10q22.3q23.3 microduplication syndrome is a variably expressed chromosomal copy-number disorder. The recurrent duplication is flanked by low-copy repeats LCR3 and LCR4 and is described as 10q22.3q23.2 in the primary literature. Overlapping duplications with different breakpoints are also reported; their gene content and clinical effects require separate interpretation. Reported manifestations include speech and motor developmental delay, intellectual disability and variable facial dysmorphism. Strabismus, hypotelorism and anteverted nares were documented in two siblings with the recurrent duplication. Microcephaly and congenital heart disease were reported in a separate individual with an overlapping duplication. Clinically unaffected relatives can carry the recurrent duplication, indicating incomplete penetrance. Increased DNA copy number is established, but altered expression of individual genes and the intervening developmental mechanisms are not established by the evidence curated here. BMPR1A has been proposed as a candidate for congenital heart disease in a duplication carrier. The GRID1 cardiac and NRG3 breast-development proposals in the 2011 series concern the reciprocal deletion and do not establish those genes as duplication susceptibility genes.
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name: 10q22.3q23.3 Microduplication Syndrome
creation_date: "2026-09-02T00:00:00Z"
description: >-
10q22.3q23.3 microduplication syndrome is a variably expressed chromosomal
copy-number disorder. The recurrent duplication is flanked by low-copy repeats
LCR3 and LCR4 and is described as 10q22.3q23.2 in the primary literature.
Overlapping duplications with different breakpoints are also reported; their
gene content and clinical effects require separate interpretation.
Reported manifestations include speech and motor developmental delay,
intellectual disability and variable facial dysmorphism. Strabismus,
hypotelorism and anteverted nares were documented in two siblings with the
recurrent duplication. Microcephaly and congenital heart disease were reported
in a separate individual with an overlapping duplication. Clinically unaffected
relatives can carry the recurrent duplication, indicating incomplete penetrance.
Increased DNA copy number is established, but altered expression of individual
genes and the intervening developmental mechanisms are not established by
the evidence curated here. BMPR1A has been proposed as a candidate for
congenital heart disease in a duplication carrier. The GRID1 cardiac and NRG3
breast-development proposals in the 2011 series concern the reciprocal deletion
and do not establish those genes as duplication susceptibility genes.
category: Genetic
synonyms:
- trisomy 10q22.3q23.3
- dup(10)(q22.3q23.3)
- 10q22.3q23.2 microduplication
- recurrent LCR3-LCR4 10q duplication
parents:
- Partial duplication of the long arm of chromosome 10
disease_term:
preferred_term: 10q22.3q23.3 microduplication syndrome
term:
id: MONDO:0017180
label: 10q22.3q23.3 microduplication syndrome
inheritance:
- name: Autosomal dominant with reduced penetrance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
The duplication arises de novo or is inherited. Penetrance is variable: the same
duplication has been identified in clinically healthy family members of affected
probands, so carrier status does not predict phenotype.
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Sibpair patients 10 and 11 inherited this duplication from their healthy mother.
explanation: The Discussion directly documents maternal transmission of the recurrent duplication to two affected children.
- reference: PMID:21248748
reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, the phenotypic spectrum is broad, and duplications have also been found in healthy family members of a proband."
explanation: Documents transmission from clinically unaffected carriers, establishing reduced penetrance.
pathophysiology:
- name: NAHR Between LCR3 and LCR4
biological_scale: MOLECULAR
description: >-
The homologous LCR3 and LCR4 sequences provide a substrate for non-allelic
homologous recombination. This is the proposed formation mechanism for the
recurrent duplication. It does not explain every overlapping duplication,
because rearrangements with unique breakpoints also occur.
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The 10q22.3q23.2 region is characterised by a complex set of low-copy repeats (LCRs), which can give rise to various genomic changes mediated by non-allelic homologous recombination (NAHR).
explanation: The Introduction describes the regional NAHR mechanism; the recurrent duplication breakpoint data support applying it to the LCR3-LCR4 gain.
quote_role: BACKGROUND
- reference: PMID:21248748
reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Five deletions and three duplications occur between LCRs3 and 4, whereas three deletions and three duplications have unique breakpoints."
explanation: >-
Recurrent LCR-bounded rearrangements support an NAHR mechanism by inference
from breakpoint architecture; the study also identifies nonrecurrent events.
downstream:
- target: Increased Dosage of the 10q22.3q23.3 Interval
causal_link_type: DIRECT
description: >-
Recombination between the repeats can produce the recurrent interval gain.
evidence:
- reference: PMID:21248748
reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Five deletions and three duplications occur between LCRs3 and 4, whereas three deletions and three duplications have unique breakpoints."
explanation: The recurrent duplication breakpoints support LCR-mediated formation.
- name: Increased Dosage of the 10q22.3q23.3 Interval
biological_scale: MOLECULAR
description: >-
The duplication adds a copy of the affected chromosomal interval. This is a
DNA dosage change, not a demonstration that every interval gene is
overexpressed. The specific molecular and cellular intermediates linking the
gain to developmental manifestations remain unresolved, and penetrance is
incomplete.
evidence:
- reference: PMID:26383923
reference_title: "Duplication of 10q22.3-q23.3 encompassing BMPR1A and NGR3 associated with congenital heart disease, microcephaly, and mild intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a de novo interstitial 8.2-Mb duplication of 10q22.3-q23.3, including BMPR1A and NGR3, was identified by Illumina SNP array platform"
explanation: Directly establishes increased DNA copy number in an affected individual.
downstream:
- target: Delayed speech and language development
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Motor delay
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Broad forehead
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Deeply set eye
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Upslanted palpebral fissure
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Smooth philtrum
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Thin upper lip vermilion
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Strabismus
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Hypotelorism
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Anteverted nares
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Abnormal heart morphology
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Microcephaly
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Intellectual disability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Micrognathia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Macrodontia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Widely spaced teeth
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Slender build
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Neurologic
name: Delayed speech and language development
description: >-
Speech and language delay is reported in duplication probands; the small
series does not establish a population frequency.
phenotype_term:
preferred_term: Delayed speech and language development
term:
id: HP:0000750
label: Delayed speech and language development
evidence:
- reference: PMID:21248748
reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Probands had speech and/or motor delays and dysmorphisms including a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip."
explanation: Reports speech delay among duplication probands.
- category: Neurologic
name: Motor delay
phenotype_term:
preferred_term: Motor delay
term:
id: HP:0001270
label: Motor delay
evidence:
- reference: PMID:21248748
reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In conclusion, duplications between LCRs3 and 4 on 10q22.3q23.2 may lead to a distinct facial appearance and delays in speech and motor development."
explanation: States motor developmental delay as a conclusion of the duplication cohort.
- category: Craniofacial
name: Broad forehead
phenotype_term:
preferred_term: Broad forehead
term:
id: HP:0000337
label: Broad forehead
evidence:
- reference: PMID:21248748
reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dysmorphisms including a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip"
explanation: Names a broad forehead among the duplication facial features.
