Phelan-McDermid Syndrome

Mendelian MONDO:0011652 Pathograph 14 Show in embeddings browser 22q13.3 microdeletion syndrome SHANK3-related neurodevelopmental disorder

Phelan-McDermid syndrome (PMS), also known as 22q13.3 deletion syndrome, is a neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene on chromosome 22q13.3. It can result from terminal deletions, ring chromosome 22, unbalanced translocations, or intragenic SHANK3 mutations. PMS is characterized by neonatal hypotonia, global developmental delay, absent or severely delayed speech, intellectual disability, and autism spectrum features. SHANK3 encodes a postsynaptic scaffolding protein critical for glutamatergic synapse formation and function. Additional features may include renal anomalies, lymphedema, seizures, and neuropsychiatric decompensation in adolescence and adulthood. Over 600 cases have been documented, though the condition is likely underdiagnosed.

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1
Inheritance
5
Pathophys.
9
Phenotypes
14
Pathograph
1
Genes
4
Medical Actions
3
Subtypes
👪

Inheritance

1
Autosomal dominant (typically de novo)
PMS follows autosomal dominant inheritance due to haploinsufficiency, but the vast majority of cases are de novo. Approximately 73% of de novo deletions are of paternal origin. Rare familial cases have been reported, including parental mosaicism and balanced translocations that segregate in unbalanced form.
Show evidence (1 reference)
PMID:12920066 SUPPORT Human Clinical
"Similar to other terminal deletion syndromes, there was an overabundance of paternal deletions."
Wilson et al. found a paternal origin bias in 22q13 deletions across 56 patients.
◆

Subtypes

3
22q13.3 deletion
The most common form (~89% of cases), caused by terminal deletions of chromosome 22q13.3 encompassing the SHANK3 gene. Deletion size is variable (100 kb to >9 Mb) and may include additional genes contributing to phenotypic variability. Approximately 73% of de novo deletions are of paternal origin.
Show evidence (1 reference)
PMID:24481935 SUPPORT Human Clinical
"22q13 genomic anomalies include terminal deletions of 22q13 (89 %), terminal deletions and interstitial duplications (9 %), and interstitial deletions (2 %)."
The largest PMS cohort study (201 patients) established that 89% of cases have terminal 22q13 deletions.
SHANK3 point mutation
Caused by pathogenic variants (missense, nonsense, frameshift) within the SHANK3 gene itself, without a cytogenetically visible deletion. Individuals with point mutations tend to have somewhat milder speech impairment compared to those with large deletions.
Show evidence (1 reference)
PMID:29719671 SUPPORT Human Clinical
"Haploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS."
De Rubeis et al. studied 17 new and 60 previously reported patients with SHANK3 point mutations, confirming that point mutations alone cause PMS.
Ring chromosome 22
Caused by formation of ring chromosome 22 with loss of distal 22q material including SHANK3. May have additional features related to ring chromosome instability.
⚙

