Potocki-Lupski Syndrome

Genetic MONDO:0012574 Pathograph 7 Show in embeddings browser hereditary disease chromosomal disorder

Potocki-Lupski syndrome (PTLS) is a rare contiguous-gene neurodevelopmental disorder caused by a recurrent ~3.7 Mb microduplication of chromosome 17p11.2 — the reciprocal copy-number gain of the deletion that causes Smith-Magenis syndrome, generated by non-allelic homologous recombination between the flanking SMS-REP low-copy repeats. Increased dosage of the dosage-sensitive gene RAI1 (retinoic acid induced 1) is the principal driver; smaller duplications that still include RAI1 (down to ~0.25 Mb) reproduce a milder form of the phenotype, establishing RAI1 gene dosage as rate-limiting. The core phenotype comprises infantile hypotonia, failure to thrive, global developmental delay with mild-to-moderate intellectual disability, prominent speech/language delay, autism spectrum features, behavioral and sleep disturbance, variable craniofacial dysmorphism, and cardiovascular anomalies (notably dilated aortic root and other structural defects). Expressivity is highly variable.

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1
Inheritance
3
Pathophys.
12
Phenotypes
7
Pathograph
2
Genes
3
Medical Actions
2
Subtypes
6
References
👪

Inheritance

1
Autosomal dominant 17p11.2 duplication, usually de novo HP:0000006
If a parent carries the 17p11.2 duplication, the recurrence risk to each sib is 50%. Where the duplication is not found in either parent, parental somatic and/or germline mosaicism keeps the recurrence risk slightly above the general population, though still under 1%. The phenotype of an inherited duplication cannot be reliably predicted.
Autosomal dominant inheritance Expressivity: VARIABLE De novo rate: The majority of affected individuals have a de novo duplication; parent-to-child transmission has been reported.
Show evidence (2 references)
PMID:28837307 SUPPORT Human Clinical
"PTLS is inherited in an autosomal dominant manner. The majority of affected individuals have a de novo duplication; however, parent-to-child transmission has been reported."
GeneReviews establishes the autosomal dominant mode and the de novo predominance.
PMID:28837307 SUPPORT Human Clinical
"If one of the parents has the 17p11.2 duplication, the risk to each sib of inheriting the duplication is 50%."
Gives the sib recurrence risk for a transmitting parent.
◆

Subtypes

2
Typical ~3.7 Mb 17p11.2 duplication
The recurrent ~3.7 Mb 17p11.2 duplication mediated by non-allelic homologous recombination between the flanking SMS-REP low-copy repeats — the reciprocal copy-number gain of the common Smith-Magenis syndrome deletion. Contains RAI1 together with the surrounding contiguous genes.
Show evidence (1 reference)
PMID:23255863 SUPPORT Human Clinical
"Deletion and duplication of the -3.7-Mb region in 17p11.2 result in two reciprocal syndrome, Smith-Magenis syndrome and Potocki-Lupski syndrome."
Defines the typical ~3.7 Mb duplication as the reciprocal copy-number event of the Smith-Magenis deletion.
Small RAI1-containing duplication (down to ~0.25 Mb)
Smaller, atypical duplications that still encompass RAI1 (reported down to ~0.25 Mb) are associated with a milder phenotype, supporting RAI1 dosage as the rate-limiting driver rather than the full contiguous interval.
Show evidence (1 reference)
PMID:23078968 SUPPORT Human Clinical
"When compared with previously reported cases, the milder phenotype of our patient may be associated with the smallest duplication in 17p11.2, 0.25Mb in length."
A ~0.25 Mb duplication still including RAI1 produced a milder phenotype, delineating a small-duplication subtype.
⚙

