Chromosome 15q24 deletion syndrome is a rare recurrent contiguous-gene microdeletion disorder. The deletions, typically 1.7-6.1 Mb, arise mostly by non-allelic homologous recombination (NAHR) between paralogous low-copy repeats (segmental duplications) clustered across the 15q24 region, labelled LCR15q24A to LCR15q24E; the smallest region of overlap spans roughly 1.1-1.2 Mb between LCR15q24B and LCR15q24C. Haploinsufficiency of one or more dosage-sensitive genes in the deleted interval produces a recognizable syndrome of global developmental delay and intellectual disability, growth retardation, a distinctive facial appearance (high anterior hairline, broad medial eyebrows, hypertelorism, downslanted palpebral fissures, long smooth philtrum, full lower lip), digital anomalies, genital anomalies in males, joint laxity and hypotonia. Less consistent features include recurrent infections, hearing loss, autism spectrum disorder and, rarely, severe congenital malformations such as congenital diaphragmatic hernia. Karyotype is usually normal and the diagnosis is made by chromosomal microarray. No single gene accounts for the phenotype; candidate dosage-sensitive genes in the critical region include SIN3A, CSK, STRA6, ARID3B, SEMA7A, CPLX3 and CYP11A1. SIN3A haploinsufficiency alone causes the clinically overlapping but distinct Witteveen-Kolk syndrome.
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Conditions with similar clinical presentations that must be differentiated from Chromosome 15q24 Deletion Syndrome:
name: Chromosome 15q24 Deletion Syndrome
category: Chromosomal
creation_date: "2026-10-30T11:04:41Z"
synonyms:
- 15q24 microdeletion syndrome
- 15q24 recurrent microdeletion syndrome
- Chromosome 15q24 microdeletion syndrome
- Del(15)(q24)
- Monosomy 15q24
description: >-
Chromosome 15q24 deletion syndrome is a rare recurrent contiguous-gene
microdeletion disorder. The deletions, typically 1.7-6.1 Mb, arise mostly by
non-allelic homologous recombination (NAHR) between paralogous low-copy
repeats (segmental duplications) clustered across the 15q24 region, labelled
LCR15q24A to LCR15q24E; the smallest region of overlap spans roughly 1.1-1.2
Mb between LCR15q24B and LCR15q24C. Haploinsufficiency of one or more
dosage-sensitive genes in the deleted interval produces a recognizable
syndrome of global developmental delay and intellectual disability, growth
retardation, a distinctive facial appearance (high anterior hairline, broad
medial eyebrows, hypertelorism, downslanted palpebral fissures, long smooth
philtrum, full lower lip), digital anomalies, genital anomalies in males,
joint laxity and hypotonia. Less consistent features include recurrent
infections, hearing loss, autism spectrum disorder and, rarely, severe
congenital malformations such as congenital diaphragmatic hernia. Karyotype
is usually normal and the diagnosis is made by chromosomal microarray. No
single gene accounts for the phenotype; candidate dosage-sensitive genes in
the critical region include SIN3A, CSK, STRA6, ARID3B, SEMA7A, CPLX3 and
CYP11A1. SIN3A haploinsufficiency alone causes the clinically overlapping but
distinct Witteveen-Kolk syndrome.
disease_term:
preferred_term: chromosome 15q24 deletion syndrome
term:
id: MONDO:0013256
label: chromosome 15q24 deletion syndrome
parents:
- Contiguous gene deletion syndrome
- Chromosomal deletion syndrome
notes: >-
The MONDO term for this syndrome is anchored to SIN3A as its causal gene, but
the recurrent 15q24 deletion is a contiguous-gene disorder spanning many
genes, and the phenotype is not attributed to any single one; SIN3A is one of
several candidate dosage-sensitive genes in the critical region. SIN3A
haploinsufficiency on its own causes Witteveen-Kolk syndrome, a separate MONDO
concept. The only GeneReviews chapter for this syndrome (PMID:22359776) has
been retired by its authors and is cited here as the historical expert
phenotype baseline alongside the primary case series; no current GeneReviews
chapter exists.
inheritance:
- name: Autosomal dominant inheritance
description: >-
The recurrent 15q24 deletion is heterozygous and acts dominantly through
haploinsufficiency; most cases are de novo, consistent with origin by NAHR
between the flanking low-copy repeats.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:17360722
reference_title: "Characterization of a recurrent 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe multiple individuals with mental retardation and overlapping de novo submicroscopic deletions of 15q24 (1.7-3.9 Mb in size)."
explanation: The 15q24 deletions reported in the original series were de novo heterozygous deletions.
- reference: PMID:22359776
reference_title: "15q24 Microdeletion Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "The 15q24 microdeletion syndrome is inherited in an autosomal dominant manner; however, all known cases have resulted from a de novo deletion."
explanation: GeneReviews genetic-counseling statement that the syndrome is autosomal dominant but arises de novo.
prevalence:
- population: General population (extrapolated)
measure_type: BIRTH_PREVALENCE
prevalence_class: BAND_1_9_PER_100000
rate_per_100000: 2.4
notes: >-
The incidence is formally unknown; PMID:22216833 extrapolates an approximate
population figure of 1 in 42,000 from the 15q13/1q21 microdeletion rates. In
an intellectual-disability/congenital-defect array-CGH referral population a
rate of about 1 in 1751 was observed.
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the overall incidence of 15q24 microdeletion in the general population may approach approximately 1 in 42,000."
explanation: Extrapolated population incidence of the 15q24 microdeletion.
- reference: PMID:22180641
reference_title: "Further clinical and molecular delineation of the 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "which occur 8-10 times less frequently than 1q21 or 15q13 microdeletions in our series."
explanation: 15q24 deletions are 8-10 times rarer than the 1q21 and 15q13 microdeletions.
genetic:
- name: Recurrent 15q24 contiguous-gene deletion
association: Causative (heterozygous contiguous-gene deletion)
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: >-
Breakpoints lie within segmental-duplication (low-copy-repeat) clusters
LCR15q24A-E, so most deletions arise by NAHR; deletion sizes and exact
breakpoints vary between patients. The smallest region of overlap
(~1.1-1.2 Mb between LCR15q24B and LCR15q24C) carries the core cognitive
phenotype. There is no single causal gene; candidate dosage-sensitive genes
in the interval include SIN3A, CSK, STRA6, ARID3B, SEMA7A, CPLX3 and
CYP11A1.
evidence:
- reference: PMID:17360722
reference_title: "Characterization of a recurrent 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "High-resolution analysis showed that in three patients both proximal and distal breakpoints co-localized to highly identical segmental duplications (>51 kb in length, > 94% identity), suggesting non-allelic homologous recombination as the likely mechanism of origin."
explanation: Establishes NAHR between segmental duplications as the mechanism generating the recurrent deletion.
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The smallest region of overlap (SRO) spans a 1.2 Mb region between LCR15q24B to LCR15q24C. There are several candidate genes within the SRO, including CYP11A1, SEMA7A, CPLX3, ARID3B, STRA6, SIN3A and CSK, that may predispose to many of the clinical features observed in individuals with 15q24 deletion syndrome."
explanation: Defines the smallest region of overlap and lists the candidate dosage-sensitive genes.
- name: SIN3A
association: Candidate dosage-sensitive gene in the critical region
relationship_type: UNKNOWN
variant_origin: GERMLINE
gene_term:
preferred_term: SIN3A
term:
id: hgnc:19353
label: SIN3A
notes: >-
SIN3A lies within the 15q24 critical region and is a transcriptional
corepressor scaffold. Its isolated haploinsufficiency causes Witteveen-Kolk
syndrome, which overlaps clinically with the 15q24 deletion but is a
distinct entity; SIN3A is therefore a candidate contributor to, not the
sole cause of, the contiguous-gene phenotype.
evidence:
- reference: PMID:33437032
reference_title: "Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A."
explanation: Defines Witteveen-Kolk syndrome as caused by SIN3A loss-of-function, a distinct disorder overlapping the 15q24 deletion phenotype.
- name: CSK
association: Candidate dosage-sensitive gene in the critical region
relationship_type: UNKNOWN
variant_origin: GERMLINE
gene_term:
preferred_term: CSK
term:
id: hgnc:2444
label: CSK
notes: >-
CSK lies within the smallest region of overlap and is one of the candidate
dosage-sensitive genes proposed to contribute to the core phenotype.
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There are several candidate genes within the SRO, including CYP11A1, SEMA7A, CPLX3, ARID3B, STRA6, SIN3A and CSK, that may predispose to many of the clinical features observed in individuals with 15q24 deletion syndrome."
explanation: CSK is listed among the candidate genes in the critical region.
