Phelan-McDermid syndrome or 22q13.3 deletion syndrome is a rare neurodevelopmental disorder characterized by generalized developmental delay, intellectual disability, absent or delayed speech, seizures, autism spectrum disorder, neonatal hypotonia, physical dysmorphic features, and recurrent medical comorbidities. Individuals with Phelan-McDermid syndrome have terminal deletions of the chromosomal region 22q13.3 encompassing SHANK3, a gene encoding a structural component of excitatory synapses indispensable for proper synaptogenesis and neuronal physiology, or point mutations within the gene. Here, we review the clinical aspects of the syndrome and the genetic findings shedding light onto the underlying etiology. We also provide an overview on the evidence from genetic studies and mouse models that supports SHANK3 haploinsufficiency as a major contributor of the neurobehavioral manifestations of Phelan-McDermid syndrome. Finally, we discuss how all these discoveries are uncovering the pathophysiology of Phelan-McDermid syndrome and are being translated into clinical trials for novel therapeutics ameliorating the core symptoms of the disorder.
WattJLOlsonIAJohnstonAWRossHSCouzinDAStephenGS. A familial pericentric inversion of chromosome 22 with a recombinant subject illustrating a “pure” partial monosomy syndrome. J Med Genet. 1985;22:283–287.
2.
NesslingerNJGorskiJLKurczynskiTW. Clinical, cytogenetic, and molecular characterization of seven patients with deletions of chromosome 22q13.3. Am J Hum Genet. 1994;54:464–472.
3.
PhelanKMcDermidHE. The 22q13.3 Deletion syndrome (Phelan-McDermid syndrome). Mol Syndromol. 2012;2:186–201.
4.
SarasuaSMBoccutoLSharpJL. Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome. Hum Genet. 2014;133:847–859.
5.
SooryaLKolevzonAZweifachJ. Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Mole Autism. 2013;4:18.
6.
LucianiJJde MasPDepetrisD. Telomeric 22q13 deletions resulting from rings, simple deletions, and translocations: cytogenetic, molecular, and clinical analyses of 32 new observations. J Med Genet. 2003;40:690–696.
7.
SarasuaSMDwivediABoccutoL. Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome). J Med Genet. 2011;48:761–766.
8.
BetancurCBuxbaumJD. SHANK3 haploinsufficiency: a “common” but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders. Mole Autism. 2013;4:17.
9.
PhilippeABoddaertNVaivre-DouretL. Neurobehavioral profile and brain imaging study of the 22q13.3 deletion syndrome in childhood. Pediatrics. 2008;122:e376–e382.
10.
DharSUdel GaudioDGermanJR. 22q13.3 deletion syndrome: clinical and molecular analysis using array CGH. Am J Med Genet. 2011;152A:573–581.
11.
AldingerKAKoganJKimonisV. Cerebellar and posterior fossa malformations in patients with autism-associated chromosome 22q13 terminal deletion. Am J Med Genet. 2013;161A:131–136.
12.
VerhoevenWMEggerJIWillemsenMHde LeijerGJKleefstraT. Phelan-McDermid syndrome in two adult brothers: atypical bipolar disorder as its psychopathological phenotype?Neuropsychiatr Dis Treat. 2012;8:175–179.
13.
DenayerAVan EschHde RavelT. Neuropsychopathology in 7 patients with the 22q13 deletion syndrome: presence of bipolar disorder and progressive loss of skills. Mol Syndromol. 2012;3:14–20.
14.
VucurovicKLandaisEDelahaigueC. Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion. Eur J Med Genet. 2012;55:625–629.
15.
DurandCMBetancurCBoeckersTM. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007;39:25–27.
16.
BonagliaMCGiordaRBeriS. Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome. PLoS Genet. 2011;7:e1002173.
17.
WillemsenMHRensenJHvan Schrojenstein-Lantman de ValkHMHamelBCKleefstraT. Adult phenotypes in Angelman- and Rett-like syndromes. Mol Syndromol. 2012;2:217–234.
18.
JeffriesARCurranSElmslieF. Molecular and phenotypic characterization of ring chromosome 22. Am J Med Genet. 2005;137:139–147.