Pathophysiology

3
17p11.2 Microduplication
A recurrent copy-number gain of the 17p11.2 region, generated by non-allelic homologous recombination between the flanking SMS-REP low-copy repeats. It is the reciprocal event of the Smith-Magenis syndrome deletion; the two share an overlapping critical interval containing RAI1.
Downstream
Increased RAI1 Dosage The duplication raises the copy number of RAI1, the dosage-sensitive gene within the interval.
Show evidence (1 reference)
PMID:23255863 SUPPORT Human Clinical
"These regions overlapped in a 2.1 Mb size containing 11 common genes, including RAI1 and SREBF."
Establishes the shared 17p11.2 critical interval (including RAI1) between the reciprocal duplication and deletion.
Increased RAI1 Dosage
RAI1 (retinoic acid induced 1) is a transcriptional regulator and the dosage-sensitive critical gene of the 17p11.2 interval. A third copy raises RAI1 expression, dysregulating RAI1-dependent transcriptional programs. This is the copy-number-gain mirror of the RAI1 haploinsufficiency that causes Smith-Magenis syndrome.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Genetic context RAI1 hgnc:9834 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns RAI1 (hgnc:9834). hgnc:9834 is a gene from the HUGO Gene Nomenclature Committee. functional_impact_category: HYPERMORPHIC
regulation of RAI1-dependent transcription GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased regulation of RAI1-dependent transcription, annotated with regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Neurodevelopmental Dysregulation Altered RAI1 dosage perturbs neurodevelopmental transcriptional programs.
Show evidence (2 references)
PMID:33043631 SUPPORT Human Clinical
"caused by duplications of the 17p11.2 region, encompassing RAI1 gene."
Attributes PTLS to duplication of the 17p11.2 region encompassing RAI1.
PMID:23078968 SUPPORT Human Clinical
"the critical PTLS region was deduced to be 1.3Mb in length, and included RAI1 and 17 other genes."
Delineates the RAI1-containing critical region for PTLS.
Neurodevelopmental Dysregulation
Dysregulation of RAI1-dependent neurodevelopmental programs produces the variably expressive cognitive, language, autistic, behavioral, and sleep phenotype. Expressivity is notably broad even among individuals with similar duplications.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Downstream
Global Developmental Delay
Intellectual Disability
Autistic Behavior
Show evidence (1 reference)
PMID:33043631 SUPPORT Human Clinical
"Its clinical presentation is extremely variable, especially for what concerns the cognitive level and the behavioral phenotype."
Documents the extreme clinical variability of the neurodevelopmental phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Potocki-Lupski 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