- name: STRA6
association: Candidate dosage-sensitive gene in the critical region
relationship_type: UNKNOWN
variant_origin: GERMLINE
gene_term:
preferred_term: STRA6
term:
id: hgnc:30650
label: STRA6
notes: >-
STRA6 (the retinol-binding-protein receptor) lies in the interval; biallelic
STRA6 mutations cause a separate anophthalmia syndrome, and its presence in
the deletion is of interest for the eye findings, though a dosage effect is
not established.
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There are several candidate genes within the SRO, including CYP11A1, SEMA7A, CPLX3, ARID3B, STRA6, SIN3A and CSK, that may predispose to many of the clinical features observed in individuals with 15q24 deletion syndrome."
explanation: STRA6 is listed among the candidate genes in the critical region.
pathophysiology:
- name: Recurrent 15q24 heterozygous deletion
description: >-
Non-allelic homologous recombination between the paralogous low-copy repeat
clusters flanking 15q24 generates a recurrent interstitial deletion of
1.7-6.1 Mb, removing one copy of every gene in the interval.
biological_scale: MOLECULAR
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The deletions range in size from 1.7-6.1 Mb and usually result from nonallelic homologous recombination (NAHR) between paralogous low-copy repeats (LCRs)."
explanation: Describes the recurrent deletion and its NAHR origin.
downstream:
- target: Haploinsufficiency of dosage-sensitive genes in the critical region
causal_link_type: DIRECT
- name: Haploinsufficiency of dosage-sensitive genes in the critical region
description: >-
Loss of one copy of the genes in the smallest region of overlap reduces
their dosage below the threshold needed for normal development. The core
cognitive phenotype maps to a ~1.1 Mb critical region, with genes just
distal contributing to facial features, implicating more than one
dosage-sensitive gene.
biological_scale: CELLULAR
biological_processes:
- preferred_term: reduced gene expression from hemizygous loci
modifier: DECREASED
term:
id: GO:0010467
label: gene expression
evidence:
- reference: PMID:17360722
reference_title: "Characterization of a recurrent 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "indicating that this represents a novel syndrome caused by haploinsufficiency of one or more dosage-sensitive genes in the minimal deletion region."
explanation: Attributes the syndrome to haploinsufficiency of dosage-sensitive genes in the deleted region.
- reference: PMID:22180641
reference_title: "Further clinical and molecular delineation of the 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the core cognitive features of the 15q24 microdeletion syndrome, including developmental delays and severe speech problems, are largely due to deletion of genes in a 1.1-Mb critical region."
explanation: Localizes the core cognitive phenotype to a 1.1 Mb critical region.
downstream:
- target: Abnormal neurodevelopment
causal_link_type: DIRECT
- target: Abnormal craniofacial morphogenesis
causal_link_type: DIRECT
- target: Connective-tissue and skeletal abnormality
causal_link_type: DIRECT
- target: Abnormal male genital development
causal_link_type: DIRECT
- target: Abnormal growth regulation
causal_link_type: DIRECT
- target: Congenital heart defect
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Abnormal neurodevelopment
description: >-
Reduced dosage of critical-region genes disturbs brain development,
producing developmental delay, intellectual disability, hypotonia and, in a
subset, autism spectrum disorder.
biological_scale: ORGANISM
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "It is characterized by growth retardation, intellectual disability, and distinct facial features"
explanation: Intellectual disability is a core feature of the syndrome.
- reference: PMID:20678247
reference_title: "A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The 15q24 microdeletion syndrome has been recently described as a recurrent, submicroscopic genomic imbalance found in individuals with intellectual disability, typical facial appearance, hypotonia, and digital and genital abnormalities."
explanation: Links the deletion to intellectual disability and hypotonia.
downstream:
- target: Global developmental delay
causal_link_type: DIRECT
- target: Intellectual disability
causal_link_type: DIRECT
- target: Hypotonia
causal_link_type: DIRECT
- target: Autistic behavior
causal_link_type: DIRECT
- target: Behavioral abnormality
causal_link_type: DIRECT
- target: Abnormal corpus callosum morphology
causal_link_type: DIRECT
- target: Microcephaly
causal_link_type: DIRECT
- name: Abnormal craniofacial morphogenesis
description: >-
Dosage reduction of critical-region genes disturbs craniofacial
morphogenesis, giving the recognizable facial gestalt.
biological_scale: ORGANISM
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Distinct facial features, including long face with high anterior hairline, epicanthal folds, hypertelorism, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, long smooth philtrum, and small mouth with full lower lip were common in all individuals."
explanation: Describes the characteristic facial gestalt arising from abnormal craniofacial development.
downstream:
- target: Hypertelorism
causal_link_type: DIRECT
- target: Downslanted palpebral fissures
causal_link_type: DIRECT
- target: High anterior hairline
causal_link_type: DIRECT
- target: Broad eyebrow
causal_link_type: DIRECT
- target: Long philtrum
causal_link_type: DIRECT
- target: Thick lower lip vermilion
causal_link_type: DIRECT
- target: Epicanthus
causal_link_type: DIRECT
- target: Protruding ear
causal_link_type: DIRECT
- name: Connective-tissue and skeletal abnormality
description: >-
The review proposes an underlying connective-tissue abnormality, manifesting
as joint laxity, hernias and scoliosis, alongside the skeletal and digital
anomalies that are the most frequent feature of the syndrome after the
neurodevelopmental findings.
biological_scale: ORGANISM
evidence:
- reference: PMID:17360722
reference_title: "Characterization of a recurrent 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "all four individuals share several major features (growth retardation, microcephaly, digital abnormalities, hypospadias and loose connective tissue) and resemble one another facially"
explanation: Loose connective tissue and digital abnormalities are shared features.
downstream:
- target: Joint hypermobility
causal_link_type: DIRECT
- target: Digit abnormalities
causal_link_type: DIRECT
- target: Clinodactyly
causal_link_type: DIRECT
- target: Toe syndactyly
causal_link_type: DIRECT
- target: Scoliosis
causal_link_type: DIRECT
- name: Abnormal male genital development
description: >-
Genital anomalies affect a majority of affected males and include
hypospadias, micropenis and cryptorchidism.
biological_scale: ORGANISM
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Genital abnormalities are reported in a majority of individuals (60%) and include hypospadias, microphallus, and cryptorchidism."
explanation: Defines the male genital anomalies of the syndrome.
downstream:
- target: Hypospadias
causal_link_type: DIRECT
- target: Micropenis
causal_link_type: DIRECT
- target: Cryptorchidism
causal_link_type: DIRECT
- name: Abnormal growth regulation
description: >-
Prenatal and postnatal growth retardation with short stature and feeding
difficulties is common, while a subset develop childhood obesity, so growth
parameters are variable.
biological_scale: ORGANISM
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, in later childhood, growth parameters were extremely variable with nearly 30% of individuals still exhibiting postnatal growth retardation and short stature, while 17% had obesity."
explanation: Describes the variable growth phenotype including short stature and obesity.
downstream:
- target: Short stature
causal_link_type: DIRECT
- target: Failure to thrive
causal_link_type: DIRECT
- target: Obesity
causal_link_type: DIRECT
phenotypes:
- category: Neurological
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:22359776
reference_title: "15q24 Microdeletion Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "The 15q24 microdeletion syndrome is characterized by global developmental delay; mild to severe (usually at least moderate) intellectual disability"
explanation: Global developmental delay is a defining feature in the GeneReviews summary.
- category: Neurological
name: Intellectual disability
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "It is characterized by growth retardation, intellectual disability, and distinct facial features"
explanation: Intellectual disability is a core feature.
- category: Neurological
name: Hypotonia
frequency: FREQUENT
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: PMID:20678247
reference_title: "A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "found in individuals with intellectual disability, typical facial appearance, hypotonia, and digital and genital abnormalities."
explanation: Hypotonia is part of the recognized phenotype.
- category: Neurological
name: Autistic behavior
frequency: OCCASIONAL
phenotype_term:
preferred_term: Autistic behavior
term:
id: HP:0000729
label: Autistic behavior
evidence:
- reference: PMID:34922566
reference_title: "Molecular and phenotypic characteristics of 15q24 microdeletion in pediatric patients with developmental disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Chromosome 15q24 microdeletion is a rare genetic disorder characterized by development delay, facial dysmorphism, congenital malformations, and occasional autism spectrum disorder (ASD)."
explanation: Autism spectrum disorder occurs in a subset of patients.