19.
DharSUdel GaudioDGermanJR. 22q13.3 deletion syndrome: clinical and molecular analysis using array CGH. Am J Med Genet. 2010;152A:573–581.
20.
WilsonHLWongACShawSR. Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J Med Genet. 2003;40:575–584.
21.
BonagliaMCGiordaRBeriS. Mosaic 22q13 deletions: evidence for concurrent mosaic segmental isodisomy and gene conversion. Eur J Hum Genet. 2009;17:426–433.
22.
BoccutoLLauriMSarasuaSM. Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders. Eur J Hum Genet. 2013;21:310–316.
23.
MoessnerRMarshallCRSutcliffeJS. Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet. 2007;81:1289–1297.
24.
GauthierJSpiegelmanDPitonA. Novel de novo SHANK3 mutation in autistic patients. Am J Med Genet. 2009;150B:421–424.
25.
LeblondCSNavaCPolgeA. Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLoS Genet. 2014;10:e1004580.
26.
De RubeisSHeXGoldbergAP. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515:209–215.
27.
BonagliaMCGiordaRBorgattiR. Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome. Am J Hum Genet. 2001;69:261–268.
28.
SebatJLakshmiBMalhotraD. Strong association of de novo copy number mutations with autism. Science. 2007;316:445–449.
29.
GuilmatreADubourgCMoscaAL. Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Arch Gen Psychiatry. 2009;66:947–956.
30.
PintoDPagnamentaATKleiL. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466:368–372.
31.
PintoDDelabyEMericoD. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet. 2014;94:677–694.
32.
RosenfeldJABallifBCTorchiaBS. Copy number variations associated with autism spectrum disorders contribute to a spectrum of neurodevelopmental disorders. Genet Med. 2010;12:694–702.
33.
BremerAGiacobiniMErikssonM. Copy number variation characteristics in subpopulations of patients with autism spectrum disorders. Am J Med Genet. 2011;156:115–124.
34.
MarshallCRNoorAVincentJB. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82:477–488.
35.
PoultneyCSGoldbergAPDrapeauE. Identification of small exonic CNV from whole-exome sequence data and application to autism spectrum disorder. Am J Hum Genet. 2013;93:607–619.
36.
SarasuaSMDwivediABoccutoL. 22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome. Genet Med. 2014;16:318–328.
37.
BonagliaMCGiordaRManiE. Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome. J Med Genet. 2006;43:822–828.
38.
DelahayeAToutainAAbouraA. Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3. Eur J Med Genet. 2009;52:328–332.
39.
WilsonHLCrollaJAWalkerD. Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development. Eur J Hum Genet. 2008;16:1301–1310.
40.
DisciglioVLo RizzoCMencarelliMA. Interstitial 22q13 deletions not involving SHANK3 gene: a new contiguous gene syndrome. Am J Med Genet. 2014;164A:1666–1676.
41.
KrummNO’RoakBJShendureJEichlerEE. A de novo convergence of autism genetics and molecular neuroscience. Trends Neurosci. 2014;37:95–105.
42.
BozdagiOSakuraiTPapapetrouD. Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol Autism. 2010;1:15.
43.
YangMBozdagiOScattoniML. Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice. J Neurosci. 2012;32:6525–6541.
44.
WangXMcCoyPARodriguizRM. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum Mol Genet. 2011;20:3093–3108.
45.
KouserMSpeedHEDeweyCM. Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission. J Neurosci. 2013;33:18448–18468.
46.
DrapeauEDorrNPElderGABuxbaumJD. Absence of strong strain effects in behavioral analyses of Shank3-deficient mice. Dis Model Mech. 2014;7:667–681.
47.
ShcheglovitovAShcheglovitovaOYazawaM. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature. 2013;503:267–271.
48.
FaillaPRomanoCAlbertiA. Schizophrenia in a patient with subtelomeric duplication of chromosome 22q. Clin Genet. 2007;71:599–601.
GauthierJChampagneNLafreniereRG. De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Proc Natl Acad Sci U S A. 2010;107:7863–7868.
51.
GongXJiangYWZhangX. High proportion of 22q13 deletions and SHANK3 mutations in Chinese patients with intellectual disability. PLoS One. 2012;7:e34739.
