T: Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders. Eur J Hum Genet. 2013, 21 (6): 620-625. 10.1038/ejhg.2012.219.PubMed CentralView ArticlePubMed
      18. Girirajan S, Johnson RL, Tassone F, Balciuniene J, Katiyar N, Fox K, Baker C, Srikanth A, Yeoh KH, Khoo SJ: Global increases in both common and rare copy number load associated with autism. Hum Mol Genet. 2013, 10.1093/hmg/ddt136. advance online publication,
      19. Hamdan FF, Gauthier J, Araki Y, Lin DT, Yoshizawa Y, Higashi K, Park AR, Spiegelman D, Dobrzeniecka S, Piton A: Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet. 2011, 88 (3): 306-316. 10.1016/j.ajhg.2011.02.001.PubMed CentralView ArticlePubMed
      20. Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, Williams C, Stalker H, Hamid R, Hannig V: A copy number variation morbidity map of developmental delay. Nat Genet. 2011, 43 (9): 838-846. 10.1038/ng.909.PubMed CentralView ArticlePubMed
      21. Gong X, Jiang YW, Zhang X, An Y, Zhang J, Wu Y, Wang J, Sun Y, Liu Y, Gao X: High proportion of 22q13 deletions and SHANK3 mutations in Chinese patients with intellectual disability. PLoS One. 2012, 7 (4): e34739-10.1371/journal.pone.0034739.PubMed CentralView ArticlePubMed
      22. Gauthier J, Spiegelman D, Piton A, Lafreniere RG, Laurent S, St-Onge J, Lapointe L, Hamdan FF, Cossette P, Mottron L: Novel de novo SHANK3 mutation in autistic patients. Am J Med Genet B Neuropsychiatr Genet. 2009, 150B (3): 421-424. 10.1002/ajmg.b.30822.View ArticlePubMed
      23. Schaaf CP, Sabo A, Sakai Y, Crosby J, Muzny D, Hawes A, Lewis L, Akbar H, Varghese R, Boerwinkle E: Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders. Hum Mol Genet. 2011, 20 (17): 3366-3375. 10.1093/hmg/ddr243.PubMed CentralView ArticlePubMed
      24. Boccuto L, Lauri M, Sarasua SM, Skinner CD, Buccella D, Dwivedi A, Orteschi D, Collins JS, Zollino M, Visconti P: Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders. Eur J Hum Genet. 2013, 21 (3): 310-316. 10.1038/ejhg.2012.175.PubMed CentralView ArticlePubMed

      This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.