Pathophysiology

5
Terminal 22q13.3 Deletion and Adjacent Gene Haploinsufficiency
Most Phelan-McDermid syndrome cases are terminal 22q13.3 deletions that include SHANK3 and variably remove adjacent genes. This contiguous-deletion branch explains why some non-neurological features, especially renal anomalies, are enriched in deletion cases but not clearly attributable to SHANK3 point mutations alone.
Downstream
SHANK3 haploinsufficiency Terminal 22q13 deletions usually include SHANK3, producing the core synaptic scaffold lesion.
Renal anomalies Adjacent genes within variably sized 22q13 deletions likely contribute to renal anomalies.
Lymphedema Lymphedema is an age-related feature observed in deletion cohorts.
Show evidence (2 references)
PMID:24481935 SUPPORT Human Clinical
"22q13 genomic anomalies include terminal deletions of 22q13 (89 %), terminal deletions and interstitial duplications (9 %), and interstitial deletions (2 %)."
The large PMS cohort shows that most cases are terminal 22q13 deletions.
PMID:35741804 SUPPORT Human Clinical
"The scientific literature suggests that up to 40% of individuals with PMS have kidney disorders, yet little research has been conducted on the renal system to assess candidate genes attributed to these disorders."
Review evidence supports renal anomalies as a deletion-region feature requiring candidate-gene assessment.
SHANK3 haploinsufficiency
SHANK3 is a master scaffolding protein at the postsynaptic density of glutamatergic synapses. It connects membrane-bound receptors including NMDA and AMPA receptors to the actin cytoskeleton. Loss of one copy of SHANK3 is the primary molecular lesion underlying core neurological features of Phelan-McDermid syndrome.
Glutamatergic neuron CL:0000679
Synapse assembly GO:0007416 Glutamate receptor signaling pathway GO:0007215
Downstream
Excitatory synapse structural deficit SHANK3 loss disrupts postsynaptic scaffolding at excitatory synapses.
Global developmental delay SHANK3 haploinsufficiency produces the core neurodevelopmental delay phenotype.
Absent speech SHANK3-associated neurodevelopmental impairment severely affects expressive speech.
Intellectual disability SHANK3 haploinsufficiency contributes to moderate-to-profound intellectual disability.
Neonatal hypotonia SHANK3-associated neurological dysfunction manifests early as neonatal hypotonia.
Show evidence (3 references)
PMID:22670140 SUPPORT Human Clinical
"Almost all of these deletions include the gene SHANK3 which encodes a scaffold protein in the postsynaptic densities of excitatory synapses, connecting membrane-bound receptors to the actin cytoskeleton."
Phelan and McDermid's comprehensive review establishes SHANK3's role as a postsynaptic scaffold protein and its centrality to PMS neurological features.
PMID:12920066 SUPPORT Human Clinical
"Our analysis therefore supports haploinsufficiency of the gene SHANK3, which codes for a structural protein of the postsynaptic density, as a major causative factor in the neurological symptoms of 22q13 deletion syndrome."
Wilson et al. found that all 45 testable patients were deleted for SHANK3, supporting its role as the critical gene.
PMID:11431708 SUPPORT Human Clinical
"ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses."
First paper linking SHANK3 (ProSAP2) disruption to 22q13.3 deletion syndrome, via a balanced translocation that disrupted the gene.
Excitatory synapse structural deficit
SHANK3 deficiency reduces postsynaptic scaffold organization at glutamatergic synapses, producing fewer structurally mature excitatory synapses and impaired glutamate receptor localization.
Glutamatergic neuron CL:0000679
Synapse assembly GO:0007416 ↓ DECREASED
Downstream
Excitatory-inhibitory imbalance Structural excitatory synapse deficits reduce excitatory synaptic output.
Excitatory-inhibitory imbalance
Loss of SHANK3 disrupts the balance between excitatory glutamatergic and inhibitory GABAergic signaling. iPSC-derived neurons from PMS patients show major defects in excitatory but not inhibitory synaptic transmission, with reduced AMPA- and NMDA-mediated currents and fewer excitatory synapses, while inhibitory transmission remains intact.
Synaptic transmission, glutamatergic GO:0035249
Downstream
Neuropsychiatric decompensation in adolescence and adulthood SHANK3-deficient neural circuits may become vulnerable to later psychiatric decompensation.
Autism spectrum disorder Excitatory synaptic dysfunction contributes to autistic behavior in PMS.
Seizures SHANK3-deficient circuit imbalance increases seizure susceptibility in a subset of patients.
Show evidence (2 references)
PMID:24132240 SUPPORT In Vitro
"We show that PMDS neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission."
Shcheglovitov et al. used iPSC-derived neurons from PMS patients to demonstrate selective excitatory synaptic deficits, providing direct human cellular evidence for E/I imbalance.
PMID:21423165 SUPPORT Model Organism
"Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice."
Peca et al. showed cortico-striatal circuit defects in Shank3 knockout mice, supporting disrupted neural circuit function.
Neuropsychiatric decompensation in adolescence and adulthood
A subset of individuals with PMS experience significant neuropsychiatric deterioration beginning in adolescence or adulthood, with features of bipolar disorder, catatonia, psychosis, and progressive loss of previously acquired skills. Mean age of onset is approximately 20 years. The underlying mechanisms are not fully understood but may involve age-dependent vulnerability of SHANK3-deficient neural circuits.
Downstream
Regression and loss of skills Adolescent/adult neuropsychiatric decompensation includes loss of previously acquired skills.
Show evidence (1 reference)
PMID:31879555 SUPPORT Human Clinical
"Clinical presentations included features of bipolar disorder, catatonia, psychosis, and loss of skills, occurring at a mean age of 20 years."
Kolevzon et al. systematically reviewed 56 PMS cases with neuropsychiatric decompensation, establishing the pattern of late-onset psychiatric features.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Phelan-McDermid Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