52.
HamdanFFGauthierJArakiY. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet. 2011;88:306–316.
53.
LeblondCSHeinrichJDelormeR. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genet. 2012;8:e1002521.
54.
SatoDLionelACLeblondCS. SHANK1 deletions in males with autism spectrum disorder. Am J Hum Genet. 2012;90:879–887.
55.
BerkelSMarshallCRWeissB. Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nat Genet. 2010;42:489–491.
56.
BoeckersTMWinterCSmallaKH. Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family. Biochem Biophys Res Commun. 1999;264:247–252.
57.
DuYWeedSAXiongWCMarshallTDParsonsJT. Identification of a novel cortactin SH3 domain-binding protein and its localization to growth cones of cultured neurons. Mol Cellular Biol. 1998;18:5838–5851.
58.
ZitzerHRichterDKreienkampHJ. Agonist-dependent interaction of the rat somatostatin receptor subtype 2 with cortactin-binding protein 1. J Biol Chem. 1999;274:18153–18156.
59.
YaoIHataYHiraoK. Synamon, a novel neuronal protein interacting with synapse-associated protein 90/postsynaptic density-95-associated protein. J Biol Chem. 1999;274:27463–27466.
60.
ShengMKimE. The postsynaptic organization of synapses. Cold Spring Harbor Perspect Biol. 2011;3.
61.
SugiyamaYKawabataISobueKOkabeS. Determination of absolute protein numbers in single synapses by a GFP-based calibration technique. Nat Methods. 2005;2:677–684.
62.
LimSNaisbittSYoonJ. Characterization of the Shank family of synaptic proteins. Multiple genes, alternative splicing, and differential expression in brain and development. J Biol Chem. 1999;274:29510–29518.
63.
WangXXuQBeyALLeeYJiangYH. Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice. Mol Autism. 2014;5:30.
ShengMKimE. The Shank family of scaffold proteins. J Cell Sci. 2000;113(Pt 11):1851–1856.
66.
BeriSTonnaNMenozziGBonagliaMCSalaCGiordaR. DNA methylation regulates tissue-specific expression of Shank3. J Neurochem. 2007;101:1380–1391.
67.
ChingTTMaunakeaAKJunP. Epigenome analyses using BAC microarrays identify evolutionary conservation of tissue-specific methylation of SHANK3. Nat Genet. 2005;37:645–651.
68.
MaunakeaAKNagarajanRPBilenkyM. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature. 2010;466:253–257.
69.
KreienkampHJ. Scaffolding proteins at the postsynaptic density: shank as the architectural framework. Handb Exp Pharmacol. 2008:365–380.
70.
BaronMKBoeckersTMVaidaB. An architectural framework that may lie at the core of the postsynaptic density. Science. 2006;311:531–535.
71.
GrabruckerAMKnightMJProepperC. Concerted action of zinc and ProSAP/Shank in synaptogenesis and synapse maturation. EMBO J. 2011;30:569–581.
72.
GundelfingerEDBoeckersTMBaronMKBowieJU. A role for zinc in postsynaptic density asSAMbly and plasticity?Trends Biochem Sci. 2006;31:366–373.
73.
NaisbittSKimETuJC. Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron. 1999;23:569–582.
74.
BoeckersTMBockmannJKreutzMRGundelfingerED. ProSAP/Shank proteins—a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease. J Neurochem. 2002;81:903–910.
75.
SalaCPiechVWilsonNRPassafaroMLiuGShengM. Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron. 2001;31:115–130.
76.
HungAYFutaiKSalaC. Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. J Neurosci. 2008;28:1697–1708.
77.
RoussignolGAngoFRomoriniS. Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons. J Neurosci. 2005;25:3560–3570.
78.
AronsMHThynneCJGrabruckerAM. Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling. J Neurosci. 2012;32:14966–14978.
79.
DurandCMPerroyJLollF. SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism. Mol Psychiatry. 2012;17:71–84.
80.
SalaCRoussignolGMeldolesiJFagniL. Key role of the postsynaptic density scaffold proteins Shank and Homer in the functional architecture of Ca2+ homeostasis at dendritic spines in hippocampal neurons. J Neurosci. 2005;25:4587–4592.