12
Cardiovascular 1
Cardiovascular Anomalies Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiovascular anomaly, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28413209 SUPPORT Human Clinical
"Among the key features of such patients are autism spectrum disorder, learning disabilities, developmental delay, attention-deficit disorder, infantile hypotonia and cardiovascular abnormalities."
Lists cardiovascular abnormalities among the key features; structural anomalies (e.g., dilated aortic root) are characteristic.
Head and Neck 3
Triangular Face HP:0000325 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Triangular face (HP:0000325). HP:0000325 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38558960 SUPPORT Human Clinical
"along with craniofacial dysmorphism characterized by a triangular face, wide forehead, dental malocclusion, and micrognathia."
Documents a triangular face as part of the PTLS craniofacial dysmorphism.
Broad Forehead HP:0000337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad forehead (HP:0000337). HP:0000337 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38558960 SUPPORT Human Clinical
"along with craniofacial dysmorphism characterized by a triangular face, wide forehead, dental malocclusion, and micrognathia."
Documents a wide (broad) forehead as part of the PTLS craniofacial dysmorphism.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38558960 SUPPORT Human Clinical
"along with craniofacial dysmorphism characterized by a triangular face, wide forehead, dental malocclusion, and micrognathia."
Documents micrognathia as part of the PTLS craniofacial dysmorphism.
Musculoskeletal 1
Infantile Hypotonia FREQUENT Floppy infant HP:0008947 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infantile hypotonia, annotated with Floppy infant (HP:0008947). HP:0008947 is a phenotype from the Human Phenotype Ontology.
A classic early feature, though one systematic neurological cohort found it less frequent than previously reported.
Show evidence (3 references)
PMID:28413209 SUPPORT Human Clinical
"Among the key features of such patients are autism spectrum disorder, learning disabilities, developmental delay, attention-deficit disorder, infantile hypotonia and cardiovascular abnormalities."
Lists infantile hypotonia among the key features of PTLS.
PMID:33043631 SUPPORT Human Clinical
"Hypotonia appears a less frequent finding than what previously reported, while motor clumsiness/coordination impairment is frequent."
A systematic cohort found hypotonia less frequent than earlier reports, qualifying its frequency.
PMID:28837307 SUPPORT Human Clinical
"Medically, hypotonia, oropharyngeal dysphagia leading to failure to thrive, congenital heart disease, hypoglycemia associated with growth hormone deficiency, and mildly dysmorphic facial features are observed."
GeneReviews chapter lists hypotonia among the core medical manifestations of PTLS.
Nervous System 6
Global Developmental Delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33043631 SUPPORT Human Clinical
"a mild to moderate cognitive impairment is present in all patients, variably associated with features of autism spectrum disorder, behavioral disturb, and sleep disturb."
Delayed milestones and cognitive impairment were present in all patients of the cohort, supporting a very frequent developmental delay.
Intellectual Disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Typically mild to moderate; milder in individuals with small RAI1-only duplications.
Show evidence (2 references)
PMID:33043631 SUPPORT Human Clinical
"a mild to moderate cognitive impairment is present in all patients, variably associated with features of autism spectrum disorder, behavioral disturb, and sleep disturb."
Mild-to-moderate cognitive impairment was present in all cohort patients.
PMID:28837307 SUPPORT Human Clinical
"Cognitively, most individuals present with developmental delay, later meeting criteria for moderate intellectual disability."
GeneReviews chapter provides the review-level anchor for intellectual disability as a near-constant PTLS feature.
Context-specific annotations (1)
Small RAI1 duplication MILD
Show evidence (1 reference)
PMID:23078968 SUPPORT Human Clinical
"When compared with previously reported cases, the milder phenotype of our patient may be associated with the smallest duplication in 17p11.2, 0.25Mb in length."
The smallest (~0.25 Mb) RAI1-containing duplication was associated with a milder cognitive phenotype, a subtype-specific severity context.
Delayed Speech and Language Development FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38558960 SUPPORT Human Clinical
"The patient exhibited neurological manifestations including speech delay and mild intellectual disability, along with craniofacial dysmorphism characterized by a triangular face, wide forehead, dental malocclusion, and micrognathia."
Documents speech delay as a neurological manifestation of PTLS.
Autistic Behavior FREQUENT HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33043631 SUPPORT Human Clinical
"a mild to moderate cognitive impairment is present in all patients, variably associated with features of autism spectrum disorder, behavioral disturb, and sleep disturb."
Autism spectrum features were variably associated across the cohort.
Sleep Disturbance FREQUENT HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33043631 SUPPORT Human Clinical
"a mild to moderate cognitive impairment is present in all patients, variably associated with features of autism spectrum disorder, behavioral disturb, and sleep disturb."
Sleep disturbance was among the variably associated features in the cohort.
Attention Deficit Hyperactivity Disorder OCCASIONAL HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28413209 SUPPORT Human Clinical
"Among the key features of such patients are autism spectrum disorder, learning disabilities, developmental delay, attention-deficit disorder, infantile hypotonia and cardiovascular abnormalities."
Lists attention-deficit disorder among the key behavioral features.
Growth 1
Failure to Thrive FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Often related to feeding/swallowing difficulty, and growth hormone deficiency has been reported.
Show evidence (1 reference)
PMID:34820340 SUPPORT Human Clinical
"PTLS is also frequently associated with failure to thrive due to swallowing difficulties or growth hormone deficiency."
Reports failure to thrive as a frequent feature, linked to swallowing difficulty or growth hormone deficiency.
🧬

Genetic Associations

2
RAI1 (Causal)
Gene: RAI1 hgnc:9834 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RAI1 (hgnc:9834). hgnc:9834 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:33043631 SUPPORT Human Clinical
"caused by duplications of the 17p11.2 region, encompassing RAI1 gene."
Identifies RAI1 as the gene encompassed by the causative 17p11.2 duplication.
17p11.2 duplication (contiguous genes) (Causal)
Show evidence (2 references)
PMID:28413209 SUPPORT Human Clinical
"there are a few genes which are considered as candidates for PTLS which include RAI1, SREBF1, DRG2, LLGL1, SHMT1 and ZFP179."
Names the contiguous candidate genes within the PTLS duplication interval.
PMID:28837307 SUPPORT Human Clinical
"A recurrent 3.7-Mb duplication accounts for approximately two thirds of 17p11.2 duplications; approximately one third are non-recurrent duplications that encompass RAI1 and vary in size from 0.41 Mb to 19.7 Mb."
GeneReviews quantifies the recurrent 3.7-Mb duplication against the non-recurrent RAI1-containing alternatives.
💊

Medical Actions

3
Multidisciplinary Supportive Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No curative therapy exists; management is symptomatic and multidisciplinary, including surveillance for cardiovascular anomalies (e.g., echocardiography for aortic-root dilation) and growth/feeding support.
Speech and Language Therapy
Action: speech and language therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is speech and language therapy, annotated with Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
Platform: Behavioral / lifestyle
For the prominent speech and language delay.
Physical and Occupational Therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
For hypotonia, motor delay, and coordination difficulty.
🔬

Diagnosis

1
Chromosomal Microarray (array CGH) (17p11.2 copy-number gain)
Chromosomal microarray (array CGH) detects and sizes the 17p11.2 duplication; MLPA and FISH with probes in the PTLS critical region confirm it.
Show evidence (1 reference)
PMID:28413209 SUPPORT Human Clinical
"This report demonstrates the importance of microarray and FISH in the diagnosis of PTLS."
Establishes microarray and FISH as the diagnostic modalities for PTLS.
📊

Prevalence

1
Live births
Birth Prevalence 5.0 per 100,000 1–9 per 100,000 (births)
Estimated at ~1 in 20,000 live births (5 per 100,000). Likely underascertained because the phenotype is mild and nonspecific relative to the reciprocal Smith-Magenis deletion.
Show evidence (1 reference)
PMID:28413209 SUPPORT Human Clinical
"a rare contiguous gene syndrome affecting 1 in 20,000 live births."
Provides the commonly cited ~1 in 20,000 live-birth frequency.
{ }

Source YAML

click to show 
name: Potocki-Lupski Syndrome
creation_date: "2026-08-22T00:00:00Z"
description: >-
  Potocki-Lupski syndrome (PTLS) is a rare contiguous-gene neurodevelopmental
  disorder caused by a recurrent ~3.7 Mb microduplication of chromosome 17p11.2 —
  the reciprocal copy-number gain of the deletion that causes Smith-Magenis
  syndrome, generated by non-allelic homologous recombination between the flanking
  SMS-REP low-copy repeats. Increased dosage of the dosage-sensitive gene RAI1
  (retinoic acid induced 1) is the principal driver; smaller duplications that
  still include RAI1 (down to ~0.25 Mb) reproduce a milder form of the phenotype,
  establishing RAI1 gene dosage as rate-limiting. The core phenotype comprises
  infantile hypotonia, failure to thrive, global developmental delay with
  mild-to-moderate intellectual disability, prominent speech/language delay,
  autism spectrum features, behavioral and sleep disturbance, variable
  craniofacial dysmorphism, and cardiovascular anomalies (notably dilated aortic
  root and other structural defects). Expressivity is highly variable.
category: Genetic
synonyms:
- 17p11.2 duplication syndrome
- dup(17)(p11.2p11.2) syndrome
- trisomy 17p11.2
- PTLS
parents:
- hereditary disease
- chromosomal disorder
disease_term:
  preferred_term: Potocki-Lupski syndrome
  term:
    id: MONDO:0012574
    label: Potocki-Lupski syndrome
has_subtypes:
- name: Typical
  display_name: Typical ~3.7 Mb 17p11.2 duplication
  description: >-
    The recurrent ~3.7 Mb 17p11.2 duplication mediated by non-allelic homologous
    recombination between the flanking SMS-REP low-copy repeats — the reciprocal
    copy-number gain of the common Smith-Magenis syndrome deletion. Contains RAI1
    together with the surrounding contiguous genes.
  evidence:
  - reference: PMID:23255863
    reference_title: "Reciprocal deletion and duplication of 17p11.2-11.2: Korean patients with Smith-Magenis syndrome and Potocki-Lupski syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deletion and duplication of the -3.7-Mb region in 17p11.2 result in two reciprocal syndrome, Smith-Magenis syndrome and Potocki-Lupski syndrome."
    explanation: Defines the typical ~3.7 Mb duplication as the reciprocal copy-number event of the Smith-Magenis deletion.
- name: Small RAI1 duplication
  display_name: Small RAI1-containing duplication (down to ~0.25 Mb)
  description: >-
    Smaller, atypical duplications that still encompass RAI1 (reported down to
    ~0.25 Mb) are associated with a milder phenotype, supporting RAI1 dosage as
    the rate-limiting driver rather than the full contiguous interval.
  evidence:
  - reference: PMID:23078968
    reference_title: "Clinical and cytogenetic features of a Potocki-Lupski syndrome with the shortest 0.25Mb microduplication in 17p11.2 including RAI1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When compared with previously reported cases, the milder phenotype of our patient may be associated with the smallest duplication in 17p11.2, 0.25Mb in length."
    explanation: A ~0.25 Mb duplication still including RAI1 produced a milder phenotype, delineating a small-duplication subtype.
inheritance:
- name: Autosomal dominant 17p11.2 duplication, usually de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  de_novo_rate: >-
    The majority of affected individuals have a de novo duplication;
    parent-to-child transmission has been reported.
  expressivity: VARIABLE
  description: >-
    If a parent carries the 17p11.2 duplication, the recurrence risk to each sib
    is 50%. Where the duplication is not found in either parent, parental somatic
    and/or germline mosaicism keeps the recurrence risk slightly above the general
    population, though still under 1%. The phenotype of an inherited duplication
    cannot be reliably predicted.
  evidence:
  - reference: PMID:28837307
    reference_title: Potocki-Lupski Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PTLS is inherited in an autosomal dominant manner. The majority of affected
      individuals have a de novo duplication; however, parent-to-child
      transmission has been reported.
    explanation: >-
      GeneReviews establishes the autosomal dominant mode and the de novo
      predominance.
  - reference: PMID:28837307
    reference_title: Potocki-Lupski Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      If one of the parents has the 17p11.2 duplication, the risk to each sib of
      inheriting the duplication is 50%.
    explanation: Gives the sib recurrence risk for a transmitting parent.
prevalence:
- population: Live births
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 5.0
  notes: >-
    Estimated at ~1 in 20,000 live births (5 per 100,000). Likely underascertained
    because the phenotype is mild and nonspecific relative to the reciprocal
    Smith-Magenis deletion.
  evidence:
  - reference: PMID:28413209
    reference_title: "Duplication 17p11.2 (Potocki-Lupski Syndrome) in a child with developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a rare contiguous gene syndrome affecting 1 in 20,000 live births."
    explanation: Provides the commonly cited ~1 in 20,000 live-birth frequency.
pathophysiology:
- name: 17p11.2 Microduplication
  biological_scale: MOLECULAR
  description: >-
    A recurrent copy-number gain of the 17p11.2 region, generated by non-allelic
    homologous recombination between the flanking SMS-REP low-copy repeats. It is
    the reciprocal event of the Smith-Magenis syndrome deletion; the two share an
    overlapping critical interval containing RAI1.
  evidence:
  - reference: PMID:23255863
    reference_title: "Reciprocal deletion and duplication of 17p11.2-11.2: Korean patients with Smith-Magenis syndrome and Potocki-Lupski syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These regions overlapped in a 2.1 Mb size containing 11 common genes, including RAI1 and SREBF."
    explanation: Establishes the shared 17p11.2 critical interval (including RAI1) between the reciprocal duplication and deletion.
  downstream:
  - target: Increased RAI1 Dosage
    causal_link_type: DIRECT
    description: The duplication raises the copy number of RAI1, the dosage-sensitive gene within the interval.
- name: Increased RAI1 Dosage
  biological_scale: MOLECULAR
  description: >-
    RAI1 (retinoic acid induced 1) is a transcriptional regulator and the
    dosage-sensitive critical gene of the 17p11.2 interval. A third copy raises
    RAI1 expression, dysregulating RAI1-dependent transcriptional programs. This
    is the copy-number-gain mirror of the RAI1 haploinsufficiency that causes
    Smith-Magenis syndrome.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: regulation of RAI1-dependent transcription
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: INCREASED
  genetic_context:
    gene:
      preferred_term: RAI1
      term:
        id: hgnc:9834
        label: RAI1
    functional_impact_category: HYPERMORPHIC
  evidence:
  - reference: PMID:33043631
    reference_title: "Neurological phenotype of Potocki-Lupski syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "caused by duplications of the 17p11.2 region, encompassing RAI1 gene."
    explanation: Attributes PTLS to duplication of the 17p11.2 region encompassing RAI1.
  - reference: PMID:23078968
    reference_title: "Clinical and cytogenetic features of a Potocki-Lupski syndrome with the shortest 0.25Mb microduplication in 17p11.2 including RAI1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the critical PTLS region was deduced to be 1.3Mb in length, and included RAI1 and 17 other genes."
    explanation: Delineates the RAI1-containing critical region for PTLS.
  downstream:
  - target: Neurodevelopmental Dysregulation
    causal_link_type: DIRECT
    description: Altered RAI1 dosage perturbs neurodevelopmental transcriptional programs.
- name: Neurodevelopmental Dysregulation
  biological_scale: CELLULAR
  description: >-
    Dysregulation of RAI1-dependent neurodevelopmental programs produces the
    variably expressive cognitive, language, autistic, behavioral, and sleep
    phenotype. Expressivity is notably broad even among individuals with similar
    duplications.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:33043631
    reference_title: "Neurological phenotype of Potocki-Lupski syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Its clinical presentation is extremely variable, especially for what concerns the cognitive level and the behavioral phenotype."
    explanation: Documents the extreme clinical variability of the neurodevelopmental phenotype.
  downstream:
  - target: Global Developmental Delay
    causal_link_type: DIRECT
  - target: Intellectual Disability
    causal_link_type: DIRECT
  - target: Autistic Behavior
    causal_link_type: DIRECT
phenotypes:
- category: Neurologic
  name: Global Developmental Delay
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:33043631
    reference_title: "Neurological phenotype of Potocki-Lupski syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a mild to moderate cognitive impairment is present in all patients, variably associated with features of autism spectrum disorder, behavioral disturb, and sleep disturb."
    explanation: Delayed milestones and cognitive impairment were present in all patients of the cohort, supporting a very frequent developmental delay.
- category: Neurologic
  name: Intellectual Disability
  frequency: VERY_FREQUENT
  notes: Typically mild to moderate; milder in individuals with small RAI1-only duplications.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:33043631
    reference_title: "Neurological phenotype of Potocki-Lupski syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a mild to moderate cognitive impairment is present in all patients, variably associated with features of autism spectrum disorder, behavioral disturb, and sleep disturb."
    explanation: Mild-to-moderate cognitive impairment was present in all cohort patients.
  - reference: PMID:28837307
    reference_title: "Potocki-Lupski Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cognitively, most individuals present with developmental delay, later meeting criteria for moderate intellectual disability."
    explanation: GeneReviews chapter provides the review-level anchor for intellectual disability as a near-constant PTLS feature.
  phenotype_contexts:
  - subtype: Small RAI1 duplication
    severity: MILD
    evidence:
    - reference: PMID:23078968
      reference_title: "Clinical and cytogenetic features of a Potocki-Lupski syndrome with the shortest 0.25Mb microduplication in 17p11.2 including RAI1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "When compared with previously reported cases, the milder phenotype of our patient may be associated with the smallest duplication in 17p11.2, 0.25Mb in length."
      explanation: The smallest (~0.25 Mb) RAI1-containing duplication was associated with a milder cognitive phenotype, a subtype-specific severity context.
- category: Neurologic
  name: Infantile Hypotonia
  frequency: FREQUENT
  notes: >-
    A classic early feature, though one systematic neurological cohort found it
    less frequent than previously reported.
  phenotype_term:
    preferred_term: Infantile hypotonia
    term:
      id: HP:0008947
      label: Floppy infant
  evidence:
  - reference: PMID:28413209
    reference_title: "Duplication 17p11.2 (Potocki-Lupski Syndrome) in a child with developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the key features of such patients are autism spectrum disorder, learning disabilities, developmental delay, attention-deficit disorder, infantile hypotonia and cardiovascular abnormalities."
    explanation: Lists infantile hypotonia among the key features of PTLS.
  - reference: PMID:33043631
    reference_title: "Neurological phenotype of Potocki-Lupski syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypotonia appears a less frequent finding than what previously reported, while motor clumsiness/coordination impairment is frequent."
    explanation: A systematic cohort found hypotonia less frequent than earlier reports, qualifying its frequency.
  - reference: PMID:28837307
    reference_title: "Potocki-Lupski Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Medically, hypotonia, oropharyngeal dysphagia leading to failure to thrive, congenital heart disease, hypoglycemia associated with growth hormone deficiency, and mildly dysmorphic facial features are observed."
    explanation: GeneReviews chapter lists hypotonia among the core medical manifestations of PTLS.
- category: Developmental
  name: Delayed Speech and Language Development
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:38558960
    reference_title: "Potocki-Lupski Syndrome in Ethiopian Child: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient exhibited neurological manifestations including speech delay and mild intellectual disability, along with craniofacial dysmorphism characterized by a triangular face, wide forehead, dental malocclusion, and micrognathia."
    explanation: Documents speech delay as a neurological manifestation of PTLS.
- category: Behavioral
  name: Autistic Behavior
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:33043631
    reference_title: "Neurological phenotype of Potocki-Lupski syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a mild to moderate cognitive impairment is present in all patients, variably associated with features of autism spectrum disorder, behavioral disturb, and sleep disturb."
    explanation: Autism spectrum features were variably associated across the cohort.
- category: Behavioral
  name: Sleep Disturbance
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:33043631
    reference_title: "Neurological phenotype of Potocki-Lupski syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a mild to moderate cognitive impairment is present in all patients, variably associated with features of autism spectrum disorder, behavioral disturb, and sleep disturb."
    explanation: Sleep disturbance was among the variably associated features in the cohort.
- category: Behavioral
  name: Attention Deficit Hyperactivity Disorder
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:28413209
    reference_title: "Duplication 17p11.2 (Potocki-Lupski Syndrome) in a child with developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the key features of such patients are autism spectrum disorder, learning disabilities, developmental delay, attention-deficit disorder, infantile hypotonia and cardiovascular abnormalities."
    explanation: Lists attention-deficit disorder among the key behavioral features.
- category: Gastrointestinal
  name: Failure to Thrive
  frequency: FREQUENT
  notes: Often related to feeding/swallowing difficulty, and growth hormone deficiency has been reported.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:34820340
    reference_title: "Case Report: Potocki-Lupski Syndrome in Five Siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PTLS is also frequently associated with failure to thrive due to swallowing difficulties or growth hormone deficiency."
    explanation: Reports failure to thrive as a frequent feature, linked to swallowing difficulty or growth hormone deficiency.
- category: Cardiovascular
  name: Cardiovascular Anomalies
  phenotype_term:
    preferred_term: Cardiovascular anomaly
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:28413209
    reference_title: "Duplication 17p11.2 (Potocki-Lupski Syndrome) in a child with developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the key features of such patients are autism spectrum disorder, learning disabilities, developmental delay, attention-deficit disorder, infantile hypotonia and cardiovascular abnormalities."
    explanation: Lists cardiovascular abnormalities among the key features; structural anomalies (e.g., dilated aortic root) are characteristic.
- category: Craniofacial
  name: Triangular Face
  phenotype_term:
    preferred_term: Triangular face
    term:
      id: HP:0000325
      label: Triangular face
  evidence:
  - reference: PMID:38558960
    reference_title: "Potocki-Lupski Syndrome in Ethiopian Child: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "along with craniofacial dysmorphism characterized by a triangular face, wide forehead, dental malocclusion, and micrognathia."
    explanation: Documents a triangular face as part of the PTLS craniofacial dysmorphism.
- category: Craniofacial
  name: Broad Forehead
  phenotype_term:
    preferred_term: Broad forehead
    term:
      id: HP:0000337
      label: Broad forehead
  evidence:
  - reference: PMID:38558960
    reference_title: "Potocki-Lupski Syndrome in Ethiopian Child: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "along with craniofacial dysmorphism characterized by a triangular face, wide forehead, dental malocclusion, and micrognathia."
    explanation: Documents a wide (broad) forehead as part of the PTLS craniofacial dysmorphism.
- category: Craniofacial
  name: Micrognathia
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:38558960
    reference_title: "Potocki-Lupski Syndrome in Ethiopian Child: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "along with craniofacial dysmorphism characterized by a triangular face, wide forehead, dental malocclusion, and micrognathia."
    explanation: Documents micrognathia as part of the PTLS craniofacial dysmorphism.
genetic:
- name: RAI1
  gene_term:
    preferred_term: RAI1
    term:
      id: hgnc:9834
      label: RAI1
  association: Causal
  relationship_type: SUSCEPTIBILITY
  notes: >-
    RAI1 is the dosage-sensitive critical gene of the 17p11.2 interval. PTLS
    results from a copy-number GAIN (increased RAI1 dosage), the reciprocal of
    the RAI1 haploinsufficiency that causes Smith-Magenis syndrome. Small
    duplications that still include RAI1 reproduce a milder phenotype.
  evidence:
  - reference: PMID:33043631
    reference_title: "Neurological phenotype of Potocki-Lupski syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "caused by duplications of the 17p11.2 region, encompassing RAI1 gene."
    explanation: Identifies RAI1 as the gene encompassed by the causative 17p11.2 duplication.
- name: 17p11.2 duplication (contiguous genes)
  association: Causal
  notes: >-
    The recurrent ~3.7 Mb 17p11.2 duplication is a copy-number gain spanning RAI1
    and additional contiguous genes (candidate contributors include SREBF1, DRG2,
    LLGL1, SHMT1, and ZFP179). No coordinate slot exists in the schema; the
    structural event is recorded here in prose (copy-number gain, 17p11.2).
  evidence:
  - reference: PMID:28413209
    reference_title: "Duplication 17p11.2 (Potocki-Lupski Syndrome) in a child with developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there are a few genes which are considered as candidates for PTLS which include RAI1, SREBF1, DRG2, LLGL1, SHMT1 and ZFP179."
    explanation: Names the contiguous candidate genes within the PTLS duplication interval.
  - reference: PMID:28837307
    reference_title: "Potocki-Lupski Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A recurrent 3.7-Mb duplication accounts for approximately two thirds of 17p11.2 duplications; approximately one third are non-recurrent duplications that encompass RAI1 and vary in size from 0.41 Mb to 19.7 Mb."
    explanation: GeneReviews quantifies the recurrent 3.7-Mb duplication against the non-recurrent RAI1-containing alternatives.
diagnosis:
- name: Chromosomal Microarray (array CGH)
  presence: 17p11.2 copy-number gain
  notes: >-
    Chromosomal microarray (array CGH) detects and sizes the 17p11.2 duplication;
    MLPA and FISH with probes in the PTLS critical region confirm it.
  evidence:
  - reference: PMID:28413209
    reference_title: "Duplication 17p11.2 (Potocki-Lupski Syndrome) in a child with developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report demonstrates the importance of microarray and FISH in the diagnosis of PTLS."
    explanation: Establishes microarray and FISH as the diagnostic modalities for PTLS.
treatments:
- name: Multidisciplinary Supportive Care
  description: >-
    No curative therapy exists; management is symptomatic and multidisciplinary,
    including surveillance for cardiovascular anomalies (e.g., echocardiography for
    aortic-root dilation) and growth/feeding support.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Speech and Language Therapy
  description: For the prominent speech and language delay.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
- name: Physical and Occupational Therapy
  description: For hypotonia, motor delay, and coordination difficulty.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
references:
- reference: PMID:23255863
  title: "Reciprocal deletion and duplication of 17p11.2-11.2: Korean patients with Smith-Magenis syndrome and Potocki-Lupski syndrome."
- reference: PMID:23078968
  title: "Clinical and cytogenetic features of a Potocki-Lupski syndrome with the shortest 0.25Mb microduplication in 17p11.2 including RAI1."
- reference: PMID:28413209
  title: "Duplication 17p11.2 (Potocki-Lupski Syndrome) in a child with developmental delay."
- reference: PMID:33043631
  title: "Neurological phenotype of Potocki-Lupski syndrome."
- reference: PMID:34820340
  title: "Case Report: Potocki-Lupski Syndrome in Five Siblings."
- reference: PMID:38558960
  title: "Potocki-Lupski Syndrome in Ethiopian Child: A Case Report."
📚

References & Deep Research

References

6
PMID:23255863
Reciprocal deletion and duplication of 17p11.2-11.2: Korean patients with Smith-Magenis syndrome and Potocki-Lupski syndrome.
No top-level findings curated for this source.
PMID:23078968
Clinical and cytogenetic features of a Potocki-Lupski syndrome with the shortest 0.25Mb microduplication in 17p11.2 including RAI1.
No top-level findings curated for this source.
PMID:28413209
Duplication 17p11.2 (Potocki-Lupski Syndrome) in a child with developmental delay.
No top-level findings curated for this source.
PMID:33043631
Neurological phenotype of Potocki-Lupski syndrome.
No top-level findings curated for this source.
PMID:34820340
Case Report: Potocki-Lupski Syndrome in Five Siblings.
No top-level findings curated for this source.
PMID:38558960
Potocki-Lupski Syndrome in Ethiopian Child: A Case Report.
No top-level findings curated for this source.