9
Genitourinary 1
Renal anomalies HP_0040282 Abnormality of the kidney HP:0000077
Show evidence (2 references)
PMID:35741804 SUPPORT Human Clinical
"The scientific literature suggests that up to 40% of individuals with PMS have kidney disorders, yet little research has been conducted on the renal system to assess candidate genes attributed to these disorders."
McCoy et al. systematically reviewed kidney disorders in PMS, finding up to 40% prevalence and identifying candidate renal genes in the 22q13 region.
PMID:29719671 SUPPORT Human Clinical
"renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3"
De Rubeis et al. found that renal anomalies were not observed in SHANK3 point mutation patients, suggesting other deleted genes in 22q13.3 are responsible.
Metabolism 1
Lymphedema HP_0040283 Lymphedema HP:0001004
Show evidence (1 reference)
PMID:24481935 SUPPORT Human Clinical
"the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age"
Sarasua et al. documented lymphedema as an age-related feature in the 201-patient PMS cohort.
Musculoskeletal 1
Neonatal hypotonia Neonatal hypotonia HP:0001319
Show evidence (1 reference)
PMID:22670140 SUPPORT Human Clinical
"this syndrome is characterized by neurological deficits which include global developmental delay, moderate to severe intellectual impairment, absent or severely delayed speech, and neonatal hypotonia"
Neonatal hypotonia is listed as one of the four core neurological features in the definitive PMS review.
Nervous System 6
Global developmental delay HP_0040281 Global developmental delay HP:0001263
Show evidence (1 reference)
PMID:22670140 SUPPORT Human Clinical
"this syndrome is characterized by neurological deficits which include global developmental delay, moderate to severe intellectual impairment, absent or severely delayed speech, and neonatal hypotonia"
Phelan and McDermid's review identifies global developmental delay as a core neurological feature of PMS.
Absent speech HP_0040281 Absent speech HP:0001344
Show evidence (2 references)
PMID:23758760 SUPPORT Human Clinical
"only five (19%) used some words spontaneously to communicate"
Soorya et al. prospectively evaluated 32 PMS patients and found that only 19% used any spontaneous words, confirming severe speech impairment as a hallmark.
PMID:12920066 SUPPORT Human Clinical
"all patients showed some degree of mental retardation and severe delay or absence of expressive speech, regardless of deletion size"
Wilson et al. found universal speech delay/absence across all deletion sizes in 56 patients.
Intellectual disability HP_0040281 Intellectual disability HP:0001249
Show evidence (1 reference)
PMID:23758760 SUPPORT Human Clinical
"Most patients (77%) exhibited severe to profound intellectual disability"
Soorya et al. prospectively assessed cognitive function in 32 PMS patients and found the majority had severe to profound intellectual disability.
Autism spectrum disorder HP_0040281 Autistic behavior HP:0000729
Show evidence (2 references)
PMID:23758760 SUPPORT Human Clinical
"The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder."
Soorya et al. used ADOS and ADI-R gold-standard instruments to establish a high ASD prevalence in PMS.
PMID:22670140 SUPPORT Human Clinical
"more than 50% of patients show autism or autistic-like behavior, and therefore it can be classified as a syndromic form of autism spectrum disorders (ASD)"
Phelan and McDermid noted >50% ASD prevalence across >600 documented cases.
Seizures HP_0040283 Seizure HP:0001250
Show evidence (2 references)
PMID:24481935 SUPPORT Human Clinical
"the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age"
Sarasua et al. documented increasing seizure prevalence with age in 201 PMS patients.
PMID:24481935 SUPPORT Human Clinical
"Seizures were reported three times more often among patients with a de novo deletion of the maternal rather than paternal chromosome 22."
Parent-of-origin effect on seizure susceptibility in PMS, with maternal deletions conferring higher risk.
Regression and loss of skills HP_0040283 Developmental regression HP:0002376
Show evidence (2 references)
PMID:31879555 SUPPORT Human Clinical
"we conducted a systematic literature review and identified 56 PMS cases showing signs of behavioral and neurologic decompensation in adolescence or adulthood"
Kolevzon et al. systematically documented neuropsychiatric decompensation and skill loss in 56 PMS cases, establishing this as a recognized feature of the syndrome.
PMID:29719671 SUPPORT Human Clinical
"Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems."
De Rubeis et al. confirmed regression occurs in SHANK3 point mutation patients as well, demonstrating that SHANK3 haploinsufficiency alone is sufficient.
🧬

Genetic Associations

1
SHANK3 (CAUSAL)
Gene: SHANK3 hgnc:14294
Show evidence (4 references)
PMID:12920066 SUPPORT Human Clinical
"all 45 cases that could be specifically tested for the terminal region at the site of SHANK3 were deleted for this gene"
Wilson et al. demonstrated that SHANK3 deletion is universal in the 22q13 deletion syndrome, establishing it as the critical gene.
PMID:17173049 SUPPORT Human Clinical
"we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders"
Durand et al. in Nature Genetics showed that SHANK3 point mutations alone cause language and social communication disorders, independent of larger deletions.
PMID:29719671 SUPPORT Human Clinical
"All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%)."
De Rubeis et al. confirmed the full PMS phenotype in individuals with SHANK3 point mutations, with 100% ID and 73% ASD.
+ 1 more reference
💊