81.
MamezaMGDvoretskovaEBamannM. SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region. J Biol Chem. 2013;288:26697–26708.
82.
CochoyDMKolevzonAKajiwaraY. Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID. Mol Autism. 2015;6:23.
83.
SilvermanJLTurnerSMBarkanCL. Sociability and motor functions in Shank1 mutant mice. Brain Res. Mar 22 2011;1380:120–137.
84.
WohrMRoulletFIHungAYShengMCrawleyJN. Communication impairments in mice lacking Shank1: reduced levels of ultrasonic vocalizations and scent marking behavior. PLoS One. 2011;6(6):e20631.
85.
SungurAOVorckelKJSchwartingRKWohrM. Repetitive behaviors in the Shank1 knockout mouse model for autism spectrum disorder: developmental aspects and effects of social context. J Neurosci Methods. 2014;234:92–100.
86.
BerkelSTangWTrevinoM. Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology. Hum. Mol. Genet. 1152012;21(2):344–357.
87.
WonHLeeHRGeeHY. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature. 2012;486:261–265.
88.
SchmeisserMJEyEWegenerS. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature. 2012;486:256–260.
89.
HamdanFFGauthierJArakiY. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet. 2011;88:306–316.
90.
BozdagiOTavassoliTBuxbaumJD. Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay. Mol Autism. 2013;4:9.
91.
KouYBetancurCXuHBuxbaumJDMa’ayanA. Network- and attribute-based classifiers can prioritize genes and pathways for autism spectrum disorders and intellectual disability. Am J Med Genet. 2012;160C:130–142.
92.
KolevzonAAngaritaBBushL. Phelan-McDermid syndrome: a review of the literature and practice parameters for medical assessment and monitoring. J Neurodev Disord. 2014;6:39.
93.
SeidaJKOspinaMBKarkhanehMHartlingLSmithVClarkB. Systematic reviews of psychosocial interventions for autism: an umbrella review. Dev Med Child Neurol. 2009;51:95–104.
94.
ReichowBWoleryM. Comprehensive synthesis of early intensive behavioral interventions for young children with autism based on the UCLA young autism project model. J Autism Dev Disord. 2009;39:23–41.
95.
WarrenZVeenstra-VanderWeeleJStoneW. Therapies for children with autism spectrum disorders. In Therapies for Children With Autism Spectrum Disorders. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
96.
BearMFHuberKMWarrenST. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004;27:370–377.
97.
EhningerDSilvaAJ. Genetics and neuropsychiatric disorders: treatment during adulthood. Nat Med. 2009;15:849–850.
98.
TropeaDGiacomettiEWilsonNR. Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci U S A. 2009;106:2029–2034.
99.
KolevzonABushLWangAT. A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome. Mol Autism. 2014;5:54.
100.
KruegerDDBearMF. Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu Rev Med. 2011;62:411–429.
101.
DolenGBearMF. Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome. J Physiol. 2008;586:1503–1508.
102.
DolenGCarpenterRLOcainTDBearMF. Mechanism-based approaches to treating fragile X. Pharmacol Ther. 2010;127:78–93.
103.
ScharfSHJaeschkeGWettsteinJGLindemannL. Metabotropic glutamate receptor 5 as drug target for Fragile X syndrome. Curr Opin Pharmacol. 2015;20:124–134.
104.
BraatSKooyRF. Insights into GABAergic system deficits in fragile X syndrome lead to clinical trials. Neuropharmacology. 2015;88C:48–54.
105.
AuerbachBDOsterweilEKBearMF. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature. 2011;480:63–68.
106.
CuratoloPMoaveroR. mTOR inhibitors in tuberous sclerosis complex. Curr Neuropharmacol. 2012;10:404–415.
107.
JouRJMateljevicNKaiserMDSugrueDRVolkmarFRPelphreyKA. Structural neural phenotype of autism: preliminary evidence from a diffusion tensor imaging study using tract-based spatial statistics. AJNR Am J Neuroradiol. 2011;32:1607–1613.