- category: Growth
name: Short stature
frequency: FREQUENT
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:19557438
reference_title: "Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report four new patients with a submicroscopic deletion in 15q24 manifesting developmental delay, short stature, hypotonia, digital abnormalities, joint laxity, genital abnormalities, and characteristic facial features."
explanation: Short stature is reported among the shared features.
- category: Growth
name: Failure to thrive
frequency: OCCASIONAL
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Feeding difficulties and failure to thrive were reported in approximately 20%."
explanation: Failure to thrive affects about 20% of individuals, an occasional finding.
- category: Craniofacial
name: Microcephaly
frequency: OCCASIONAL
phenotype_term:
preferred_term: Microcephaly
term:
id: HP:0000252
label: Microcephaly
evidence:
- reference: PMID:17360722
reference_title: "Characterization of a recurrent 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "all four individuals share several major features (growth retardation, microcephaly, digital abnormalities, hypospadias and loose connective tissue)"
explanation: Microcephaly was shared by the original patients.
- category: Craniofacial
name: Hypertelorism
frequency: FREQUENT
phenotype_term:
preferred_term: Hypertelorism
term:
id: HP:0000316
label: Hypertelorism
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "distinct facial features including long face with high anterior hairline, hypertelorism, epicanthal folds, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, small mouth, long smooth philtrum, and full lower lip"
explanation: Hypertelorism is part of the characteristic facial gestalt.
- category: Craniofacial
name: Downslanted palpebral fissures
frequency: FREQUENT
phenotype_term:
preferred_term: Downslanted palpebral fissures
term:
id: HP:0000494
label: Downslanted palpebral fissures
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "distinct facial features including long face with high anterior hairline, hypertelorism, epicanthal folds, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, small mouth, long smooth philtrum, and full lower lip"
explanation: Downslanting palpebral fissures are part of the facial gestalt.
- category: Craniofacial
name: High anterior hairline
frequency: FREQUENT
phenotype_term:
preferred_term: High anterior hairline
term:
id: HP:0009890
label: High anterior hairline
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "distinct facial features including long face with high anterior hairline, hypertelorism, epicanthal folds, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, small mouth, long smooth philtrum, and full lower lip"
explanation: A high anterior hairline is part of the facial gestalt.
- category: Craniofacial
name: Broad eyebrow
frequency: FREQUENT
phenotype_term:
preferred_term: Broad medial eyebrows
term:
id: HP:0011229
label: Broad eyebrow
evidence:
- reference: PMID:17360722
reference_title: "Characterization of a recurrent 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "resemble one another facially (high anterior hair line, broad medial eyebrows, hypertelorism, downslanted palpebral fissures, broad nasal base, long smooth philtrum and full lower lip)"
explanation: Broad medial eyebrows are part of the facial gestalt.
- category: Craniofacial
name: Long philtrum
frequency: FREQUENT
phenotype_term:
preferred_term: Long smooth philtrum
term:
id: HP:0000343
label: Long philtrum
evidence:
- reference: PMID:17360722
reference_title: "Characterization of a recurrent 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "resemble one another facially (high anterior hair line, broad medial eyebrows, hypertelorism, downslanted palpebral fissures, broad nasal base, long smooth philtrum and full lower lip)"
explanation: A long smooth philtrum is part of the facial gestalt.
- category: Craniofacial
name: Thick lower lip vermilion
frequency: FREQUENT
phenotype_term:
preferred_term: Full lower lip
term:
id: HP:0000179
label: Thick lower lip vermilion
evidence:
- reference: PMID:17360722
reference_title: "Characterization of a recurrent 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "resemble one another facially (high anterior hair line, broad medial eyebrows, hypertelorism, downslanted palpebral fissures, broad nasal base, long smooth philtrum and full lower lip)"
explanation: A full lower lip is part of the facial gestalt.
- category: Musculoskeletal
name: Joint hypermobility
frequency: FREQUENT
phenotype_term:
preferred_term: Joint laxity / loose connective tissue
term:
id: HP:0001382
label: Joint hypermobility
evidence:
- reference: PMID:19557438
reference_title: "Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "manifesting developmental delay, short stature, hypotonia, digital abnormalities, joint laxity, genital abnormalities, and characteristic facial features."
explanation: Joint laxity is a recurring feature.
- category: Genitourinary
name: Hypospadias
frequency: FREQUENT
phenotype_term:
preferred_term: Hypospadias
term:
id: HP:0000047
label: Hypospadias
evidence:
- reference: PMID:17360722
reference_title: "Characterization of a recurrent 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "all four individuals share several major features (growth retardation, microcephaly, digital abnormalities, hypospadias and loose connective tissue)"
explanation: Hypospadias was shared by the original male patients.
- category: Immunological
name: Recurrent infections
frequency: FREQUENT
description: >-
Recurrent chest, upper airway and ear infections; the cause is unknown.
phenotype_term:
preferred_term: Recurrent infections
term:
id: HP:0002719
label: Recurrent infections
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Nearly 40% of individuals with 15q24 deletion syndrome had a history of recurrent infections, such as chest, upper airway, and ear infections."
explanation: Recurrent infections affect nearly 40% of individuals, a frequent finding.
- category: Auditory
name: Hearing impairment
frequency: OCCASIONAL
phenotype_term:
preferred_term: Hearing loss
term:
id: HP:0000365
label: Hearing impairment
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Other less frequent findings include hearing loss, growth hormone deficiency, hernias, and obesity."
explanation: Hearing loss is among the less frequent findings.
- category: Respiratory
name: Congenital diaphragmatic hernia
frequency: VERY_RARE
description: >-
A rare but severe congenital malformation reported in a subset of patients.
phenotype_term:
preferred_term: Congenital diaphragmatic hernia
term:
id: HP:0000776
label: Congenital diaphragmatic hernia
evidence:
- reference: PMID:19233321
reference_title: "Congenital diaphragmatic hernia is part of the new 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "this patient has a large congenital diaphragmatic hernia, as was described in one other patient with a 15q24 microdeletion, indicating that this feature might be part of the syndrome."
explanation: Congenital diaphragmatic hernia is reported as a rare part of the syndrome.
- category: Hematologic
name: Myelodysplasia
frequency: VERY_RARE
description: >-
Rare haematological complication; childhood myelodysplastic syndrome has
been reported in an individual with the 15q24 deletion.
phenotype_term:
preferred_term: Myelodysplastic syndrome
term:
id: HP:0002863
label: Myelodysplasia
evidence:
- reference: PMID:22140075
reference_title: "Myelodysplastic syndrome in a child with 15q24 deletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report on a 13-year-old boy with this syndrome manifesting childhood myelodysplastic syndrome (MDS)."
explanation: Documents childhood MDS in a patient with the 15q24 deletion.
- category: Skeletal
name: Digit abnormalities
frequency: VERY_FREQUENT
description: >-
The most frequent non-neurological feature: proximally implanted or
hypoplastic thumbs, clinodactyly, brachydactyly, overriding toes, toe
syndactyly and small hands, in approximately 90% of individuals.
phenotype_term:
preferred_term: Digital abnormalities (thumbs, clinodactyly, brachydactyly, toe syndactyly, small hands)
term:
id: HP:0011297
label: Abnormal digit morphology
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Digit abnormalities such as proximally implanted and/or hypoplastic thumbs, clinodactyly, brachydactyly, overriding toes, toe syndactyly, and small hands were found in approximately 90% of individuals with 15q24 deletion."
explanation: Digit abnormalities are present in about 90% of individuals.
- category: Skeletal
name: Clinodactyly
frequency: FREQUENT
phenotype_term:
preferred_term: Clinodactyly
term:
id: HP:0030084
label: Clinodactyly
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Digit abnormalities such as proximally implanted and/or hypoplastic thumbs, clinodactyly, brachydactyly, overriding toes, toe syndactyly, and small hands were found in approximately 90% of individuals with 15q24 deletion."
explanation: Clinodactyly is among the digit abnormalities.
- category: Skeletal
name: Toe syndactyly
frequency: FREQUENT
phenotype_term:
preferred_term: Toe syndactyly
term:
id: HP:0001770
label: Toe syndactyly
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Digit abnormalities such as proximally implanted and/or hypoplastic thumbs, clinodactyly, brachydactyly, overriding toes, toe syndactyly, and small hands were found in approximately 90% of individuals with 15q24 deletion."
explanation: Toe syndactyly is among the digit abnormalities.
- category: Skeletal
name: Scoliosis
frequency: OCCASIONAL
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In addition, many individuals were reported to have joint laxity and scoliosis."
explanation: Scoliosis occurs in many individuals, consistent with the proposed connective-tissue abnormality.