Medical Actions

4
Speech and language therapy
Augmentative and alternative communication strategies are essential for individuals with absent or limited speech, including picture exchange systems, speech-generating devices, and sign language.
Behavioral therapy
Applied behavior analysis (ABA) and other behavioral interventions targeting autism spectrum features, adaptive skills, and challenging behaviors.
Antiepileptic medication
Seizure management with anticonvulsant medications tailored to the individual seizure type and response.
Insulin-like growth factor 1 (IGF-1) therapy
IGF-1 has been investigated as a targeted treatment for PMS. Preclinical studies showed that IGF-1 restores excitatory synaptic deficits in iPSC-derived PMS neurons. A pilot controlled trial in children showed improvement in social impairment and restrictive behaviors.
Show evidence (2 references)
PMID:24132240 SUPPORT In Vitro
"Excitatory synaptic transmission in PMDS neurons can be corrected by restoring SHANK3 expression or by treating neurons with insulin-like growth factor 1 (IGF1)."
Shcheglovitov et al. demonstrated in Nature that IGF-1 rescues synaptic deficits in iPSC-derived neurons from PMS patients, providing the preclinical rationale.
PMID:25685306 SUPPORT Human Clinical
"Compared to the placebo phase, the IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale, respectively."
Kolevzon et al. conducted the first controlled trial of IGF-1 in 9 PMS children, showing significant improvement in social and behavioral domains.
{ }