- category: Craniofacial
name: Deeply set eye
phenotype_term:
preferred_term: Deeply set eye
term:
id: HP:0000490
label: Deeply set eye
evidence:
- reference: PMID:21248748
reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dysmorphisms including a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip"
explanation: Names deep-set eyes among the duplication facial features.
- category: Craniofacial
name: Upslanted palpebral fissure
phenotype_term:
preferred_term: Upslanted palpebral fissure
term:
id: HP:0000582
label: Upslanted palpebral fissure
evidence:
- reference: PMID:21248748
reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dysmorphisms including a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip"
explanation: Names upslanting palpebral fissures among the duplication facial features.
- category: Craniofacial
name: Smooth philtrum
phenotype_term:
preferred_term: Smooth philtrum
term:
id: HP:0000319
label: Smooth philtrum
evidence:
- reference: PMID:21248748
reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dysmorphisms including a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip"
explanation: Names a smooth philtrum among the duplication facial features.
- category: Craniofacial
name: Thin upper lip vermilion
phenotype_term:
preferred_term: Thin upper lip vermilion
term:
id: HP:0000219
label: Thin upper lip vermilion
evidence:
- reference: PMID:21248748
reference_title: "The phenotype of recurrent 10q22q23 deletions and duplications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dysmorphisms including a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip"
explanation: Names a thin upper lip among the duplication facial features.
- category: Cardiovascular
name: Abnormal heart morphology
description: >-
A cardiac defect was reported in an individual with an overlapping 8.2-Mb
duplication. This single case does not establish the frequency of cardiac
disease in carriers of the recurrent LCR3-LCR4 duplication.
phenotype_term:
preferred_term: Abnormal heart morphology
term:
id: HP:0001627
label: Abnormal heart morphology
evidence:
- reference: PMID:26383923
reference_title: "Duplication of 10q22.3-q23.3 encompassing BMPR1A and NGR3 associated with congenital heart disease, microcephaly, and mild intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We present an additional case with multiple congenital anomalies that include microcephaly, cardiac defect, and mild intellectual disability"
explanation: Reports a cardiac defect in an individual carrying the 10q22.3-q23.3 duplication.
- category: Neurologic
name: Microcephaly
phenotype_term:
preferred_term: Microcephaly
term:
id: HP:0000252
label: Microcephaly
evidence:
- reference: PMID:26383923
reference_title: "Duplication of 10q22.3-q23.3 encompassing BMPR1A and NGR3 associated with congenital heart disease, microcephaly, and mild intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We present an additional case with multiple congenital anomalies that include microcephaly, cardiac defect, and mild intellectual disability"
explanation: Reports microcephaly in an individual carrying the duplication.
- category: Cognitive
name: Intellectual disability
notes: >-
Intellectual disability was reported in the siblings with the recurrent
duplication, while the separate 2015 case was described as mild. Cognitive
outcome across carriers is variable and includes normal development.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Sibpair patients 10 and 11 were mentally retarded.
explanation: The Discussion reports intellectual disability in the siblings with the recurrent duplication, without limiting the severity to mild.
- reference: PMID:26383923
reference_title: "Duplication of 10q22.3-q23.3 encompassing BMPR1A and NGR3 associated with congenital heart disease, microcephaly, and mild intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We present an additional case with multiple congenital anomalies that include microcephaly, cardiac defect, and mild intellectual disability"
explanation: Reports mild intellectual disability in an individual carrying the duplication.
- category: Ophthalmologic
name: Strabismus
phenotype_term:
preferred_term: Strabismus
term:
id: HP:0000486
label: Strabismus
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: show upslanting palpebral fissures, strabismus, hypotelorism, a smooth philtrum and anteverted nares.
explanation: Figure 3B describes strabismus in siblings 10 and 11 with the recurrent duplication.
- category: Craniofacial
name: Hypotelorism
phenotype_term:
preferred_term: Hypotelorism
term:
id: HP:0000601
label: Hypotelorism
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: show upslanting palpebral fissures, strabismus, hypotelorism, a smooth philtrum and anteverted nares.
explanation: Figure 3B describes hypotelorism in siblings 10 and 11 with the recurrent duplication.
- category: Craniofacial
name: Anteverted nares
phenotype_term:
preferred_term: Anteverted nares
term:
id: HP:0000463
label: Anteverted nares
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: show upslanting palpebral fissures, strabismus, hypotelorism, a smooth philtrum and anteverted nares.
explanation: Figure 3B describes anteverted nares in siblings 10 and 11 with the recurrent duplication.
- category: Craniofacial
name: Micrognathia
phenotype_term:
preferred_term: Micrognathia
term:
id: HP:0000347
label: Micrognathia
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Micrognathia | − | + | −
explanation: Table 2 records micrognathia in the sibling column (patients 10–11); patient 9 and patient 12 are negative.
- category: Craniofacial
name: Full cheeks
notes: >-
Reported only in patient 9 with an overlapping nonrecurrent duplication and
patient 12 with an additional de novo 16p13.11 deletion; an independent effect
of the recurrent 10q duplication is not established.
phenotype_term:
preferred_term: Full cheeks
term:
id: HP:0000293
label: Full cheeks
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Full cheeks | + | − | +
explanation: Table 2 records full cheeks in patients 9 and 12, but not in siblings 10–11.
- category: Craniofacial
name: Macrodontia
phenotype_term:
preferred_term: Macrodontia
term:
id: HP:0001572
label: Macrodontia
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Large wide spaced teeth | + | + |
explanation: Table 2 records large teeth in patient 9 and siblings 10–11; no dental finding is recorded for patient 12.
- category: Craniofacial
name: Widely spaced teeth
phenotype_term:
preferred_term: Widely spaced teeth
term:
id: HP:0000687
label: Widely spaced teeth
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Large wide spaced teeth | + | + |
explanation: Table 2 records wide tooth spacing in patient 9 and siblings 10–11; the blank patient 12 column is not a negative finding.
- category: Craniofacial
name: Thick lower lip vermilion
notes: >-
Reported only in patient 9 with an overlapping nonrecurrent duplication and
patient 12 with an additional de novo 16p13.11 deletion; an independent effect
of the recurrent 10q duplication is not established.
phenotype_term:
preferred_term: Thick lower lip vermilion
term:
id: HP:0000179
label: Thick lower lip vermilion
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Full lower lip | + | − | +
explanation: Table 2 records a full lower lip in patients 9 and 12.
- category: Craniofacial
name: Low-set ears
phenotype_term:
preferred_term: Low-set ears
term:
id: HP:0000369
label: Low-set ears
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Low and prominent ears | + | − | −
explanation: Table 2 records low ears in patient 9, who has an overlapping nonrecurrent duplication.
- category: Craniofacial
name: Protruding ear
phenotype_term:
preferred_term: Protruding ear
term:
id: HP:0000411
label: Protruding ear
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Low and prominent ears | + | − | −
explanation: Table 2 records prominent ears in patient 9, who has an overlapping nonrecurrent duplication.
- category: Growth
name: Slender build
phenotype_term:
preferred_term: Slender build
term:
id: HP:0001533
label: Slender build
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Thin built | − | + | −
explanation: Table 2 records a thin build in siblings 10–11 with the recurrent duplication.
- category: Otolaryngologic
name: Recurrent ear infections
phenotype_term:
preferred_term: Recurrent ear infections
term:
id: HP:0410018
label: Recurrent ear infections
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Recurrent ear infections infancy | + |
explanation: Table 2 reports recurrent infant ear infections in patient 9, who carries an overlapping nonrecurrent duplication.
notes: An individual-case observation; no frequency in recurrent LCR3-LCR4 duplication carriers is established.
- category: Behavioral
name: Reduced social responsiveness
phenotype_term:
preferred_term: Impaired social interaction
term:
id: HP:0012760
label: Reduced social responsiveness
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Patients 9 and 12 displayed speech delay and impaired social interaction.
explanation: The Discussion reports impaired social interaction in two duplication probands.
notes: Patient 9 has an overlapping nonrecurrent duplication and patient 12 also has a de novo 16p13.11 deletion. These observations do not isolate the effect of the recurrent 10q duplication or establish autism spectrum disorder.
genetic:
- name: BMPR1A
gene_term:
preferred_term: BMPR1A
term:
id: hgnc:1076
label: BMPR1A
association: Candidate dosage-sensitive gene within the duplicated interval
relationship_type: SUSCEPTIBILITY
notes: >-
Proposed for the cardiac phenotype. Note the two proposals come from different
arms: van Bon et al. named BMPR1A and GRID1 as candidates while describing the
deletion cohort, whereas Tang et al. proposed BMPR1A independently on the
duplication side. That independent duplication-side proposal is what makes the
attribution credible here rather than borrowed from the reciprocal deletion.
Typed SUSCEPTIBILITY because candidacy has not been upgraded to a demonstrated
mechanism in either report.
evidence:
- reference: PMID:26383923
reference_title: "Duplication of 10q22.3-q23.3 encompassing BMPR1A and NGR3 associated with congenital heart disease, microcephaly, and mild intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our study is consistent with the hypothesis that the BMPR1A is a plausible candidate gene for congenital heart disease (CHD)"
explanation: The independent proposal made on the duplication side, in the source's own hypothetical terms.
notes: >-
The 2011 series separates recurrent LCR3-LCR4 duplications from overlapping
nonrecurrent gains and small intragenic NRG3 duplications. The latter were
considered most likely non-pathogenic by the authors and are not used here to
attribute tetralogy of Fallot or genital anomalies to the recurrent syndrome.
Table 2 contains four individuals, with two siblings grouped into one column;
its column count must not be used as the patient denominator. No population
phenotype frequencies are inferred from this ascertained series. The Discussion
and Table 2 disagree about speech delay in patient 12, further precluding a
reliable case-fraction estimate from that source.
diagnosis:
- name: Chromosomal microarray
description: >-
The duplication is detected by genome-wide copy-number analysis; reported cases
were ascertained by array CGH or SNP array.
evidence:
- reference: PMID:21248748
reference_title: The phenotype of recurrent 10q22q23 deletions and duplications.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The submicroscopic aberrations were detected by array analysis using different array platforms.
explanation: The Methods establish array-based ascertainment of the 2011 duplication cohort.
- reference: PMID:26383923
reference_title: "Duplication of 10q22.3-q23.3 encompassing BMPR1A and NGR3 associated with congenital heart disease, microcephaly, and mild intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a de novo interstitial 8.2-Mb duplication of 10q22.3-q23.3, including BMPR1A and NGR3, was identified by Illumina SNP array platform"
explanation: Documents SNP array as the diagnostic modality that identified the duplication.
references:
- reference: PMID:21248748
title: "The phenotype of recurrent 10q22q23 deletions and duplications."
- reference: PMID:26383923
title: "Duplication of 10q22.3-q23.3 encompassing BMPR1A and NGR3 associated with congenital heart disease, microcephaly, and mild intellectual disability."
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Review regional duplication evidence and recover full-text phenotype coverage · 2026-09-21T01:12:00Z · View source
Reviewed the whole entry, all existing evidence, and the matching Falcon deep-research report and citations. Independently checked claim-to-source alignment and phenotype specificity. The entry had no prior REVIEW event. Source coverage: PMID:21248748 previously claimed full-text availability but contained the abstract and publisher landing-page material without the Results, tables or Discussion. Regenerated it with just fetch-reference after adapting the ignored local PMC provider to the modern PMC article container and HTML fallback. The resulting cache includes the actual article, Table 2 and Figure 3 captions; Figure 2 was also inspected for gene position. No reference cache was hand-edited. PMID:26383923 and the Siggberg 2010 DOI cache were read as abstracts; their unavailable full text was not treated as verified evidence. The latter abstract does not establish its reported individual 10q case and adds no independently quotable disease-specific claim. Corrected deletion-to-duplication extrapolation: GRID1 and NRG3 candidate assignments came from deletion-side findings, and PTEN is outside the recurrent interval shown in Figure 2. Retained BMPR1A only as the hypothesis proposed independently in the 2015 duplication case. Separated the proposed NAHR event from increased DNA dosage, removed unsupported expression and developmental-process assertions, and used unknown-intermediate clinical links. Individual facial findings no longer arise causally from a facial gestalt node. Findings confined to atypical or additionally confounded individuals are retained as observations without an asserted causal edge. Added 13 specific phenotypes from the full-text table, figure caption and Discussion, removed the redundant facial gestalt, and broadened mild intellectual disability to the severity range actually documented. The table represents four individuals because two siblings share a column; neither column counts nor the report's 3/3 estimates are population frequencies. Patient 12 has an additional 16p13.11 deletion, and the table and Discussion disagree about that patient's speech delay. Small intragenic NRG3 duplications considered likely nonpathogenic by the authors are not used to attribute tetralogy of Fallot or genital anomalies to this syndrome. Content-completeness checklist: - Phenotypes: adequate for the verifiable regional-duplication evidence; 23 specific observations cover the major supported organ-system themes. No frequency estimates were inferred from the ascertained case series. - Subtypes: adequate scope distinction between recurrent and overlapping gains; no independently established mapped subtypes were identified. - Pathophysiology: adequate for available evidence. More detailed neural, cardiac and chromatin mechanisms in the report remain hypotheses without duplication-specific experimental support; no invented GO bindings added. - Treatments/trials: no trial-supported treatment surfaced. The report's supportive-care suggestions are explicitly expert-practice inference and are not stated in the cited primary text. This is a non-blocking evidence gap; unsupported treatment snippets were not manufactured. - Genetics: adequate CNV and inheritance scope, reduced penetrance and candidate-gene qualification. No verified modifier or expression study. - Diagnostics/biomarkers: array-based diagnosis backed by Methods and the 2015 SNP-array case. No validated biochemical biomarker was identified. - References: the principal full-text source is now actively mined across clinical, inheritance, mechanistic and diagnostic findings. All 33 evidence items have source-consistent titles and exact cached snippets. - Overall consumption: central verifiable findings are represented; the report's denominator mistakes and reciprocal-deletion extrapolations were corrected against the primary source rather than imported. Identity preflight: the automated gene-based check skips this multigene CNV; manual review confirmed MONDO:0017180 and its synonyms, ORPHA:276422, GARD:21052 and MEDGEN:1682781 against the disease concept. GeneReviews and StatPearls checks found no chapter in the 2026-09-10 Bookshelf snapshot. Live HPO lookup supported HP:0410018 for recurrent ear infections without assuming otitis media; the obsolete impaired-social-interaction term was replaced by its current HP:0012760 mapping. Existing coarse cardiac binding remains appropriate because the accessible abstract specifies only a defect. Validation: schema, ontology terms and all 33/33 cached snippets pass. Causal targets, entity references, duplicate keys and coarse phenotype checks pass. An independent peer review checked table denominators, confounding, ontology specificity and the revised mechanistic claims.
Create: 10q22.3q23.3 Microduplication Syndrome · 2026-09-02T17:12:55Z · View source
Created the entry for the recurrent LCR3-LCR4 duplication at 10q22.3q23.3, the reciprocal of the better-characterised microdeletion. Deep research was run with falcon; that report cited only two sources (no PMIDs, two DOIs), so the evidence base was built by direct PubMed search instead. Primary sources are van Bon et al. 2011 (PMID:21248748), the cohort describing six duplications and the duplication facial gestalt, speech/motor delay and reduced penetrance, and Tang et al. 2015 (PMID:26383923), the duplication case report adding microcephaly, cardiac defect and mild intellectual disability. The pathograph is modelled as NAHR between LCR3/LCR4 -> increased dosage of the interval -> phenotypes, with edges to the case-report phenotypes marked INDIRECT_UNKNOWN_INTERMEDIATES because no interval gene has been established as the driver; BMPR1A and GRID1 are recorded as candidates in the sources' own hypothetical terms. Hypotonia and behavioural difficulty were dropped from the initial draft because no cited source supported them. The cytoband convention conflict (10q22.3q23.2 vs 10q22.3q23.3 for the same rearrangement) is recorded in the entry description. Validated with just validate (17/17 snippets verified, term validation passed), check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values and check-qualifier-terms.
10q22.3q23.3 microduplication syndrome is an exceptionally rare, variably expressed chromosomal copy-number disorder caused by an interstitial gain of material on chromosome 10q. The best-supported recurrent form is an approximately 7.2–7.4-Mb duplication between low-copy repeats LCR3 and LCR4, usually described as 10q22.3q23.2; somewhat larger, nonrecurrent duplications may extend into q23.3. The most reproducible manifestations are developmental—especially speech/language delay—mild-to-moderate intellectual or learning impairment, behavioral/social difficulties, and variable facial dysmorphism. Congenital heart disease and microcephaly have been reported in individual larger-duplication cases, but their frequencies and causal relationship remain uncertain. Both de novo and inherited events occur, including transmission from apparently healthy relatives, indicating variable expressivity and probable incomplete penetrance. (bon2011thephenotypeof pages 4-5, siggberg2010arraycghin pages 8-9, bon2011thephenotypeof pages 1-2)
The evidence base is extremely small. The principal syndrome-defining study is van Bon et al., published online 19 January 2011 and in print April 2011, DOI: https://doi.org/10.1038/ejhg.2010.211. It studied 14 people with 10q22q23 rearrangements, including six duplications, only three of which were recurrent LCR3–LCR4 events. Siggberg et al., published June 2010, reported a 7.21-Mb duplication in an array-CGH cohort; DOI: https://doi.org/10.1002/ajmg.a.33402. No syndrome-specific primary publication from 2023–2024 was retrieved, and no controlled natural-history study, registry, guideline, or treatment trial was identified. Therefore, percentages below are case-series counts—not population estimates. (bon2011thephenotypeof pages 1-2, siggberg2010arraycghin pages 4-5)
| Domain | Supported finding | Evidence strength/limitations | Suggested ontology terms |
|---|---|---|---|
| Genomic lesion / NAHR | Germline interstitial duplication of 10q22.3–q23.2/q23.3; recurrent approximately 7.2–7.4 Mb rearrangements can be bounded by low-copy repeats LCR3 and LCR4, consistent with non-allelic homologous recombination. Larger and unique-breakpoint duplications also occur. | Strong evidence for the structural lesion; LCR-mediated NAHR is strongly supported for recurrent events. Breakpoints vary, so each case requires genome-build-specific coordinates. (bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 2-3, siggberg2010arraycghin pages 9-10) | structural chromosome anomaly; chromosomal duplication; GO:0090200 — positive regulation of release of sister chromatid cohesion; GO:0006310 — DNA recombination |
| Neurodevelopment | Developmental delay, motor delay, intellectual disability, and learning difficulties are recurrently reported. In one three-case tabulation, developmental delay occurred in all three individuals. | Moderate case-series evidence but very small, clinically ascertained samples; severity is variable and additional CNVs sometimes confound attribution. (bon2011thephenotypeof pages 4-5, siggberg2010arraycghin pages 8-9, bon2011thephenotypeof pages 1-2) | HP:0012758 — Neurodevelopmental delay; HP:0001263 — Global developmental delay; HP:0001249 — Intellectual disability; HP:0001270 — Motor delay |
| Speech and language | Delayed speech and language development is a prominent manifestation; two of three tabulated duplication cases had speech delay. | Moderate evidence from a small cohort; no population-based frequency or standardized language testing is available. (bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 1-2) | HP:0000750 — Delayed speech and language development |
| Behavior / social interaction | Impaired social interaction and behavioral abnormalities have been described; autism, hyperactivity, and aggression occur in the broader 10q22q23 cohort but cannot all be assigned specifically to duplication carriers. | Limited duplication-specific evidence; impaired social interaction occurred in two of three tabulated cases, while broader behavioral counts mix deletion and duplication cases. (bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 5-7) | HP:0000729 — Autistic behavior; HP:0000752 — Hyperactivity; HP:0000718 — Aggressive behavior; impaired social interaction |
| Craniofacial morphology | Reported features include broad forehead, deep-set eyes, upslanting palpebral fissures, smooth philtrum, thin upper lip, full cheeks, micrognathia, anteverted nares, and large widely spaced teeth. | Moderate descriptive evidence for a recognizable but variable pattern; none is obligatory or independently diagnostic. (bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 1-2, bon2011thephenotypeof pages 5-7) | HP:0000337 — Broad forehead; HP:0000490 — Deeply set eye; HP:0000582 — Upslanted palpebral fissure; HP:0000319 — Smooth philtrum; HP:0000219 — Thin upper lip vermilion; HP:0000347 — Micrognathia; HP:0000463 — Anteverted nares |
| Eyes and ears | Strabismus, hypotelorism, low-set or prominent ears, and recurrent infant ear infections have been reported. | Limited case-series evidence; visual problems in one NRG3-duplication case were considered more likely related to prematurity. (bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 5-7) | HP:0000486 — Strabismus; HP:0000601 — Hypotelorism; HP:0000369 — Low-set ears; HP:0000413 — Atresia of the external auditory canal not supported and should not be assigned; recurrent otitis media |
| Congenital heart disease / microcephaly | Congenital heart disease and microcephaly were associated with an 18.6 Mb de novo duplication; tetralogy of Fallot was reported with an intragenic NRG3 duplication. | Rare single-case associations only; no causal gene, penetrance estimate, or reliable frequency has been established. Growth and head circumference are otherwise variable. (siggberg2010arraycghin pages 8-9, bon2011thephenotypeof pages 5-7) | HP:0001627 — Abnormal heart morphology; HP:0001636 — Tetralogy of Fallot; HP:0000252 — Microcephaly |
| Penetrance / inheritance | Both de novo and inherited duplications occur, including maternal and paternal transmission; apparently healthy relatives can carry overlapping duplications. | Strong evidence for variable expressivity and probable incomplete penetrance, but penetrance cannot be quantified. Some inherited small duplications were judged likely non-pathogenic. (bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 1-2, siggberg2010arraycghin pages 8-9) | HP:0003829 — Incomplete penetrance; variable expressivity; autosomal inheritance |
| Candidate dosage mechanisms | Increased dosage across a multigene interval is the leading hypothesis. BMPR1A, NRG3, GRID1, PTEN, and WAPL are biologically plausible candidates, but no individual gene has been proven to drive the duplication phenotype. | Hypothesis-level evidence only. Findings from 10q22q23 deletions, especially PTEN/BMPR1A loss phenotypes, must not be extrapolated to duplications. (bon2011thephenotypeof pages 1-2, bon2011thephenotypeof pages 5-7, siggberg2010arraycghin pages 8-9) | gene dosage; GO:0006355 — regulation of DNA-templated transcription; GO:0007399 — nervous system development; GO:0007507 — heart development |
| Diagnostics | Chromosomal microarray—array CGH or SNP array—is the primary detection method. Parental testing clarifies inheritance; FISH or MLPA may confirm selected findings, while sequencing-based CNV analysis or genome sequencing may refine breakpoints and detect additional variants. | Strong clinical-laboratory evidence for CMA detection. Conventional karyotyping can miss microduplications; exact interpretation requires coordinates, genome build, gene content, inheritance, phenotype, and comparison with curated CNV databases. (bon2011thephenotypeof pages 2-3, siggberg2010arraycghin pages 4-5, siggberg2010arraycghin pages 6-7) | chromosomal microarray analysis; array comparative genomic hybridization; fluorescence in situ hybridization; multiplex ligation-dependent probe amplification; genome sequencing |
| Management | Care is supportive and phenotype-directed: developmental assessment, early speech/language therapy, physical and occupational therapy, behavioral assessment, audiology and ophthalmology evaluation, and cardiac evaluation when clinically indicated. | Expert-practice inference from manifestations; no syndrome-specific guideline, controlled treatment study, or response-rate evidence was identified. (bon2011thephenotypeof pages 1-2, bon2011thephenotypeof pages 4-5) | NCIT: C61560 — Supportive Care; NCIT: C15329 — Speech Therapy; NCIT: C15330 — Physical Therapy; occupational therapy; early intervention |
| Unsupported or unavailable domains | No established environmental, infectious, lifestyle, metabolic, immune, or protective factors; no validated biochemical biomarker, syndrome-specific drug, pharmacogenomic rule, gene/RNA/cell therapy, clinical trial, natural animal disease, whole-duplication model, single-cell study, spatial transcriptomic study, or diagnostic multi-omics signature was identified. | Absence of published evidence is not proof of biological absence; the literature consists mainly of old, small human case series, with no syndrome-specific 2023–2024 primary research retrieved. (bon2011thephenotypeof pages 1-2, bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 5-7, siggberg2010arraycghin pages 8-9) | Not applicable / no supported ontology annotation beyond chromosomal duplication and phenotype-directed care |
Table: Compact evidence map for 10q22.3q23.3 microduplication syndrome, separating supported duplication findings from rare associations and unsupported domains. Ontology identifiers are included only where sufficiently established.
This is a constitutional chromosomal microduplication disorder, not a single-gene disease. It encompasses overlapping but nonidentical duplications of 10q22.3–q23.2/q23.3. The recurrent rearrangement is bounded by LCR3 and LCR4; duplications with unique breakpoints or substantially different extents should be recorded separately because their gene content and pathogenicity can differ. Small inherited duplications within the region have sometimes been judged likely benign, emphasizing that “10q22.3q23.3 duplication” is not by itself a sufficient pathogenic classification. (bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 2-3)
Common names include:
A distinct, confidently verified disease-specific OMIM, Orphanet, MeSH, MONDO, ICD-10, or ICD-11 identifier was not established from the retrieved primary literature. For knowledge-base curation, the record should therefore use a chromosomal-duplication parent concept and preserve the exact ISCN/genomic coordinates. Broad clinical coding may use “other specified chromosome abnormality,” but such codes are not syndrome-specific. The evidence is aggregated from published clinical case series and diagnostic cohorts, not longitudinal EHR-derived population data. (bon2011thephenotypeof pages 1-2, siggberg2010arraycghin pages 4-5)
The initiating lesion is a usually germline interstitial duplication of chromosome 10. Recurrent events are most plausibly generated by non-allelic homologous recombination (NAHR) between LCR3 and LCR4 during meiosis. Unique-breakpoint events can arise through other structural-variant mechanisms. Both de novo and inherited duplications have been documented. (bon2011thephenotypeof pages 2-3, siggberg2010arraycghin pages 9-10, bon2011thephenotypeof pages 4-5)
The causal “risk factor” is carriage of the duplication. If a parent carries it, each pregnancy has a theoretical 50% transmission probability, but phenotype and severity cannot be predicted because penetrance and expressivity are variable. For a confirmed de novo event, recurrence is expected to be low but not zero because parental germline mosaicism cannot be excluded. Balanced parental rearrangements should be considered when the child’s architecture is atypical.
No environmental, infectious, toxic, occupational, lifestyle, sex-specific, founder, consanguinity-related, or ancestry-specific risk factor has been established. No genetic or environmental protective factor, modifier allele, or gene–environment interaction has been demonstrated. Apparently unaffected carriers are evidence of incomplete penetrance, not of a known protective exposure. (bon2011thephenotypeof pages 1-2)
In one three-case duplication table, developmental delay was present in 3/3, speech delay in 2/3, and impaired social interaction in 2/3. Another 7.21-Mb case had intellectual disability and dysmorphic features. Reported severity is generally mild to moderate but variable; formal IQ, adaptive-function, and longitudinal trajectory data are insufficient. Additional CNVs in some individuals complicate attribution. Suggested HPO annotations are Global developmental delay (HP:0001263), Neurodevelopmental delay (HP:0012758), Intellectual disability (HP:0001249), Motor delay (HP:0001270), and Delayed speech and language development (HP:0000750). (bon2011thephenotypeof pages 4-5, siggberg2010arraycghin pages 8-9)
Impaired social interaction and behavioral problems are reported. Autism, hyperactivity, and aggression occurred in the broader 10q22q23 cohort, but the available text mixes deletion and duplication probands; these must not be assigned universal duplication frequencies. Appropriate case-level terms include Autistic behavior (HP:0000729), Hyperactivity (HP:0000752), and Aggressive behavior (HP:0000718) only when clinically documented. (bon2011thephenotypeof pages 5-7)
Variable findings include broad forehead, triangular face, deep-set eyes, upslanting palpebral fissures, laterally flared eyebrows, smooth philtrum, thin upper lip, full lower lip or cheeks, anteverted nares, micrognathia, hypotelorism, prominent or low-set ears, and large widely spaced teeth. Siblings with the same duplication shared upslanting palpebral fissures, strabismus, hypotelorism, smooth philtrum, and anteverted nares, supporting—but not proving—a recognizable facial pattern. None is obligatory or diagnostic. Suggested terms include Broad forehead (HP:0000337), Deeply set eye (HP:0000490), Upslanted palpebral fissure (HP:0000582), Smooth philtrum (HP:0000319), Thin upper-lip vermilion (HP:0000219), Micrognathia (HP:0000347), Anteverted nares (HP:0000463), Strabismus (HP:0000486), and Hypotelorism (HP:0000601). (bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 5-7)
Recurrent infant ear infections were observed in some cases; use Recurrent otitis media as a phenotype term where documented. A vision problem in one intragenic NRG3 duplication case was considered more likely related to prematurity and should not be treated as definitive syndrome evidence. (bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 5-7)
Head size and growth are variable. A separate 18.6-Mb de novo duplication was associated with microcephaly and congenital heart disease, while tetralogy of Fallot was reported with an intragenic NRG3 duplication. These are single-case associations, not established core features. Suggested terms are Microcephaly (HP:0000252), Abnormal heart morphology (HP:0001627), and Tetralogy of Fallot (HP:0001636) when present. Seizures were not reported in the summarized recurrent-duplication table. (bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 5-7, siggberg2010arraycghin pages 8-9)
No EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life data exist. Likely burdens arise from communication difficulty, learning support needs, social/behavioral challenges, and therapies or procedures required for congenital anomalies. These are clinical inferences rather than measured syndrome-specific outcomes.
The defining variant is a germline structural copy-number gain, generally present in three copies. In hg18-era reports, recurrent duplications were approximately 81.6–89.0 Mb; another duplication was 79.4–86.6 Mb, and smaller unique duplications included approximately 84.2–85.0 Mb and 84.5–84.8 Mb. Coordinates must never be transferred between genome builds without liftover, and exact breakpoints may remain uncertain when they lie inside repetitive LCRs. (bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 2-3)
A Finnish patient carried a 7.21-Mb dup(10)(q22.3q23.2). Because its breakpoints did not disrupt a known gene, the authors proposed a regional dosage effect. In contemporary ACMG/ClinGen practice, classification must be performed for the individual CNV using size, gene content, dosage evidence, inheritance, phenotype specificity, population databases, and any additional variants; it cannot be inferred solely from the cytoband label. Population allele frequency is not meaningfully expressible as a single SNV-like frequency for these heterogeneous CNVs. (siggberg2010arraycghin pages 8-9)
Genes frequently discussed within overlapping intervals include BMPR1A, NRG3, GRID1, PTEN, and WAPL, but no single gene has been proven to account for the duplication phenotype. BMPR1A and GRID1 have been proposed in cardiac development and NRG3 in developmental phenotypes, but much of this discussion derives from deletion cases. Loss of PTEN and BMPR1A causes recognizable deletion/contiguous-gene phenotypes; those loss-of-function effects must not be extrapolated to increased dosage. No validated modifier genes, syndrome-specific methylation signature, or other epigenetic mechanism has been demonstrated. (bon2011thephenotypeof pages 1-2, bon2011thephenotypeof pages 5-7, siggberg2010arraycghin pages 8-9)
No toxin, radiation exposure, pollution, diet, exercise pattern, alcohol, smoking, medication, infection, or maternal illness is known to cause or modify this constitutional duplication syndrome. Infectious agents and public-health exposure control are not applicable to etiology. Routine healthy lifestyle and immunization advice remains appropriate for general health but does not prevent the chromosomal lesion.
Candidate pathway annotations should remain hypothesis-level: BMP/TGF-β receptor signaling for BMPR1A, PI3K–AKT regulation for PTEN, neuregulin signaling for NRG3, glutamatergic signaling for GRID1, and cohesin/chromosome organization for WAPL. Suggested broad GO processes are DNA recombination (GO:0006310), nervous-system development (GO:0007399), heart development (GO:0007507), and regulation of DNA-templated transcription. Relevant inferred cell classes include neural progenitor cells, neurons, neural-crest-derived craniofacial cells, and cardiomyocyte/cardiac progenitor lineages; no syndrome-specific Cell Ontology assignment has been experimentally validated.
No duplication-specific apoptosis, autophagy, metabolic, immune, inflammatory, tissue-injury, biochemical, transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, multi-omic, CRISPR-screen, or RNAi-screen result was identified. (bon2011thephenotypeof pages 1-2, bon2011thephenotypeof pages 5-7)
The best-supported system is the nervous system, reflected by developmental, cognitive, language, and behavioral manifestations. Craniofacial structures, eyes, ears, and dentition are variably affected. The cardiovascular system is a possible secondary domain in selected cases. Suggested anatomy concepts include brain (UBERON:0000955), head (UBERON:0000033), eye (UBERON:0000970), ear (UBERON:0001690), and heart (UBERON:0000948). No consistent lateralization is reported. (bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 5-7, siggberg2010arraycghin pages 8-9)
At tissue/cell and subcellular levels, direct pathology has not been established. Nuclear/chromosomal organization is relevant to formation of the structural variant, but no disease-specific histopathology, organ biopsy phenotype, or cellular compartment abnormality has been demonstrated.
The duplication is present from conception. Congenital dysmorphism or structural malformations may be recognizable prenatally or neonatally, whereas developmental, language, learning, and behavioral manifestations generally become evident during infancy or childhood. The disorder is lifelong, but evidence does not support formal stages, a degenerative course, episodic relapses, or remission. Developmental skills may improve with maturation and intervention, although persistent support needs can remain. No longitudinal progression rate or critical-window study exists. Early childhood is nevertheless the practical window for developmental surveillance and early intervention. (bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 1-2)
Both de novo and autosomally transmitted duplications occur. Reported events include maternal and paternal inheritance; apparently healthy relatives and paternally inherited small duplications demonstrate incomplete penetrance and variable expressivity. The recurrent lesion is not appropriately described as a classic autosomal-dominant Mendelian disorder with known penetrance. No anticipation, founder effect, consanguinity association, sex bias, ethnic enrichment, or geographic clustering has been demonstrated. (bon2011thephenotypeof pages 4-5, bon2011thephenotypeof pages 1-2)
Prevalence, incidence, carrier frequency, sex ratio, and age distribution are unknown. The few published cases cannot support cases-per-100,000 estimates. Ascertainment through developmental-disability cohorts also produces substantial selection bias. In one Finnish cohort of 150 patients with intellectual disability/dysmorphism or malformations and normal karyotypes, genome-wide array CGH found reportable abnormalities in 28 index patients (18.6% overall yield), but only one relevant 10q duplication was described; this is not a syndrome-prevalence estimate. (siggberg2010arraycghin pages 4-5)
Karyotyping can detect larger duplications or balanced rearrangements but may miss a 7-Mb or smaller event depending on resolution. Single-gene testing, mitochondrial DNA testing, repeat-expansion testing, liquid biopsy, metabolomics, and epigenomic testing are not diagnostic for this syndrome.
After molecular confirmation, assess development, speech/language, adaptive behavior, hearing, vision, growth/head circumference, and dysmorphology. Cardiac examination and echocardiography are reasonable if a murmur, prenatal anomaly, cyanosis, or larger duplication is present; evidence is insufficient to mandate repeated echocardiography in every asymptomatic carrier.
Differential diagnoses include 10q22q23 deletion syndrome, PTEN hamartoma-tumor syndrome, BMPR1A-related juvenile polyposis, other pathogenic CNVs causing developmental delay, and monogenic neurodevelopmental syndromes. Gastrointestinal polyposis and cancer susceptibility associated with PTEN/BMPR1A loss should not automatically be assigned to duplication carriers. (bon2011thephenotypeof pages 1-2, bon2011thephenotypeof pages 5-7)
There are no standardized syndrome-specific clinical criteria, biochemical biomarkers, newborn-screening program, or population carrier-screening recommendation.
No survival curves, mortality rates, life-expectancy estimates, hospitalization rates, disability-adjusted life years, or validated prognostic biomarkers are available. Available cases do not establish a progressive lethal disorder; prognosis is instead expected to depend on the degree of neurodevelopmental disability, behavioral needs, congenital malformations, additional genomic findings, and access to intervention. The recovery potential for congenital intellectual disability is limited, but functional communication, motor skills, and participation may improve with appropriate support.
No evidence establishes increased cancer risk from duplication alone. Applying cancer surveillance designed for PTEN or BMPR1A loss-of-function syndromes solely because those genes are duplicated would be unsupported. (bon2011thephenotypeof pages 1-2, bon2011thephenotypeof pages 5-7)
There is no disease-modifying pharmacotherapy, approved targeted treatment, gene therapy, genome editing, RNA therapy, cell therapy, immunotherapy, or validated pharmacogenomic rule. No syndrome-specific interventional clinical trial or NCT identifier was found. (bon2011thephenotypeof pages 1-2, bon2011thephenotypeof pages 4-5)
Management is individualized:
No response rates or syndrome-specific adverse-event profile have been published. “Precision medicine” currently means precise breakpoint/gene-content interpretation and phenotype-directed care, not a gene-dosage-targeted drug.
The chromosomal event generally cannot be prevented by lifestyle or vaccination. Primary prevention is limited to informed reproductive choices after genetic counseling. Secondary prevention consists of early molecular diagnosis, developmental screening, hearing/vision assessment, and timely treatment of congenital anomalies. Tertiary prevention includes therapies, educational support, behavioral care, and management of complications.
For an affected family, counseling should include parental testing, recurrence-risk interpretation, prenatal diagnosis by chorionic-villus sampling or amniocentesis with CMA, and—when a familial pathogenic/likely pathogenic duplication is established—preimplantation genetic testing for structural rearrangements. Noninvasive prenatal screening may suggest a large CNV but is not diagnostic. Variable penetrance means prenatal detection cannot reliably predict severity. Cascade testing is reasonable for relatives when results will alter reproductive counseling or clinical evaluation. (bon2011thephenotypeof pages 1-2, bon2011thephenotypeof pages 4-5)
No naturally occurring homologous whole-region microduplication syndrome was identified in companion animals, livestock, or wildlife. There is no zoonotic potential or cross-species transmission because this is a constitutional genomic disorder. Orthologs of interval genes occur in common vertebrate models, but gene-level orthology does not establish an animal counterpart of the human CNV. No relevant breed or VBO term is supported.
No validated mouse, rat, zebrafish, Drosophila, C. elegans, organoid, iPSC, or cell-line model reproducing the complete human 10q22.3q23.3 duplication was identified. Individual interval genes have conventional knockout or transgenic models, but loss-of-function models—particularly for Pten or Bmpr1a—do not model three-copy human dosage and cannot establish the duplication mechanism. The best future models would be engineered syntenic duplications or patient-derived iPSC neural and cardiac differentiation systems, followed by allele/dosage-rescue experiments. These are research recommendations, not current validated resources. (bon2011thephenotypeof pages 1-2, bon2011thephenotypeof pages 5-7)
PMIDs were not present in the retrieved full-text evidence and are therefore not supplied rather than risk misidentification. The literature search found no adequate 2023–2024 syndrome-specific update; consequently, the current disease definition still rests primarily on these small 2010–2011 human clinical datasets. All mechanistic statements beyond LCR-mediated rearrangement should be curated as inferred/hypothesis-level, and all frequencies should retain their original tiny denominators.
References
(bon2011thephenotypeof pages 4-5): Bregje W M van Bon, Jorune Balciuniene, Gary Fruhman, Sandesh Chakravarthy Sreenath Nagamani, Diane L Broome, Elizabeth Cameron, Danielle Martinet, Eliane Roulet, Sebastien Jacquemont, Jacques S Beckmann, Mira Irons, Lorraine Potocki, Brendan Lee, Sau Wai Cheung, Ankita Patel, Melissa Bellini, Angelo Selicorni, Roberto Ciccone, Margherita Silengo, Annalisa Vetro, Nine V Knoers, Nicole de Leeuw, Rolph Pfundt, Barry Wolf, Petr Jira, Swaroop Aradhya, Pawel Stankiewicz, Han G Brunner, Orsetta Zuffardi, Scott B Selleck, James R Lupski, and Bert B A de Vries. The phenotype of recurrent 10q22q23 deletions and duplications. European Journal of Human Genetics, 19:400-408, Apr 2011. URL: https://doi.org/10.1038/ejhg.2010.211, doi:10.1038/ejhg.2010.211. This article has 87 citations and is from a domain leading peer-reviewed journal.
(siggberg2010arraycghin pages 8-9): Linda Siggberg, Sirpa Ala‐Mello, Elisa Jaakkola, Esa Kuusinen, Robert Schuit, Jürgen Kohlhase, Detlef Böhm, Jaakko Ignatius, and Sakari Knuutila. Array cgh in molecular diagnosis of mental retardation—a study of 150 finnish patients. American Journal of Medical Genetics Part A, 152A:1398-1410, Jun 2010. URL: https://doi.org/10.1002/ajmg.a.33402, doi:10.1002/ajmg.a.33402. This article has 59 citations.
(bon2011thephenotypeof pages 1-2): Bregje W M van Bon, Jorune Balciuniene, Gary Fruhman, Sandesh Chakravarthy Sreenath Nagamani, Diane L Broome, Elizabeth Cameron, Danielle Martinet, Eliane Roulet, Sebastien Jacquemont, Jacques S Beckmann, Mira Irons, Lorraine Potocki, Brendan Lee, Sau Wai Cheung, Ankita Patel, Melissa Bellini, Angelo Selicorni, Roberto Ciccone, Margherita Silengo, Annalisa Vetro, Nine V Knoers, Nicole de Leeuw, Rolph Pfundt, Barry Wolf, Petr Jira, Swaroop Aradhya, Pawel Stankiewicz, Han G Brunner, Orsetta Zuffardi, Scott B Selleck, James R Lupski, and Bert B A de Vries. The phenotype of recurrent 10q22q23 deletions and duplications. European Journal of Human Genetics, 19:400-408, Apr 2011. URL: https://doi.org/10.1038/ejhg.2010.211, doi:10.1038/ejhg.2010.211. This article has 87 citations and is from a domain leading peer-reviewed journal.
(siggberg2010arraycghin pages 4-5): Linda Siggberg, Sirpa Ala‐Mello, Elisa Jaakkola, Esa Kuusinen, Robert Schuit, Jürgen Kohlhase, Detlef Böhm, Jaakko Ignatius, and Sakari Knuutila. Array cgh in molecular diagnosis of mental retardation—a study of 150 finnish patients. American Journal of Medical Genetics Part A, 152A:1398-1410, Jun 2010. URL: https://doi.org/10.1002/ajmg.a.33402, doi:10.1002/ajmg.a.33402. This article has 59 citations.
(bon2011thephenotypeof pages 2-3): Bregje W M van Bon, Jorune Balciuniene, Gary Fruhman, Sandesh Chakravarthy Sreenath Nagamani, Diane L Broome, Elizabeth Cameron, Danielle Martinet, Eliane Roulet, Sebastien Jacquemont, Jacques S Beckmann, Mira Irons, Lorraine Potocki, Brendan Lee, Sau Wai Cheung, Ankita Patel, Melissa Bellini, Angelo Selicorni, Roberto Ciccone, Margherita Silengo, Annalisa Vetro, Nine V Knoers, Nicole de Leeuw, Rolph Pfundt, Barry Wolf, Petr Jira, Swaroop Aradhya, Pawel Stankiewicz, Han G Brunner, Orsetta Zuffardi, Scott B Selleck, James R Lupski, and Bert B A de Vries. The phenotype of recurrent 10q22q23 deletions and duplications. European Journal of Human Genetics, 19:400-408, Apr 2011. URL: https://doi.org/10.1038/ejhg.2010.211, doi:10.1038/ejhg.2010.211. This article has 87 citations and is from a domain leading peer-reviewed journal.
(siggberg2010arraycghin pages 9-10): Linda Siggberg, Sirpa Ala‐Mello, Elisa Jaakkola, Esa Kuusinen, Robert Schuit, Jürgen Kohlhase, Detlef Böhm, Jaakko Ignatius, and Sakari Knuutila. Array cgh in molecular diagnosis of mental retardation—a study of 150 finnish patients. American Journal of Medical Genetics Part A, 152A:1398-1410, Jun 2010. URL: https://doi.org/10.1002/ajmg.a.33402, doi:10.1002/ajmg.a.33402. This article has 59 citations.
(bon2011thephenotypeof pages 5-7): Bregje W M van Bon, Jorune Balciuniene, Gary Fruhman, Sandesh Chakravarthy Sreenath Nagamani, Diane L Broome, Elizabeth Cameron, Danielle Martinet, Eliane Roulet, Sebastien Jacquemont, Jacques S Beckmann, Mira Irons, Lorraine Potocki, Brendan Lee, Sau Wai Cheung, Ankita Patel, Melissa Bellini, Angelo Selicorni, Roberto Ciccone, Margherita Silengo, Annalisa Vetro, Nine V Knoers, Nicole de Leeuw, Rolph Pfundt, Barry Wolf, Petr Jira, Swaroop Aradhya, Pawel Stankiewicz, Han G Brunner, Orsetta Zuffardi, Scott B Selleck, James R Lupski, and Bert B A de Vries. The phenotype of recurrent 10q22q23 deletions and duplications. European Journal of Human Genetics, 19:400-408, Apr 2011. URL: https://doi.org/10.1038/ejhg.2010.211, doi:10.1038/ejhg.2010.211. This article has 87 citations and is from a domain leading peer-reviewed journal.
(siggberg2010arraycghin pages 6-7): Linda Siggberg, Sirpa Ala‐Mello, Elisa Jaakkola, Esa Kuusinen, Robert Schuit, Jürgen Kohlhase, Detlef Böhm, Jaakko Ignatius, and Sakari Knuutila. Array cgh in molecular diagnosis of mental retardation—a study of 150 finnish patients. American Journal of Medical Genetics Part A, 152A:1398-1410, Jun 2010. URL: https://doi.org/10.1002/ajmg.a.33402, doi:10.1002/ajmg.a.33402. This article has 59 citations.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 2 |
| Resolved | 2 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 2 |
| On topic | 0 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 33 |
| Resolved | 33 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 0 |
| Terms whose name was checked | 2 |
| Terms named correctly | 1 |
| Terms named as a different term | 0 |
| Terms whose name is worth a second look | 1 |
The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0003829 (1 mention) - the report calls it "Incomplete penetrance"; HP calls it Typified by incomplete penetrance, and lists "Incomplete penetrance" among its other namesEvery term resolved, and every label the report gave matched.