- category: Behavioral
name: Behavioral abnormality
frequency: FREQUENT
description: >-
Behavior abnormalities (autism, hyperactivity, aggression, attention deficit
disorder) in about 37% of individuals.
phenotype_term:
preferred_term: Behavioral abnormalities
term:
id: HP:0000708
label: Atypical behavior
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Behavior abnormalities, such as autism, hyperactivity, aggression, and attention deficit disorder have been reported in 37% individuals with 15q24 deletion syndrome."
explanation: Behavior abnormalities affect about 37% of individuals.
- category: Craniofacial
name: Epicanthus
frequency: FREQUENT
phenotype_term:
preferred_term: Epicanthal folds
term:
id: HP:0000286
label: Epicanthus
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Distinct facial features, including long face with high anterior hairline, epicanthal folds, hypertelorism, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, long smooth philtrum, and small mouth with full lower lip were common in all individuals."
explanation: Epicanthal folds are part of the facial gestalt.
- category: Craniofacial
name: Protruding ear
frequency: FREQUENT
description: >-
Ear abnormalities in nearly two-thirds of individuals: large ears, ear lobe
pits, anteverted ear lobes and protuberant ears.
phenotype_term:
preferred_term: Ear abnormalities (large, protuberant, lobe pits)
term:
id: HP:0000411
label: Protruding ear
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ear abnormalities were variable, but present in nearly two-thirds of individuals and included large ears, ear lobe pits, anteverted ear lobes, and protuberant ears."
explanation: Ear abnormalities, bound via the protruding-ear term, affect nearly two-thirds of individuals.
- category: Cardiovascular
name: Congenital heart defect
frequency: OCCASIONAL
description: >-
Congenital heart defects, including tetralogy of Fallot and ventricular
septal defects, in about 20% of individuals.
phenotype_term:
preferred_term: Congenital heart defect
term:
id: HP:0001627
label: Abnormal heart morphology
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Birth defects have been reported in several individuals including congenital heart defects (such as tetralogy of Fallot and ventricular septal defects) in four (~20%)"
explanation: Congenital heart defects affect about 20% of individuals.
- category: Neurological
name: Abnormal corpus callosum morphology
frequency: FREQUENT
description: >-
Abnormal brain MRI in about half of individuals, with dysplastic or abnormal
corpus callosum, cortical atrophy, focal cortical dysplasia and hypoplastic
olfactory bulbs.
phenotype_term:
preferred_term: Abnormal brain MRI (corpus callosum dysplasia, cortical atrophy)
term:
id: HP:0001273
label: Abnormal corpus callosum morphology
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The features in those with abnormalities are variable and include: dysplastic or abnormal corpus callosum, cortical atrophy, focal cortical dysplasia, and hypoplastic olfactory bulbs."
explanation: Corpus callosum abnormality is one of the brain MRI findings; the ~50% figure covers all brain MRI abnormalities, and the corpus-callosum-specific share is not given.
- category: Genitourinary
name: Micropenis
frequency: FREQUENT
phenotype_term:
preferred_term: Microphallus
term:
id: HP:0000054
label: Micropenis
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Genital abnormalities are reported in a majority of individuals (60%) and include hypospadias, microphallus, and cryptorchidism."
explanation: Microphallus is part of the male genital anomalies affecting 60% of individuals.
- category: Genitourinary
name: Cryptorchidism
frequency: FREQUENT
phenotype_term:
preferred_term: Cryptorchidism
term:
id: HP:0000028
label: Cryptorchidism
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Genital abnormalities are reported in a majority of individuals (60%) and include hypospadias, microphallus, and cryptorchidism."
explanation: Cryptorchidism is part of the male genital anomalies affecting 60% of individuals.
- category: Growth
name: Obesity
frequency: OCCASIONAL
phenotype_term:
preferred_term: Childhood obesity
term:
id: HP:0001513
label: Obesity
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, in later childhood, growth parameters were extremely variable with nearly 30% of individuals still exhibiting postnatal growth retardation and short stature, while 17% had obesity."
explanation: Childhood obesity affects about 17% of individuals.
- category: Ophthalmologic
name: Strabismus
frequency: FREQUENT
phenotype_term:
preferred_term: Strabismus
term:
id: HP:0000486
label: Strabismus
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Strabismus | 7/18 (39%)"
explanation: Strabismus was present in 7 of 18 individuals (39%), a frequent finding.
- category: Ophthalmologic
name: Nystagmus
frequency: OCCASIONAL
phenotype_term:
preferred_term: Nystagmus
term:
id: HP:0000639
label: Nystagmus
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Nystagmus | 2/18 (11%)"
explanation: Nystagmus was present in 2 of 18 individuals (11%), an occasional finding.
diagnosis:
- name: Chromosomal microarray analysis
description: >-
The karyotype is typically normal; the diagnosis is established by detecting
a heterozygous copy-number loss at 15q24 by array comparative genomic
hybridization or SNP array.
diagnosis_term:
preferred_term: Genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Karyotypes are typically normal, and the deletions were detected in these individuals by array comparative genomic hybridization (aCGH)."
explanation: Chromosomal microarray, not karyotype, detects the deletion.
- reference: PMID:22359776
reference_title: "15q24 Microdeletion Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "The diagnosis is established by demonstration of a heterozygous deletion at chromosome 15q24, most often involving a 1.1-Mb region between 72.2 and 73.3 Mb of the reference genome (NCBI Build 36 / hg18) using whole-genome and targeted molecular methods that determine the copy number of sequences within the deleted region."
explanation: GeneReviews diagnostic criterion for establishing the 15q24 deletion.
- name: Brain MRI
description: >-
Structural brain anomalies occur in about half of cases, so brain MRI is
indicated in any individual with an abnormal neurological examination.
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "As structural brain anomalies have been reported in approximately half of all of cases of 15q24 deletion, brain magnetic resonance imaging (MRI) studies are indicated in any individual with 15q24 deletion and abnormal neurological examination."
explanation: Brain MRI is recommended given the frequency of structural brain anomalies.
differential_diagnoses:
- name: Witteveen-Kolk syndrome (SIN3A haploinsufficiency)
description: >-
Isolated SIN3A haploinsufficiency causes a neurodevelopmental disorder that
overlaps the 15q24 deletion phenotype but is a distinct entity with milder,
gene-specific features and a DNA methylation episignature.
distinguishing_features:
- Intragenic SIN3A variant or SIN3A-only deletion rather than a multi-gene 15q24 deletion
- A SIN3A-specific DNA methylation episignature
evidence:
- reference: PMID:36399132
reference_title: "DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene."
explanation: Defines Witteveen-Kolk syndrome as SIN3A haploinsufficiency, distinct from the contiguous-gene deletion.
- name: Other recurrent microdeletion syndromes
description: >-
Other submicroscopic recurrent deletions (for example 1q21 and 15q13)
present with overlapping developmental delay and dysmorphism and are
distinguished by the chromosomal location of the copy-number change.
distinguishing_features:
- The specific deleted interval identified on chromosomal microarray
evidence:
- reference: PMID:22180641
reference_title: "Further clinical and molecular delineation of the 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "which occur 8-10 times less frequently than 1q21 or 15q13 microdeletions in our series."
explanation: Places 15q24 among the recurrent microdeletion syndromes distinguished by locus.
treatments:
- name: Speech and language therapy
description: >-
Speech therapy for the developmental delay and severe speech problems that
are part of the core phenotype.
action_category: THERAPEUTIC
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: speech and language therapy
term:
id: NCIT:C159273
label: Speech Language Therapy
target_mechanisms:
- target: Global developmental delay
description: Addresses expressive and receptive language delay.
evidence:
- reference: PMID:22359776
reference_title: "15q24 Microdeletion Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "MANAGEMENT: Treatment of manifestations: Speech, occupational, and physical therapies; routine treatment of ophthalmologic, cardiac, neurologic findings; specialized learning programs to meet individual needs Surveillance: Routine pediatric care; routine developmental assessments; monitoring of specific identified medical issues"
explanation: GeneReviews lists speech therapy among the treatments of manifestations.
- name: Physical therapy
description: >-
Physical therapy for hypotonia and motor delay.
action_category: THERAPEUTIC
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: physical therapy
term:
id: NCIT:C15302
label: Physical Therapy
target_mechanisms:
- target: Hypotonia
description: Supports motor development in the presence of hypotonia.
evidence:
- reference: PMID:22359776
reference_title: "15q24 Microdeletion Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "MANAGEMENT: Treatment of manifestations: Speech, occupational, and physical therapies; routine treatment of ophthalmologic, cardiac, neurologic findings; specialized learning programs to meet individual needs Surveillance: Routine pediatric care; routine developmental assessments; monitoring of specific identified medical issues"
explanation: GeneReviews lists physical therapy among the treatments of manifestations.
- name: Occupational therapy
description: >-
Occupational therapy as part of the developmental support programme.
action_category: THERAPEUTIC
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: occupational therapy
term:
id: NCIT:C121351
label: Occupational Therapy
target_mechanisms:
- target: Global developmental delay
description: Supports adaptive and fine-motor development.
evidence:
- reference: PMID:22359776
reference_title: "15q24 Microdeletion Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "MANAGEMENT: Treatment of manifestations: Speech, occupational, and physical therapies; routine treatment of ophthalmologic, cardiac, neurologic findings; specialized learning programs to meet individual needs Surveillance: Routine pediatric care; routine developmental assessments; monitoring of specific identified medical issues"
explanation: GeneReviews lists occupational therapy among the treatments of manifestations.
- name: Developmental surveillance and multidisciplinary care
description: >-
Routine pediatric care, developmental assessments and multidisciplinary
surveillance (ophthalmologic, audiologic, cardiac, neurologic), with weight
monitoring for the risk of childhood obesity.
action_category: SCREENING
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: surveillance and supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Management involves a multi-disciplinary approach to care with the primary care physician and clinical geneticist playing a crucial role in providing appropriate screening, surveillance, and care for individuals with this syndrome."
explanation: Multidisciplinary surveillance is the basis of management.
- name: Behavioral therapy
description: >-
Behavioral therapy for the autism, hyperactivity and attention problems seen
in a substantial minority of individuals.
action_category: THERAPEUTIC
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: behavioral therapy
term:
id: NCIT:C15184
label: Behavioral Intervention
target_mechanisms:
- target: Behavioral abnormality
description: Addresses the behavioral phenotype.
evidence:
- reference: PMID:22216833
reference_title: "Chromosome 15q24 microdeletion syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Behavioral therapy may benefit individuals with this syndrome."
explanation: Behavioral therapy is recommended for the behavioral phenotype.
references:
- reference: PMID:22359776
title: "15q24 Microdeletion Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
tags:
- GeneReviews
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: Chromosome 15q24 Deletion Syndrome · 2026-10-30T11:09:45Z · View source
De novo curation of the recurrent 15q24 contiguous-gene microdeletion syndrome. Modelled as a Chromosomal entry: NAHR between LCR15q24 segmental duplications -> recurrent heterozygous deletion -> haploinsufficiency of dosage-sensitive genes in the SRO (candidate genes SIN3A, CSK, STRA6, ARID3B, SEMA7A, CPLX3, CYP11A1) -> neurodevelopmental, craniofacial and connective-tissue phenotypes. Distinguished from SIN3A-only Witteveen-Kolk syndrome in differential diagnoses and notes. Deep research: openscientist (17/17 refs verified, 0 confabulation; preflight-dr PASS). Evidence from primary case series (PMID:17360722, 19557438, 22180641, 22216833, 19233321, 20678247, 34922566, 22140075) and the retired GeneReviews chapter (PMID:22359776) tagged as historical baseline. Validated with just validate (0 issues) plus entity-refs, causal-targets, coarse-phenotypes, qualifier-terms, duplicate-keys, block-scalar-comments, logical-rules, genereviews.
Disease: Chromosome 15q24 Deletion Syndrome MONDO ID: MONDO:0013256 · OMIM: 613406 · Causal gene: SIN3A (SIN3 transcription regulator family member A; HGNC:19353; chromosome 15q24.2) Category: Chromosomal (contiguous-gene microdeletion syndrome)
Chromosome 15q24 deletion syndrome is a rare, usually de novo contiguous-gene microdeletion disorder of chromosome band 15q24. Its single most important, dosage-sensitive driver gene is SIN3A, which encodes the scaffold protein of a SIN3–HDAC1/2 histone-deacetylase transcriptional corepressor complex and is a MeCP2 interactor required for cortical neurogenesis. Critically, the disease named here is a SIN3A disorder: heterozygous loss-of-function point variants in SIN3A alone reproduce the core neurodevelopmental phenotype of the microdeletion and define the overlapping Witteveen–Kolk syndrome (WITKOS, OMIM 613406). This shared OMIM identity confirms that SIN3A haploinsufficiency explains the central cognitive and craniofacial features, while additional co-deleted genes (e.g., STRA6, NEO1, CYP11A1) account for the rarer multi-organ malformations seen only in larger deletions.
Clinically, the syndrome is characterized by prenatal/postnatal growth retardation, usually mild intellectual disability with prominent speech delay, microcephaly, short stature, and a distinctive facial gestalt (long face with high anterior hairline, hypertelorism, epicanthal folds, downslanting palpebral fissures, sparse broad medial eyebrows, broad/depressed nasal bridge, small mouth, long smooth philtrum, full lower lip). Variable features include digital/skeletal anomalies, male genital abnormalities (hypospadias, micropenis), hypotonia, behavior problems (ASD, ADHD), recurrent infections, and eye problems; rare but severe congenital malformations (structural brain anomalies, cardiac defects, congenital diaphragmatic hernia, intestinal atresia, imperforate anus, myelomeningocele) occur chiefly with larger deletions. Inheritance is autosomal dominant with high penetrance but highly variable expressivity.
There is no disease-modifying therapy. Diagnosis is by chromosomal microarray (for the deletion) or exome/genome sequencing (for intragenic SIN3A variants), supported by a robust, predominantly hypomethylated DNA-methylation episignature that is diagnostic for WITKOS/SIN3A haploinsufficiency. Management is supportive, anticipatory, and multidisciplinary. This report synthesizes 12 confirmed findings across 25 reviewed papers into a full disease-knowledge-base entry spanning etiology, phenotype, molecular mechanism, anatomy, temporal course, epidemiology, diagnostics, prognosis, treatment, prevention, and model systems.
The defining molecular insight linking the 15q24 microdeletion to a monogenic disorder came from Witteveen et al. (2016), who identified dominant loss-of-function mutations in SIN3A (chromosome 15q24.2) in individuals with mild intellectual disability and autism spectrum disorder who also shared "striking features, including facial dysmorphisms, microcephaly and short stature. This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome" (PMID: 27399968). Balasubramanian et al. (2021) then characterized 28 patients with SIN3A loss-of-function variants (24 truncating, 3 missense, 1 in-frame gain), establishing that the gene-level disorder, now termed Witteveen–Kolk syndrome (OMIM 613406), "is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A" (PMID: 33437032). Because the point-mutation disorder and the microdeletion share the same OMIM number (613406) and the same core phenotype, SIN3A is confirmed as the principal dosage-sensitive driver of the neurodevelopmental core of the 15q24 deletion syndrome.
Mefford et al. (2012) characterized 15 patients carrying nine distinct deletions ranging 266 kb–3.75 Mb and showed that "the core cognitive features of the 15q24 microdeletion syndrome, including developmental delays and severe speech problems, are largely due to deletion of genes in a 1.1-Mb critical region" (PMID: 22180641). Recurrence arises from the local genomic architecture: "The majority of breakpoints lie within segmental duplication (SD) blocks. Low sequence identity and large intervals of unique sequence between SD blocks likely contribute to the rarity of 15q24 deletions, which occur 8-10 times less frequently than 1q21 or 15q13 microdeletions" (PMID: 22180641). Liu et al. (2020) further refined the region, proposing a 650-kb LCR15q24A-B interval (including NEO1) relevant to ASD, with the LCR B–D interval linked to developmental delay, dysmorphism, and recurrent infection (PMID: 31953991). The smallest region of overlap has been placed at ~1.2 Mb between LCR15q24B and LCR15q24C.
Mechanistically, SIN3A is the scaffold of the SIN3 core corepressor complex. Jayaprakash et al. (2021) define its composition: "The SIN3 core complex comprises the eponymous proteins SIN3A or SIN3B, the catalytically active proteins HDAC1 or HDAC2, the histone chaperone retinoblastoma-associated protein 46/retinoblastoma-binding protein 7 (RBAP46/RBBP7) or RBAP48/RBBP4, the SIN3-associated protein 30 (SAP30), and the suppressor of defective silencing 3 (SDS3)" (PMID: 33130996). The complex deacetylates histones to repress transcription. Witteveen et al. (2016) demonstrated the disease-relevant function: SIN3A interacts with MeCP2, and "in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain" (PMID: 27399968). Germline deletion of the catalytic partner HDAC1 is embryonic-lethal in mouse and reduces Sin3A/NuRD/CoREST complex activity (PMID: 20404188), underscoring the essential nature of this corepressor machinery.
Magoulas & El-Hattab (2012) provide the authoritative phenotype overview: the syndrome "is characterized by growth retardation, intellectual disability, and distinct facial features including long face with high anterior hairline, hypertelorism, epicanthal folds, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, small mouth, long smooth philtrum, and full lower lip. Other common findings include skeletal and digital abnormalities, genital abnormalities in males, hypotonia, behavior problems, recurrent infections, and eye problems" (PMID: 22216833). Less frequent findings include hearing loss, growth hormone deficiency, hernias, and obesity. Importantly, "Congenital malformations, while rare, can be severe and include structural brain anomalies, cardiovascular malformations, congenital diaphragmatic hernia, intestinal atresia, imperforate anus, and myelomeningocele" (PMID: 22216833). The reported smallest region of overlap is ~1.2 Mb between LCR15q24B and LCR15q24C.
Dannenberg et al. (2005), using conditional mSin3A deletion, showed that "mSin3A was shown to play an essential role in early embryonic development and in the proliferation and survival of primary, immortalized, and transformed cells" (PMID: 15998811). Time-course profiling after deletion "revealed deregulation of genes involved in cell cycle regulation, DNA replication, DNA repair, apoptosis, chromatin modifications, and mitochondrial metabolism" (PMID: 15998811), operating through Myc-Mad, E2F, and p53 transcriptional networks, with mSin3A/HDAC mediating p53 deacetylation. The in-vivo brain knockdown by Witteveen et al. (reduced cortical neurogenesis, altered neuronal identity, aberrant corticocortical projections) provides the neurodevelopmental counterpart in a dosage-reduction context (PMID: 27399968).
Coenen-van der Spek et al. (2023) studied genome-wide DNA methylation in peripheral blood of 20 individuals with heterozygous SIN3A alterations and identified a novel, robust episignature. "A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case" (PMID: 36399132). The signature distinguishes WITKOS from controls and from other neurodevelopmental disorders with episignatures, is sensitive across degrees of phenotypic severity, and resolved a previously uncertain (VUS) case — making it a powerful functional diagnostic adjunct.
Due et al. (2026) performed structural and thermodynamic studies of the Sin3A PAH1 (paired amphipathic helix 1) αα-hub domain, relating "αα-hub stability to function by structural and thermodynamic studies of the Sin3A-paired amphipathic helix 1 (PAH1) wt hub domain and two predicted loss-of-function variants (A126V and K155E) found in patients with the neurodevelopmental Witteveen-Kolk syndrome" (PMID: 41759735). This shows that WITKOS missense variants cause disease by destabilizing the protein-interaction hub, a loss-of-function mechanism. The dosage-sensitivity model is reinforced by the paralog: Latypova et al. (2021) showed that SIN3B (19p13.11) haploinsufficiency causes an overlapping syndrome "hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants" (PMID: 33811806), with zebrafish sin3b disruption producing craniofacial defects.
The largest systematically phenotyped cohort (Balasubramanian et al. 2021; n=28, 17 males, 11 females, mean age 8.2 y) provides frequency estimates. Among 16 patients ≥8 years assessed: "eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common" (PMID: 33437032). In patients ≥2 years, 3 had ASD and 4 had ADHD; growth and feeding difficulties were characteristic. 27 of 28 variants were novel (24 truncating, 3 missense, 1 large in-frame gain spanning exons 10–12).
| Phenotype | Frequency (Balasubramanian 2021, n=28) |
|---|---|
| Mild ID (of 16 assessed ≥8 y) | 8/16 (50%) |
| Moderate ID | 4/16 (22%) |
| Severe ID | 1/16 (6%) |
| Normal cognition | 4/16 (25%) |
| Seizures | 4/28 (14%) |
| Hypotonia | 12/28 (43%) |
| ASD (patients ≥2 y) | 3 |
| ADHD (patients ≥2 y) | 4 |
15q24 microdeletions are typically de novo. Sharp et al. (2007) described "multiple individuals with mental retardation and overlapping de novo submicroscopic deletions of 15q24" (PMID: 17360722), arising through non-allelic homologous recombination (NAHR) between paralogous low-copy repeats. Because "Karyotypes are typically normal, and the deletions were detected in these individuals by array comparative genomic hybridization (aCGH)" (PMID: 22216833), chromosomal microarray is the first-line test for the deletion. Intragenic SIN3A point variants are predominantly de novo heterozygous loss-of-function (truncating) variants inherited in an autosomal dominant manner (PMID: 33437032; PMID: 27399968), detected by exome/genome sequencing or gene panels.
No targeted or disease-modifying therapy exists; care is supportive and anticipatory. Balasubramanian et al. (2021) advise that "Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients" (PMID: 33437032). Interventions target individual manifestations: early developmental/speech/physical/occupational therapy for DD/ID; antiepileptic drugs for seizures; surgical repair of hypospadias, diaphragmatic hernia, intestinal atresia, imperforate anus, and congenital heart defects; management of recurrent infections; growth hormone evaluation for GH deficiency; and endocrine evaluation for pubertal delay/hypogonadotropic hypogonadism (Correa Brito et al. 2024, PMID: 38528912). Janssen et al. (2026) reported "the first documented treatment of behavioral problems in WITKOS," a personalized psychological intervention with improved functioning at follow-up (PMID: 41245232).
Brain MRI in WITKOS "showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly" (PMID: 27399968). Onset is congenital/prenatal for structural malformations, with developmental delay manifesting in infancy/early childhood; the core neurodevelopmental phenotype is non-progressive/static. The primary affected organ is the brain (cerebral cortex, UBERON:0000956), with multi-system involvement of craniofacial skeleton, external genitalia (male), digits/skeleton, eyes, ears, and (rarely) heart, diaphragm, and gastrointestinal tract. No reduced life expectancy is established for isolated SIN3A-related disorder, although rare severe congenital malformations can cause early morbidity/mortality (PMID: 22216833).
Beyond SIN3A, the 15q24 critical region contains additional dosage/function-sensitive genes that plausibly account for non-neurodevelopmental features in larger deletions. STRA6 (stimulated by retinoic acid 6; a retinol/RBP4 receptor in vitamin A/retinoic-acid signaling) causes Matthew-Wood/PDAC syndrome (MCOPS9, MIM 601186) when biallelically mutated: "Mutations in retinoic acid 6 gene (STRA6) have been reported in clinically diagnosed patients with MWS" (PMID: 30204971), a syndrome with microphthalmia/anophthalmia, pulmonary hypoplasia, congenital diaphragmatic hernia, and cardiac defects — paralleling the rare eye, diaphragmatic hernia, and heart anomalies of the deletion. NEO1 (neogenin), within LCR15q24A-B, is proposed as ASD-relevant: "the ASD phenotype in this individual is potentially attributed by genes particularly NEO1 within the newly proposed critical region" (PMID: 31953991). CYP11A1 (cholesterol side-chain cleavage) relates to steroidogenesis and adrenal-gonadal function. A deletion case involving CYP1A1/EDC3 presented with poor immunity, laryngeal stridor, and lower-limb swelling (PMID: 34922566), further supporting multigene contributions.
Chromosome 15q24 deletion syndrome (MONDO:0013256; OMIM 613406) is a rare contiguous-gene microdeletion disorder caused by loss of a segment of chromosome band 15q24. Its central dosage-sensitive gene is SIN3A. The gene-level disorder produced by intragenic SIN3A loss-of-function variants is Witteveen–Kolk syndrome (WITKOS), which shares OMIM 613406 and most of the core phenotype. Key identifiers: MONDO:0013256; OMIM 613406; Orphanet ORPHA:94065 (15q24 microdeletion syndrome). ICD-10 maps to Q93.5 (other deletions of part of a chromosome); ICD-11 to LD44 (chromosomal deletions). Synonyms: 15q24 microdeletion syndrome; 15q24 recurrent microdeletion syndrome; Del(15)(q24); monosomy 15q24; Witteveen–Kolk syndrome (for the SIN3A-restricted form). Information is drawn predominantly from aggregated disease-level resources (OMIM, Orphanet) and from published patient series/case reports rather than from EHR-derived individual-patient datasets.
Causal factors: The disease is genetic. The deletion arises by non-allelic homologous recombination (NAHR) between flanking low-copy repeats/segmental duplications at 15q24, generating recurrent de novo deletions (PMID: 17360722; PMID: 22180641). Haploinsufficiency of SIN3A is the primary driver of the neurodevelopmental core; additional co-deleted genes contribute organ-specific features in larger deletions (F012).
Genetic risk factors: The principal risk factor is the presence of segmental-duplication architecture at 15q24 predisposing to NAHR. There are no established modifier genes, though deletion size (number of genes removed) correlates with severity and breadth of malformations.
Environmental risk factors / protective factors: None established. As a de novo structural/monogenic disorder, there are no recognized environmental triggers, lifestyle risk factors, or protective alleles/exposures. Advanced parental age is not established as a risk factor. Gene–environment interactions: none documented.
Phenotypes span physical manifestations (dysmorphism, growth failure), clinical signs (hypotonia, microcephaly), behavioral changes (ASD, ADHD), and neurodevelopmental deficits (ID, speech delay). Characteristic age of onset is congenital/early childhood; the core neurocognitive phenotype is static (non-progressive), while a single case report describes progressive cerebellar ataxia and dystonia broadening the spectrum (PMID: 39576496). Severity is typically mild for ID, with variable expressivity.
Suggested HPO terms: - Intellectual disability, mild — HP:0001256 (50% of ≥8 y assessed; F008) - Delayed speech and language development — HP:0000750 - Microcephaly — HP:0000252 - Short stature — HP:0004322 - Hypertelorism — HP:0000316 - Downslanted palpebral fissures — HP:0000494 - Epicanthus — HP:0000286 - Depressed nasal bridge — HP:0005280 - Long philtrum — HP:0000343 - Muscular hypotonia — HP:0001252 (43%) - Seizures — HP:0001250 (14%) - Autistic behavior — HP:0000729 - Attention deficit hyperactivity disorder — HP:0007018 - Hypospadias — HP:0000047; Micropenis — HP:0000054 - Recurrent infections — HP:0002719
Quality of life: Impact is driven mainly by cognitive/speech impairment and behavior problems affecting education, independence, and communication; isolated cases carry high QoL burden from severe malformations. No disease-specific QoL instruments (EQ-5D/SF-36) have been applied in published cohorts.
Causal gene: SIN3A (HGNC:19353; NCBI Gene 25942; UniProt Q96ST3; chromosome 15q24.2; OMIM gene 607776). Variant classes: heterozygous loss-of-function — nonsense, frameshift, splice-site, and whole-gene deletion; rare destabilizing missense (e.g., p.Ala126Val, p.Lys155Glu in PAH1; p.Pro351Ser) and one large in-frame gain (exons 10–12). In the 28-patient series, 24/28 were truncating, 3 missense, 1 in-frame; 27/28 novel (PMID: 33437032). Classification: pathogenic/likely pathogenic per ACMG for truncating LOF; missense variants supported by structural destabilization data (PMID: 41759735). Allele frequency: pathogenic variants are absent/ultra-rare in gnomAD; SIN3A is highly loss-of-function-intolerant. Origin: germline, predominantly de novo. Functional consequence: loss of function / haploinsufficiency.
Co-deleted genes of interest (contiguous-gene mechanism): STRA6, NEO1, CYP11A1, CYP1A1, EDC3 (F012). Modifier genes: none firmly established; deletion size is the main modifier of expressivity. Epigenetic information: SIN3A haploinsufficiency produces a diagnostic, predominantly hypomethylated blood DNA-methylation episignature (PMID: 36399132). Chromosomal abnormality: interstitial deletion 15q24, ~0.1–3.75 Mb; recurrent breakpoints in SD blocks; detected by CMA/aCGH.
No environmental factors, toxins, radiation, occupational exposures, lifestyle factors, or infectious agents are implicated in causing or triggering this disorder. It is a de novo genetic condition. Recurrent infections observed in some patients are a consequence of the deletion (possible immune component), not an environmental cause.
Ordered causal chain (initiating lesion → clinical manifestation):
Branch (larger deletions only): Co-deletion of neighboring genes contributes organ-specific features — STRA6 loss leads to disrupted retinoic-acid/vitamin-A signaling → ocular, diaphragmatic, and cardiac malformations (Matthew-Wood-like); NEO1 loss contributes to ASD; CYP11A1 loss may contribute to steroidogenic/gonadal effects. (inferred from gene function and overlapping syndromes — [PMID: 30204971], [PMID: 31953991])
Molecular pathways: transcriptional corepression via histone deacetylation (not classical signaling cascades); retinoic-acid signaling (STRA6 branch). Cellular processes: neurogenesis, neuronal differentiation/identity, cell-cycle and survival control, apoptosis. Protein dysfunction: loss of function / haploinsufficiency; missense variants destabilize the PAH1 αα-hub protein-interaction domain (PMID: 41759735). Epigenetic changes: global shift toward hypomethylation (episignature). GO/CL suggestions: histone deacetylation GO:0016575, negative regulation of transcription by RNA Pol II GO:0000122, chromatin organization GO:0006325, cerebral cortex neuron differentiation GO:0021895, neurogenesis GO:0022008; cell types — neural progenitor/radial glial cell CL:0000047/CL:0000681, glutamatergic cortical projection neuron CL:0000679.
Organ level — primary: brain, especially cerebral cortex (UBERON:0000956); corpus callosum (UBERON:0002336); lateral ventricles (ventriculomegaly). Secondary/other systems: craniofacial skeleton (UBERON:0010323/facial dysmorphism), eyes (UBERON:0000970), ears (hearing), external male genitalia (UBERON:0000079; hypospadias/micropenis), digits/skeleton (UBERON:0002544), and — rarely in larger deletions — heart (UBERON:0000948), diaphragm (UBERON:0001103; CDH), and gastrointestinal tract (UBERON:0001555; intestinal atresia, imperforate anus). Tissue/cell level: nervous tissue; cortical neural progenitors and projection neurons. Subcellular level: nucleus (GO:0005634) — chromatin/corepressor complex (GO:0016580, Sin3-type complex). Lateralization: malformations are generally bilateral/midline (corpus callosum, facial midline); no consistent lateralization.
Onset: congenital — structural malformations are prenatal; growth retardation prenatal/postnatal; developmental delay apparent in infancy/early childhood. Onset pattern: chronic/static. Progression: the core neurodevelopmental phenotype is non-progressive and lifelong; developmental trajectory improves with therapy but ID persists. A rare report documents progressive cerebellar ataxia/dystonia, an atypical course (PMID: 39576496). Disease course: chronic, lifelong; no remission/relapse pattern. Critical periods: fetal corticogenesis (for brain phenotype) and early childhood (developmental intervention window).
Epidemiology: rare; exact prevalence not firmly established (Orphanet classifies it on the order of <1/1,000,000). 15q24 deletions occur 8–10× less frequently than 1q21 or 15q13 microdeletions (PMID: 22180641). Inheritance: autosomal dominant; the overwhelming majority are de novo. Penetrance: high/essentially complete for the neurodevelopmental phenotype. Expressivity: highly variable (ID from absent to severe; malformations present only in a minority). Anticipation: not applicable (not a repeat-expansion disorder). Germline mosaicism: possible but not well documented; gives low recurrence risk. Founder effects / consanguinity: not applicable (dominant, de novo). Carrier frequency: not applicable. Demographics: no ethnic predilection; both sexes affected (male-genital phenotypes are sex-limited; the Balasubramanian cohort was 17 M : 11 F). Geographic distribution: worldwide, no endemic clustering.
First-line genetic testing: chromosomal microarray (CMA/aCGH) detects the deletion; karyotype is typically normal (PMID: 22216833). For intragenic SIN3A variants: whole-exome/whole-genome sequencing or multigene neurodevelopmental panels including SIN3A; MLPA has been used to detect 15q24 deletions (PMID: 34922566). FISH can confirm a known deletion. Epigenomic diagnostic: the predominantly hypomethylated WITKOS episignature serves as a functional confirmatory test and resolves VUS (PMID: 36399132). Imaging: brain MRI may show corpus callosum hypoplasia and ventriculomegaly (PMID: 27399968). Clinical evaluation: growth monitoring, developmental/cognitive assessment, dysmorphology exam, genital exam in males, ophthalmologic and audiologic evaluation, and endocrine work-up (GH, pubertal/HH assessment; PMID: 38528912). Differential diagnosis: other microdeletion/ID syndromes with overlapping dysmorphism and ID (e.g., other contiguous-gene syndromes, SIN3B-related syndrome [PMID: 33811806], Kabuki syndrome, and MeCP2-pathway disorders); episignature and CMA/sequencing distinguish them. Screening: no population newborn screening; cascade testing is usually not needed given de novo origin, but parental testing informs recurrence risk.
Survival/mortality: no reduced life expectancy is established for isolated SIN3A-related disorder; the core phenotype is compatible with normal lifespan. Rare severe congenital malformations (CDH, complex heart defects, intestinal atresia) in larger deletions can cause significant early morbidity and, uncommonly, mortality (PMID: 22216833). Morbidity/function: chief long-term burden is mild (occasionally moderate) ID, speech/communication impairment, and behavioral issues, with variable impact on independence. Complications: recurrent infections, feeding/growth difficulties, seizures, and endocrine issues (GH deficiency, hypogonadotropic hypogonadism). Recovery potential: developmental skills improve with early intervention, but cognitive impairment is lifelong. Prognostic factors: deletion size and presence of major malformations are the main determinants of outcome; cognitive severity ranges from normal to severe. No validated molecular prognostic biomarkers.
There is no disease-modifying or targeted therapy. Management is supportive, anticipatory, and multidisciplinary (PMID: 33437032). Components, with suggested NCIT intervention concepts: - Developmental/rehabilitative: early intervention, speech therapy (NCIT:C15300 Speech Therapy), physical and occupational therapy, special education. - Neurologic: antiepileptic drugs for seizures (NCIT:C264 Anticonvulsant Agent). - Behavioral/psychiatric: personalized psychological treatment (first documented in WITKOS, with improved functioning; PMID: 41245232); ADHD/ASD-directed behavioral and, where indicated, pharmacologic management. - Surgical (NCIT:C15329 Surgery): repair of hypospadias, congenital diaphragmatic hernia, intestinal atresia, imperforate anus, and congenital heart defects. - Endocrine: growth hormone therapy for documented GH deficiency (NCIT:C1646 Recombinant Human Growth Hormone); hormonal treatment for pubertal delay/hypogonadotropic hypogonadism (PMID: 38528912). - Infectious: management of recurrent infections; immune evaluation when indicated. - Pharmacogenomics / advanced therapeutics (gene, cell, RNA, immunotherapy): none established or applicable. No clinical trials of disease-specific agents are available.
Primary prevention: none possible, as the disorder is a de novo genetic event. Secondary prevention: early developmental screening enables prompt intervention to optimize function. Tertiary prevention: anticipatory surveillance (growth, endocrine, ophthalmologic, audiologic, seizure monitoring) to prevent/limit complications. Genetic counseling: recurrence risk is low for parents of a child with a de novo deletion/variant (empiric risk slightly above baseline due to possible germline mosaicism); affected individuals who reproduce have a 50% transmission risk (autosomal dominant). Reproductive options: prenatal diagnosis (CMA on CVS/amniocentesis) and preimplantation genetic testing are available when a parental variant is known. Immunization/public-health/environmental interventions: not applicable.
Taxonomy/orthologs: SIN3A is deeply conserved; mouse Sin3a (NCBI Gene 20466; Mus musculus, NCBI:txid10090) and zebrafish orthologs are established functional models. Natural disease: no naturally occurring companion-animal or wildlife disease corresponding to 15q24 deletion syndrome is documented in OMIA. Comparative biology: the corepressor mechanism (SIN3–HDAC) is conserved from yeast to humans, underscoring evolutionary conservation of the disease-relevant pathway; the paralog SIN3B is similarly conserved and disease-associated (PMID: 33811806). Transmission/zoonosis: not applicable.
Segmental duplications (LCRs) flanking 15q24
│ non-allelic homologous recombination
▼
de novo 15q24 deletion ──OR── intragenic SIN3A LOF / destabilizing missense
│ │
▼ ▼
SIN3A HAPLOINSUFFICIENCY ◄──────────────────
│
▼
Impaired SIN3–HDAC1/2 corepressor complex + weakened MeCP2 interaction
(SIN3A·HDAC1/2·RBBP4/7·SAP30·SDS3; histone deacetylation lost)
│
▼
Dysregulated repression of SIN3 targets (cell cycle, DNA repair,
apoptosis, chromatin, mitochondrial metabolism; Myc-Mad/E2F/p53)
│
▼
Reduced cortical neurogenesis · altered neuronal identity · aberrant projections
│
▼
Corpus callosum hypoplasia, ventriculomegaly, microcephaly
│
▼
MILD ID · speech delay · ASD/ADHD · hypotonia · facial gestalt · short stature
│
┌─────────────┴─────────────────────── (larger deletions only) ──────────────┐
│ Co-deletion of STRA6 → retinoic-acid signaling defect → eye/diaphragm/heart │
│ Co-deletion of NEO1 → ASD contribution │
│ Co-deletion of CYP11A1 → steroidogenic/gonadal effects │
└─────────────────────────────────────────────────────────────────────────────┘
The investigation produced a coherent two-tier model. Tier 1 (monogenic core): SIN3A haploinsufficiency impairs an epigenetic corepressor machine, disrupting the transcriptional programs of cortical neurogenesis and producing the invariant neurodevelopmental and craniofacial phenotype shared by the microdeletion and Witteveen–Kolk syndrome. The convergent evidence — OMIM identity (613406), point variants reproducing the phenotype, a diagnostic hypomethylated episignature, structural destabilization of missense variants, and a parallel SIN3B syndrome — makes this the most strongly supported conclusion. Tier 2 (contiguous-gene modifiers): the breadth and severity of non-neurodevelopmental malformations scale with deletion size because additional dosage-sensitive genes (STRA6, NEO1, CYP11A1) are removed, explaining why larger deletions add ocular, diaphragmatic, cardiac, and gonadal features absent in isolated SIN3A variants.
| PMID | Title (abbrev.) | Role in this report |
|---|---|---|
| 27399968 | SIN3A haploinsufficiency causes mild ID (MeCP2 interactor) | Links SIN3A to the microdeletion; mouse corticogenesis mechanism; MRI findings (F001, F003, F005, F011) |
| 33437032 | Study of 28 individuals with SIN3A-related disorder | WITKOS definition; quantified phenotype frequencies; management; variant spectrum (F001, F008, F009, F010) |
| 22180641 | Delineation of the 15q24 microdeletion syndrome | 1.1 Mb critical region; SD-mediated recurrence; rarity (F002) |
| 22216833 | Chromosome 15q24 microdeletion syndrome | Full phenotype spectrum; CMA diagnosis; rare severe malformations (F004, F009, F011) |
| 33130996 | REST/NRSF-SIN3 corepressor complex | SIN3 core complex composition (F003) |
| 15998811 | mSin3A regulates transcriptional networks | Essential role; p53/Myc-Mad/E2F network dysregulation (F005) |
| 36399132 | DNA methylation episignature for WITKOS | Diagnostic hypomethylated episignature (F006) |
| 41759735 | Sin3A-PAH1 αα-hub stability/variant defects | Structural basis of missense LOF (F007) |
| 33811806 | SIN3B haploinsufficiency syndrome | Paralog supports dosage mechanism (F007) |
| 17360722 | Recurrent 15q24 microdeletion | De novo origin; NAHR (F009) |
| 20404188 | HDAC1 controls ES cell differentiation | Catalytic-partner essentiality; corepressor-complex dependence (F003) |
| 31953991 | Refining 15q24 critical regions for autism | NEO1 as co-deleted ASD gene (F002, F012) |
| 30204971 | Matthew-Wood syndrome (STRA6) | STRA6 co-deletion → eye/diaphragm/heart (F012) |
| 38528912 | SIN3A LOF causing hypogonadotropic hypogonadism | Endocrine phenotype/management (F010) |
| 41245232 | Personalized treatment in WITKOS | Emerging behavioral intervention (F010) |
| 34922566 | 15q24 microdeletion in pediatric DD | Smaller LCR B–C deletions; CYP1A1/EDC3 case (F012) |
| 39576496 | WITKOS with dystonia/cerebellar ataxia | Expands phenotype spectrum (Section 8) |
All abstract quotations used in the Key Findings were drawn from the verified citation snippets in the knowledge state. Papers on PP2A/HDAC lactylation, MDM2 PROTACs, CaMKII, IFI16/KSHV, ARID4B, and MeCP2/SEC are mechanistically adjacent (they illuminate SIN3–HDAC biology) but were not used to attribute disease-specific clinical claims.
Report compiled from 12 confirmed findings and 25 reviewed papers over 5 iterations. Evidence sources: human clinical series/case reports, mouse and zebrafish models, in vitro biochemistry/structural biology, and computational/epigenomic classifiers, as indicated per claim.
Checked with linkml-reference-validator 0.4.0.
| Outcome | Count |
|---|---|
| References checked | 17 |
| Resolved | 17 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 20 |
| Quoted claims found in source | 20 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 17 |
| On topic | 12 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 42 |
| Resolved | 38 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 2 |
| Unverifiable | 2 |
These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
GO:0016575 (obsolete histone deacetylation) (1 mention)GO:0016580 (obsolete Sin3 complex) (1 mention) - replaced by GO:0070822Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.
38 of 42 terms resolved to a current term; the rest could not be looked up either way.