Source YAML

click to show 
name: Phelan-McDermid Syndrome
creation_date: '2026-04-06T19:41:20Z'
updated_date: '2026-04-20T17:29:15Z'
category: Mendelian
description: >
  Phelan-McDermid syndrome (PMS), also known as 22q13.3 deletion syndrome, is a
  neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene on
  chromosome 22q13.3. It can result from terminal deletions, ring chromosome 22,
  unbalanced translocations, or intragenic SHANK3 mutations. PMS is characterized
  by neonatal hypotonia, global developmental delay, absent or severely delayed
  speech, intellectual disability, and autism spectrum features. SHANK3 encodes a
  postsynaptic scaffolding protein critical for glutamatergic synapse formation
  and function. Additional features may include renal anomalies, lymphedema,
  seizures, and neuropsychiatric decompensation in adolescence and adulthood.
  Over 600 cases have been documented, though the condition is likely underdiagnosed.
disease_term:
  preferred_term: Phelan-McDermid syndrome
  term:
    id: MONDO:0011652
    label: Phelan-McDermid syndrome
parents:
- 22q13.3 microdeletion syndrome
- SHANK3-related neurodevelopmental disorder
has_subtypes:
- name: 22q13.3 deletion
  description: >
    The most common form (~89% of cases), caused by terminal deletions of
    chromosome 22q13.3 encompassing the SHANK3 gene. Deletion size is variable
    (100 kb to >9 Mb) and may include additional genes contributing to
    phenotypic variability. Approximately 73% of de novo deletions are of
    paternal origin.
  evidence:
  - reference: PMID:24481935
    reference_title: "Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "22q13 genomic anomalies include terminal deletions of 22q13 (89 %), terminal deletions and interstitial duplications (9 %), and interstitial deletions (2 %)."
    explanation: The largest PMS cohort study (201 patients) established that 89% of cases have terminal 22q13 deletions.
- name: SHANK3 point mutation
  description: >
    Caused by pathogenic variants (missense, nonsense, frameshift) within the
    SHANK3 gene itself, without a cytogenetically visible deletion. Individuals
    with point mutations tend to have somewhat milder speech impairment compared
    to those with large deletions.
  evidence:
  - reference: PMID:29719671
    reference_title: "Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Haploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS."
    explanation: De Rubeis et al. studied 17 new and 60 previously reported patients with SHANK3 point mutations, confirming that point mutations alone cause PMS.
- name: Ring chromosome 22
  description: >
    Caused by formation of ring chromosome 22 with loss of distal 22q material
    including SHANK3. May have additional features related to ring chromosome
    instability.
inheritance:
- name: Autosomal dominant (typically de novo)
  description: >
    PMS follows autosomal dominant inheritance due to haploinsufficiency, but the
    vast majority of cases are de novo. Approximately 73% of de novo deletions are
    of paternal origin. Rare familial cases have been reported, including parental
    mosaicism and balanced translocations that segregate in unbalanced form.
  evidence:
  - reference: PMID:12920066
    reference_title: "Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similar to other terminal deletion syndromes, there was an overabundance of paternal deletions."
    explanation: Wilson et al. found a paternal origin bias in 22q13 deletions across 56 patients.
pathophysiology:
- name: Terminal 22q13.3 Deletion and Adjacent Gene Haploinsufficiency
  description: >
    Most Phelan-McDermid syndrome cases are terminal 22q13.3 deletions that
    include SHANK3 and variably remove adjacent genes. This contiguous-deletion
    branch explains why some non-neurological features, especially renal
    anomalies, are enriched in deletion cases but not clearly attributable to
    SHANK3 point mutations alone.
  evidence:
  - reference: PMID:24481935
    reference_title: "Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "22q13 genomic anomalies include terminal deletions of 22q13 (89 %), terminal deletions and interstitial duplications (9 %), and interstitial deletions (2 %)."
    explanation: The large PMS cohort shows that most cases are terminal 22q13 deletions.
  - reference: PMID:35741804
    reference_title: "State of the Science for Kidney Disorders in Phelan-McDermid Syndrome: UPK3A, FBLN1, WNT7B, and CELSR1 as Candidate Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The scientific literature suggests that up to 40% of individuals with PMS have kidney disorders, yet little research has been conducted on the renal system to assess candidate genes attributed to these disorders."
    explanation: Review evidence supports renal anomalies as a deletion-region feature requiring candidate-gene assessment.
  downstream:
  - target: SHANK3 haploinsufficiency
    description: Terminal 22q13 deletions usually include SHANK3, producing the core synaptic scaffold lesion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22670140
      reference_title: "The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Almost all of these deletions include the gene SHANK3 which encodes a scaffold protein in the postsynaptic densities of excitatory synapses, connecting membrane-bound receptors to the actin cytoskeleton."
      explanation: The review directly links 22q13 deletions to SHANK3 loss.
  - target: Renal anomalies
    description: Adjacent genes within variably sized 22q13 deletions likely contribute to renal anomalies.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35741804
      reference_title: "State of the Science for Kidney Disorders in Phelan-McDermid Syndrome: UPK3A, FBLN1, WNT7B, and CELSR1 as Candidate Genes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The scientific literature suggests that up to 40% of individuals with PMS have kidney disorders, yet little research has been conducted on the renal system to assess candidate genes attributed to these disorders."
      explanation: Review evidence supports kidney disorders in PMS and frames candidate genes outside SHANK3.
  - target: Lymphedema
    description: Lymphedema is an age-related feature observed in deletion cohorts.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24481935
      reference_title: "Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age"
      explanation: The 201-patient cohort supports lymphedema as an age-related PMS feature.
- name: SHANK3 haploinsufficiency
  conforms_to: "excitatory_synapse_scaffold_disruption#Postsynaptic Scaffold Disruption"
  description: >
    SHANK3 is a master scaffolding protein at the postsynaptic density of
    glutamatergic synapses. It connects membrane-bound receptors including NMDA
    and AMPA receptors to the actin cytoskeleton. Loss of one copy of SHANK3 is
    the primary molecular lesion underlying core neurological features of
    Phelan-McDermid syndrome.
  evidence:
  - reference: PMID:22670140
    reference_title: "The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Almost all of these deletions include the gene SHANK3 which encodes a scaffold protein in the postsynaptic densities of excitatory synapses, connecting membrane-bound receptors to the actin cytoskeleton."
    explanation: Phelan and McDermid's comprehensive review establishes SHANK3's role as a postsynaptic scaffold protein and its centrality to PMS neurological features.
  - reference: PMID:12920066
    reference_title: "Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our analysis therefore supports haploinsufficiency of the gene SHANK3, which codes for a structural protein of the postsynaptic density, as a major causative factor in the neurological symptoms of 22q13 deletion syndrome."
    explanation: Wilson et al. found that all 45 testable patients were deleted for SHANK3, supporting its role as the critical gene.
  - reference: PMID:11431708
    reference_title: "Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses."
    explanation: First paper linking SHANK3 (ProSAP2) disruption to 22q13.3 deletion syndrome, via a balanced translocation that disrupted the gene.
  cell_types:
  - preferred_term: Glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: Synapse assembly
    term:
      id: GO:0007416
      label: synapse assembly
  - preferred_term: Glutamate receptor signaling pathway
    term:
      id: GO:0007215
      label: glutamate receptor signaling pathway
  downstream:
  - target: Excitatory synapse structural deficit
    description: SHANK3 loss disrupts postsynaptic scaffolding at excitatory synapses.
    causal_link_type: DIRECT
  - target: Global developmental delay
    description: SHANK3 haploinsufficiency produces the core neurodevelopmental delay phenotype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22670140
      reference_title: "The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "this syndrome is characterized by neurological deficits which include global developmental delay, moderate to severe intellectual impairment, absent or severely delayed speech, and neonatal hypotonia"
      explanation: The PMS review identifies global developmental delay as part of the core SHANK3-associated neurological syndrome.
  - target: Absent speech
    description: SHANK3-associated neurodevelopmental impairment severely affects expressive speech.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:12920066
      reference_title: "Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "all patients showed some degree of mental retardation and severe delay or absence of expressive speech, regardless of deletion size"
      explanation: The molecular characterization study links SHANK3-region deletions to severe expressive-speech impairment.
  - target: Intellectual disability
    description: SHANK3 haploinsufficiency contributes to moderate-to-profound intellectual disability.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23758760
      reference_title: "Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most patients (77%) exhibited severe to profound intellectual disability"
      explanation: Prospective PMS evaluation documents severe-to-profound intellectual disability in most patients.
  - target: Neonatal hypotonia
    description: SHANK3-associated neurological dysfunction manifests early as neonatal hypotonia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22670140
      reference_title: "The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "this syndrome is characterized by neurological deficits which include global developmental delay, moderate to severe intellectual impairment, absent or severely delayed speech, and neonatal hypotonia"
      explanation: The PMS review identifies neonatal hypotonia as a core neurological feature.
- name: Excitatory synapse structural deficit
  conforms_to: "excitatory_synapse_scaffold_disruption#Excitatory Postsynaptic Structural Deficit"
  description: >
    SHANK3 deficiency reduces postsynaptic scaffold organization at
    glutamatergic synapses, producing fewer structurally mature excitatory
    synapses and impaired glutamate receptor localization.
  cell_types:
  - preferred_term: Glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: Synapse assembly
    modifier: DECREASED
    term:
      id: GO:0007416
      label: synapse assembly
  downstream:
  - target: Excitatory-inhibitory imbalance
    description: Structural excitatory synapse deficits reduce excitatory synaptic output.
- name: Excitatory-inhibitory imbalance
  conforms_to: "excitatory_synapse_scaffold_disruption#Impaired Synaptic Plasticity and Excitatory-Inhibitory Imbalance"
  description: >
    Loss of SHANK3 disrupts the balance between excitatory glutamatergic and
    inhibitory GABAergic signaling. iPSC-derived neurons from PMS patients show
    major defects in excitatory but not inhibitory synaptic transmission, with
    reduced AMPA- and NMDA-mediated currents and fewer excitatory synapses, while
    inhibitory transmission remains intact.
  evidence:
  - reference: PMID:24132240
    reference_title: "SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that PMDS neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission."
    explanation: Shcheglovitov et al. used iPSC-derived neurons from PMS patients to demonstrate selective excitatory synaptic deficits, providing direct human cellular evidence for E/I imbalance.
  - reference: PMID:21423165
    reference_title: "Shank3 mutant mice display autistic-like behaviours and striatal dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice."
    explanation: Peca et al. showed cortico-striatal circuit defects in Shank3 knockout mice, supporting disrupted neural circuit function.
  biological_processes:
  - preferred_term: Synaptic transmission, glutamatergic
    term:
      id: GO:0035249
      label: synaptic transmission, glutamatergic
  downstream:
  - target: Neuropsychiatric decompensation in adolescence and adulthood
    description: SHANK3-deficient neural circuits may become vulnerable to later psychiatric decompensation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Autism spectrum disorder
    description: Excitatory synaptic dysfunction contributes to autistic behavior in PMS.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23758760
      reference_title: "Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder."
      explanation: Prospective evaluation documents high ASD prevalence in PMS.
  - target: Seizures
    description: SHANK3-deficient circuit imbalance increases seizure susceptibility in a subset of patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24481935
      reference_title: "Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age"
      explanation: The 201-patient cohort identifies seizures as an age-related PMS feature.
- name: Neuropsychiatric decompensation in adolescence and adulthood
  description: >
    A subset of individuals with PMS experience significant neuropsychiatric
    deterioration beginning in adolescence or adulthood, with features of
    bipolar disorder, catatonia, psychosis, and progressive loss of previously
    acquired skills. Mean age of onset is approximately 20 years. The
    underlying mechanisms are not fully understood but may involve
    age-dependent vulnerability of SHANK3-deficient neural circuits.
  evidence:
  - reference: PMID:31879555
    reference_title: "Neuropsychiatric decompensation in adolescents and adults with Phelan-McDermid syndrome: a systematic review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical presentations included features of bipolar disorder, catatonia, psychosis, and loss of skills, occurring at a mean age of 20 years."
    explanation: Kolevzon et al. systematically reviewed 56 PMS cases with neuropsychiatric decompensation, establishing the pattern of late-onset psychiatric features.
  downstream:
  - target: Regression and loss of skills
    description: Adolescent/adult neuropsychiatric decompensation includes loss of previously acquired skills.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31879555
      reference_title: "Neuropsychiatric decompensation in adolescents and adults with Phelan-McDermid syndrome: a systematic review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical presentations included features of bipolar disorder, catatonia, psychosis, and loss of skills, occurring at a mean age of 20 years."
      explanation: The systematic review directly documents loss of skills during PMS decompensation.
phenotypes:
- name: Global developmental delay
  description: >
    Most individuals with PMS show significant global developmental delay
    apparent in the first year of life, affecting motor, cognitive, and
    language milestones.
  frequency: HP_0040281
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:22670140
    reference_title: "The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this syndrome is characterized by neurological deficits which include global developmental delay, moderate to severe intellectual impairment, absent or severely delayed speech, and neonatal hypotonia"
    explanation: Phelan and McDermid's review identifies global developmental delay as a core neurological feature of PMS.
- name: Absent speech
  description: >
    Absent or severely delayed expressive language is a hallmark feature.
    In prospective evaluation, only 19% of patients used some words
    spontaneously to communicate.
  frequency: HP_0040281
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:23758760
    reference_title: "Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "only five (19%) used some words spontaneously to communicate"
    explanation: Soorya et al. prospectively evaluated 32 PMS patients and found that only 19% used any spontaneous words, confirming severe speech impairment as a hallmark.
  - reference: PMID:12920066
    reference_title: "Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all patients showed some degree of mental retardation and severe delay or absence of expressive speech, regardless of deletion size"
    explanation: Wilson et al. found universal speech delay/absence across all deletion sizes in 56 patients.
- name: Intellectual disability
  description: >
    Moderate to profound intellectual disability is present in the majority
    of individuals with PMS. In prospective studies, 77% exhibited severe
    to profound intellectual disability.
  frequency: HP_0040281
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:23758760
    reference_title: "Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients (77%) exhibited severe to profound intellectual disability"
    explanation: Soorya et al. prospectively assessed cognitive function in 32 PMS patients and found the majority had severe to profound intellectual disability.
- name: Neonatal hypotonia
  description: >
    Hypotonia is frequently the first clinical sign, often noted at birth
    or in early infancy, and contributes to feeding difficulties and
    delayed motor milestones.
  phenotype_term:
    preferred_term: Neonatal hypotonia
    term:
      id: HP:0001319
      label: Neonatal hypotonia
  evidence:
  - reference: PMID:22670140
    reference_title: "The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this syndrome is characterized by neurological deficits which include global developmental delay, moderate to severe intellectual impairment, absent or severely delayed speech, and neonatal hypotonia"
    explanation: Neonatal hypotonia is listed as one of the four core neurological features in the definitive PMS review.
- name: Autism spectrum disorder
  description: >
    A high proportion of individuals with PMS meet diagnostic criteria for
    autism spectrum disorder. In prospective evaluation with gold-standard
    instruments, 84% met criteria for ASD and 75% for autistic disorder.
  frequency: HP_0040281
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:23758760
    reference_title: "Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder."
    explanation: Soorya et al. used ADOS and ADI-R gold-standard instruments to establish a high ASD prevalence in PMS.
  - reference: PMID:22670140
    reference_title: "The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "more than 50% of patients show autism or autistic-like behavior, and therefore it can be classified as a syndromic form of autism spectrum disorders (ASD)"
    explanation: Phelan and McDermid noted >50% ASD prevalence across >600 documented cases.
- name: Seizures
  description: >
    Seizures occur in a significant proportion of PMS patients, with
    variable age of onset and seizure types. The proportion reporting
    seizures increases with age. Seizures are reported approximately three
    times more often in patients with maternal-origin deletions.
  frequency: HP_0040283
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:24481935
    reference_title: "Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age"
    explanation: Sarasua et al. documented increasing seizure prevalence with age in 201 PMS patients.
  - reference: PMID:24481935
    reference_title: "Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures were reported three times more often among patients with a de novo deletion of the maternal rather than paternal chromosome 22."
    explanation: Parent-of-origin effect on seizure susceptibility in PMS, with maternal deletions conferring higher risk.
- name: Renal anomalies
  description: >
    Structural renal anomalies occur in up to 40% of individuals with PMS,
    including renal cysts, hypoplasia, agenesis, hydronephrosis,
    vesicoureteral reflux, kidney dysplasia, horseshoe kidneys, and
    pyelectasis. Candidate genes beyond SHANK3 in the 22q13 region include
    UPK3A, FBLN1, WNT7B, and CELSR1.
  frequency: HP_0040282
  phenotype_term:
    preferred_term: Renal anomaly
    term:
      id: HP:0000077
      label: Abnormality of the kidney
  evidence:
  - reference: PMID:35741804
    reference_title: "State of the Science for Kidney Disorders in Phelan-McDermid Syndrome: UPK3A, FBLN1, WNT7B, and CELSR1 as Candidate Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The scientific literature suggests that up to 40% of individuals with PMS have kidney disorders, yet little research has been conducted on the renal system to assess candidate genes attributed to these disorders."
    explanation: McCoy et al. systematically reviewed kidney disorders in PMS, finding up to 40% prevalence and identifying candidate renal genes in the 22q13 region.
  - reference: PMID:29719671
    reference_title: "Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3"
    explanation: De Rubeis et al. found that renal anomalies were not observed in SHANK3 point mutation patients, suggesting other deleted genes in 22q13.3 are responsible.
- name: Lymphedema
  description: >
    Peripheral lymphedema is an age-related feature of PMS that increases
    in prevalence with age, reported in approximately 8-15% of patients in
    cohort studies.
  frequency: HP_0040283
  phenotype_term:
    preferred_term: Lymphedema
    term:
      id: HP:0001004
      label: Lymphedema
  evidence:
  - reference: PMID:24481935
    reference_title: "Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age"
    explanation: Sarasua et al. documented lymphedema as an age-related feature in the 201-patient PMS cohort.
- name: Regression and loss of skills
  description: >
    Progressive loss of previously acquired motor, language, and cognitive
    skills occurs in a subset of PMS patients, typically in adolescence
    or adulthood. This can be accompanied by neuropsychiatric features
    including bipolar disorder and catatonia.
  frequency: HP_0040283
  phenotype_term:
    preferred_term: Regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:31879555
    reference_title: "Neuropsychiatric decompensation in adolescents and adults with Phelan-McDermid syndrome: a systematic review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we conducted a systematic literature review and identified 56 PMS cases showing signs of behavioral and neurologic decompensation in adolescence or adulthood"
    explanation: Kolevzon et al. systematically documented neuropsychiatric decompensation and skill loss in 56 PMS cases, establishing this as a recognized feature of the syndrome.
  - reference: PMID:29719671
    reference_title: "Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems."
    explanation: De Rubeis et al. confirmed regression occurs in SHANK3 point mutation patients as well, demonstrating that SHANK3 haploinsufficiency alone is sufficient.
genetic:
- name: SHANK3
  gene_term:
    preferred_term: SHANK3
    term:
      id: hgnc:14294
      label: SHANK3
  association: CAUSAL
  features: >
    Loss-of-function variants including terminal 22q13.3 deletions (100 kb to >9 Mb),
    intragenic point mutations (nonsense, frameshift, missense), and ring chromosome 22
  evidence:
  - reference: PMID:12920066
    reference_title: "Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all 45 cases that could be specifically tested for the terminal region at the site of SHANK3 were deleted for this gene"
    explanation: Wilson et al. demonstrated that SHANK3 deletion is universal in the 22q13 deletion syndrome, establishing it as the critical gene.
  - reference: PMID:17173049
    reference_title: "Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders"
    explanation: Durand et al. in Nature Genetics showed that SHANK3 point mutations alone cause language and social communication disorders, independent of larger deletions.
  - reference: PMID:29719671
    reference_title: "Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%)."
    explanation: De Rubeis et al. confirmed the full PMS phenotype in individuals with SHANK3 point mutations, with 100% ID and 73% ASD.
  - reference: CGGV:assertion_e941703a-0f30-4f4c-a997-bc3b4295f289-2018-12-12T110000.000Z
    reference_title: "SHANK3 / Phelan-McDermid syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SHANK3 | HGNC:14294 | Phelan-McDermid syndrome | MONDO:0011652 | AD | Definitive"
    explanation: ClinGen classifies the SHANK3-Phelan-McDermid syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
treatments:
- name: Speech and language therapy
  description: >
    Augmentative and alternative communication strategies are essential for
    individuals with absent or limited speech, including picture exchange
    systems, speech-generating devices, and sign language.
- name: Behavioral therapy
  description: >
    Applied behavior analysis (ABA) and other behavioral interventions
    targeting autism spectrum features, adaptive skills, and challenging
    behaviors.
- name: Antiepileptic medication
  description: >
    Seizure management with anticonvulsant medications tailored to the
    individual seizure type and response.
- name: Insulin-like growth factor 1 (IGF-1) therapy
  description: >
    IGF-1 has been investigated as a targeted treatment for PMS. Preclinical
    studies showed that IGF-1 restores excitatory synaptic deficits in
    iPSC-derived PMS neurons. A pilot controlled trial in children showed
    improvement in social impairment and restrictive behaviors.
  evidence:
  - reference: PMID:24132240
    reference_title: "SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Excitatory synaptic transmission in PMDS neurons can be corrected by restoring SHANK3 expression or by treating neurons with insulin-like growth factor 1 (IGF1)."
    explanation: Shcheglovitov et al. demonstrated in Nature that IGF-1 rescues synaptic deficits in iPSC-derived neurons from PMS patients, providing the preclinical rationale.
  - reference: PMID:25685306
    reference_title: "A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared to the placebo phase, the IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale, respectively."
    explanation: Kolevzon et al. conducted the first controlled trial of IGF-1 in 9 PMS children, showing significant improvement in social and behavioral domains.
datasets: