SIN3A-Related Intellectual Disability Syndrome

Mendelian MONDO:0044699 Pathograph 27 Show in embeddings browser Autosomal Dominant Syndromic Intellectual Disability

SIN3A-related intellectual disability syndrome (Witteveen-Kolk syndrome) is an autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function of SIN3A, the scaffold subunit of the SIN3-HDAC transcriptional corepressor complex. Most cases carry de novo truncating intragenic variants; missense variants in the PAH1 partner-binding domain and small 15q24 deletions that remove SIN3A also occur. Affected individuals usually have global developmental delay with mild intellectual disability or low-normal intelligence, speech and motor delay, a recognisable facial gestalt (broad tall forehead, downslanting palpebral fissures, small mouth, thin upper lip, pointed chin), microcephaly, short stature, feeding difficulties and hypotonia, with autism, attention deficit and psychiatric problems in a minority. Seizures, palatal defects, hearing loss, subtle brain anomalies (ventriculomegaly, corpus callosum hypoplasia) and syndromic hypogonadotropic hypogonadism are reported. A predominantly hypomethylated DNA methylation episignature in blood supports the diagnosis.

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Inheritance

1
Autosomal dominant inheritance HP:0000006
Heterozygous SIN3A loss of function acts dominantly. Most variants arise de novo, but familial transmission occurs, and expressivity is variable, with some carriers having intelligence in the normal range.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:36399132 SUPPORT Human clinical
"Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene."
States autosomal dominant inheritance through heterozygous loss of function.
PMID:33437032 SUPPORT Human clinical
"Patient 15 with c.3310C>T, p.(Arg1104*) variant is a family member of a patient we have previously reported in Witteveen et al."
Familial recurrence of a truncating variant.
PMID:33437032 SUPPORT Human clinical
"Patients with disease causing variants in SIN3A usually have mild global developmental delay/ID, with some even having tested IQs in the normal range with variable penetrance."
Variable expressivity and penetrance.
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Subtypes

2
SIN3A-related intellectual disability syndrome due to a point mutation MONDO:0044700
SIN3A hgnc:19353 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SIN3A (hgnc:19353). hgnc:19353 is a gene from the HUGO Gene Nomenclature Committee.
Intragenic SIN3A variants, mostly truncating (nonsense, frameshift and splice) and predicted to cause loss of function, with a few missense variants in the PAH1 domain and one in-frame multi-exon duplication. This is the majority form; in the largest cohort 24 of 28 variants were truncating.
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12."
Variant spectrum of the intragenic form in a 28-patient cohort.
SIN3A-related intellectual disability syndrome due to a 15q24 deletion including SIN3A
SIN3A hgnc:19353 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SIN3A (hgnc:19353). hgnc:19353 is a gene from the HUGO Gene Nomenclature Committee.
Heterozygous 15q24.1-q24.2 microdeletions that remove the whole SIN3A gene, reported as Witteveen-Kolk syndrome when the deletion is small (a 550 kb deletion in one man with Kallmann syndrome; a 1.6 Mb deletion in a child with the classic phenotype). MONDO has no term for this form below MONDO:0044699. Larger recurrent LCR-mediated 15q24 deletions with a more severe contiguous-gene phenotype are curated in Chromosome_15q24_Deletion_Syndrome; the size boundary between the two concepts is not sharp and some reports call large deletions WITKOS.
Show evidence (4 references)
PMID:27399968 SUPPORT Human clinical
"This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome."
The founding report linked the SIN3A point-mutation phenotype to atypical 15q24 deletions.
PMID:36758531 SUPPORT Human clinical
"A 550 kb deletion at 15q24.1, including the whole SIN3A gene, was identified in S1"
A small deletion removing SIN3A in a patient with a Witteveen-Kolk overlap phenotype.
PMID:38841330 SUPPORT Human clinical
"Affymetrix CytoScan 750K microarray showed a de novo 1.6-Mb deletion at 15q24.1q24.2, including the whole SIN3A gene."
A de novo SIN3A-spanning deletion in a child with classic WITKOS features.
+ 1 more reference
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Pathophysiology

6
SIN3A Haploinsufficiency
Heterozygous truncating variants and whole-gene deletions reduce the dose of SIN3A. Truncating variants are distributed across the gene and no genotype-phenotype correlation or missense hotspot has been found, which supports haploinsufficiency as the principal mechanism.
SIN3A hgnc:19353 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SIN3A (hgnc:19353). hgnc:19353 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
transcription corepressor activity GO:0003714 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased transcription corepressor activity (GO:0003714). GO:0003714 is a molecular function from the Gene Ontology.
Downstream
Reduced SIN3A-HDAC Corepressor Activity Halving SIN3A dose is expected to reduce the amount of assembled SIN3A-HDAC corepressor; this has not been measured directly in patient cells.
Show evidence (2 references)
PMID:27399968 SUPPORT Human clinical
"Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability"
Founding report establishing SIN3A haploinsufficiency as the disease mechanism.
PMID:33437032 SUPPORT Human clinical
"As expected, majority of patients in published literature and this cohort appear to have truncating variants reinforcing haploinsufficiency as likely mechanism of pathogenicity"
Predominance of truncating variants supports haploinsufficiency.
SIN3A PAH1 Domain Partner-Binding Defect
The few disease-associated missense variants include A126V and K155E in the PAH1 domain, the amphipathic-helix hub that binds transcription factors and SIN3A-associated proteins. Recombinant PAH1 carrying either variant binds SAP25 and TET1 less tightly (K155E more than 15-fold weaker for TET1), so these alleles impair specific partner recruitment rather than abolishing the protein.
SIN3A hgnc:19353 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SIN3A (hgnc:19353). hgnc:19353 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
transcription corepressor activity GO:0003714 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased transcription corepressor activity (GO:0003714). GO:0003714 is a molecular function from the Gene Ontology.
Downstream
Reduced SIN3A-HDAC Corepressor Activity Weaker binding of PAH1 partners is expected to reduce recruitment of the corepressor to its target genes; this has not been shown in patient cells.
Show evidence (2 references)
PMID:41759735 SUPPORT In vitro / ex vivo
"The variants of Sin3A-PAH1 exhibit lower affinities for both SAP25 and Tet1, with a >15-fold reduction in the affinity of PAH1-K155E for Tet1."
Biophysical measurement of reduced partner binding by two patient missense variants.
PMID:33437032 SUPPORT Computational
"Both altered residues by c.377C>T, p.(Ala126Val) and c.463A>G, p.(Lys155Glu) were predicted to be part of the SAP25 SID-binding surface."
Structural modelling placed both missense residues on the SAP25 binding surface.
Reduced SIN3A-HDAC Corepressor Activity
SIN3A is the scaffold of a corepressor complex containing HDAC1 and HDAC2 that is recruited by sequence-specific repressors and by the methyl-CpG binding protein MeCP2, linking DNA methylation to histone deacetylation and transcriptional repression. Reduced SIN3A function is expected to weaken repression at its target genes. Mouse embryos lacking Sin3a entirely die around implantation, so the patient state is a partial loss of an essential regulator.
SIN3-HDAC corepressor complex GO:0070822 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves SIN3-HDAC corepressor complex, annotated with Sin3-type complex (GO:0070822). GO:0070822 is a protein complex from the Gene Ontology.
negative regulation of transcription by RNA polymerase II GO:0000122 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of transcription by RNA polymerase II (GO:0000122). GO:0000122 is a biological process from the Gene Ontology.
transcription corepressor activity GO:0003714 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased transcription corepressor activity (GO:0003714). GO:0003714 is a molecular function from the Gene Ontology.
Downstream
Impaired Cortical Neurogenesis and Neuronal Identity Shown by Sin3a knockdown in the developing mouse cortex; which SIN3A target genes mediate the effect is not known.
Blood DNA Hypomethylation Episignature The episignature is a genome-wide readout of SIN3A haploinsufficiency in blood; how reduced corepressor activity produces the methylation changes is not established.
Short stature The genetic link is established; the mechanism of growth restriction is unknown.
Feeding difficulties The genetic link is established; the mechanism is unknown.
Hypogonadotropic hypogonadism Attributed to SIN3A rather than to neighbouring 15q24 genes because intragenic SIN3A variants cause it; the effect on the GnRH axis is not characterised.
Broad forehead Craniofacial features follow from SIN3A loss by unknown developmental mechanisms.
Cleft palate Craniofacial features follow from SIN3A loss by unknown developmental mechanisms.
Show evidence (5 references)
PMID:9150135 SUPPORT In vitro / ex vivo
"We have found that the mammalian transcriptional repressor Sin3 (mSin3) exists in a complex with histone deacetylases HDAC1 and HDAC2."
Defines the SIN3-HDAC corepressor complex.
PMID:9620804 SUPPORT In vitro / ex vivo
"We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases."
MeCP2 recruits the SIN3A-HDAC complex, the interaction named in the founding SIN3A disease report.
PMID:30279502 SUPPORT BACKGROUND In vitro / ex vivo
"The Sin3A protein sits at the centre of the complex, mediating multiple simultaneous protein-protein interactions via its four paired-amphipathic helix (PAH) domains (PAH1-4)."
SIN3A is the scaffold that docks partners through its PAH domains.
+ 2 more references
Impaired Cortical Neurogenesis and Neuronal Identity
In utero knockdown of Sin3a in the embryonic mouse cortex reduced the production of cortical neurons from progenitors and altered the identity of the neurons produced. This is the cellular step proposed to underlie the cognitive phenotype, and reduced neurogenesis is a plausible basis of the microcephaly, although that link has not been tested directly.
cortical neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cortical neural progenitor cell, annotated with neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology. cerebral cortex neuron CL:0010012 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebral cortex neuron (CL:0010012). CL:0010012 is a cell type from the Cell Ontology.
cortical neurogenesis GO:0022008 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cortical neurogenesis, annotated with neurogenesis (GO:0022008). GO:0022008 is a biological process from the Gene Ontology. cerebral cortex neuron differentiation GO:0021895 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cerebral cortex neuron differentiation (GO:0021895). GO:0021895 is a biological process from the Gene Ontology.
cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral cortex (UBERON:0000956). UBERON:0000956 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Sin3a in utero knockdown in embryonic mouse cortex Mouse recapitulates Focal knockdown of Sin3a in the developing cortex reduces neurogenesis and alters neuronal identity.
Downstream
Disrupted Cortical Integrity and Connectivity
Microcephaly Inferred: reduced cortical neurogenesis is a plausible cause of small head size, but head size was not reported in the knockdown experiments.
Show evidence (2 references)
PMID:27399968 SUPPORT Model organism
"in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain"
Mouse cortical knockdown phenotype.
PMID:27399968 SUPPORT Model organism
"SIN3A can be considered to be a key transcriptional regulator of cortical brain development"
Authors' conclusion on the role of SIN3A in cortical development.
Disrupted Cortical Integrity and Connectivity
Aberrant corticocortical projections in the knockdown mouse and subtle structural anomalies on patient MRI (ventriculomegaly, corpus callosum hypoplasia or dysplasia, delayed myelination) indicate abnormal cortical development and connectivity, which the authors propose underlies the cognitive and behavioural phenotype.
cerebral cortex development GO:0021987 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cerebral cortex development (GO:0021987). GO:0021987 is a biological process from the Gene Ontology. corticocortical axon guidance GO:0007411 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal corticocortical axon guidance, annotated with axon guidance (GO:0007411). GO:0007411 is a biological process from the Gene Ontology.
cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral cortex (UBERON:0000956). UBERON:0000956 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Sin3a in utero knockdown in embryonic mouse cortex Mouse partially recapitulates Knockdown produces aberrant corticocortical projections.
Downstream
Mild intellectual disability
Global developmental delay
Delayed speech and language development
Motor delay
Autism spectrum disorder
Attention deficit hyperactivity disorder
Psychiatric and behavioural problems
Seizures
Hypotonia
Ventriculomegaly
Hypoplasia of the corpus callosum
Show evidence (1 reference)
PMID:27399968 SUPPORT Human clinical
"Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly."
Patient MRI shows subtle structural brain anomalies.
Blood DNA Hypomethylation Episignature
Peripheral blood DNA from individuals with SIN3A haploinsufficiency shows a predominantly hypomethylated genome-wide methylation profile that distinguishes them from controls and from other neurodevelopmental disorders with episignatures. It is a diagnostic readout rather than a cause of the clinical features.
peripheral blood leukocyte CL:0000738 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves peripheral blood leukocyte, annotated with leukocyte (CL:0000738). CL:0000738 is a cell type from the Cell Ontology.
epigenetic regulation of gene expression GO:0040029 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal epigenetic regulation of gene expression (GO:0040029). GO:0040029 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:36399132 SUPPORT Human clinical
"A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case."
Episignature identified in 20 individuals with SIN3A alterations.
PMID:36399132 SUPPORT Human clinical
"The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants."
The signature is present across the severity range.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for SIN3A-Related Intellectual Disability Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

31
Cardiovascular 1
Cardiac anomalies Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiac anomalies, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38841330 SUPPORT REVIEW SYNTHESIS Human clinical
"We have also summarized the clinical features of WITKOS patients in the medical literature and cardiac abnormalities detected in 4 out of 10 patients in studies that clearly state that cardiac examination was performed in the patients."
Pooled literature frequency of cardiac abnormalities.
Digestive 2
Feeding difficulties 15/28 HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"15/28 (54%) of patients had feeding difficulties with at least two patients documented to require nasogastric tube feeding mainly in the neonatal period."
Feeding difficulties frequency.
Gastroesophageal reflux HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38841330 SUPPORT Human clinical
"Also, a barium esophagogram suggested severe motility disorder and gastroesophageal reflux disease."
Single-patient finding; frequency unknown.
Ear 1
Hearing impairment 5/28 HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"Other reported features included hearing loss (5/28; 18%) of which 1 patient had sensorineural hearing loss, two patients had conductive hearing loss and two patients had mixed hearing loss."
Hearing loss types and frequency.
Endocrine 1
Hypogonadotropic hypogonadism HP:0000044 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogonadotropic hypogonadism (HP:0000044). HP:0000044 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:36758531 SUPPORT Human clinical
"Rare SIN3A pathogenic variants were identified in these 2 unrelated patients with CHH phenotypic features."
Two unrelated patients with congenital HH and SIN3A defects.
PMID:38528912 SUPPORT Human clinical
"In conclusion, these findings point to SIN3A as the gene in 15q24 related to the reproductive phenotype in patients with overlapping WITKOS and Kallmann syndrome."
An intragenic frameshift variant with Kallmann syndrome attributes the reproductive phenotype to SIN3A.
PMID:41409308 SUPPORT Human clinical
"Patient 2 was followed up with a preliminary diagnosis of hypogonadotropic hypogonadism (HH) and a new de novo pathogenic variation in the SIN3A gene."
A further de novo SIN3A case presenting with HH.
Genitourinary 2
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36758531 SUPPORT BACKGROUND Human clinical
"Although micropenis and cryptorchidism have been reported in this syndrome, WITKOS has not been formally associated with CHH so far."
Cryptorchidism has been reported in WITKOS.
Micropenis HP:0000054 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micropenis (HP:0000054). HP:0000054 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36758531 SUPPORT BACKGROUND Human clinical
"Although micropenis and cryptorchidism have been reported in this syndrome, WITKOS has not been formally associated with CHH so far."
Micropenis has been reported in WITKOS.
Head and Neck 8
Microcephaly 13/28 HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33437032 SUPPORT Human clinical
"13/28 (46%) patients in our cohort had head circumference at least two standard deviations (SD) below the mean."
Microcephaly frequency.
PMID:27399968 SUPPORT Human clinical
"in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature"
Microcephaly in the founding cohort.
Broad forehead HP:0000337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad forehead (HP:0000337). HP:0000337 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33437032 SUPPORT Human clinical
"Common facial features included a broad, tall forehead; small mouth, thin upper lip with pointed chin and down-slanting palpebral fissures (see Fig. 3)."
Component of the reported facial gestalt.
PMID:33437032 SUPPORT Human clinical
"Fourteen (50%) patients were reported to have craniofacial dysmorphism."
Frequency of craniofacial dysmorphism overall in the cohort.
High forehead HP:0000348 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tall forehead, annotated with High forehead (HP:0000348). HP:0000348 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"Common facial features included a broad, tall forehead; small mouth, thin upper lip with pointed chin and down-slanting palpebral fissures (see Fig. 3)."
Component of the reported facial gestalt.
Downslanted palpebral fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"Common facial features included a broad, tall forehead; small mouth, thin upper lip with pointed chin and down-slanting palpebral fissures (see Fig. 3)."
Component of the reported facial gestalt.
Small mouth Narrow mouth HP:0000160 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small mouth, annotated with Narrow mouth (HP:0000160). HP:0000160 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"Common facial features included a broad, tall forehead; small mouth, thin upper lip with pointed chin and down-slanting palpebral fissures (see Fig. 3)."
Component of the reported facial gestalt.
Thin upper lip vermilion HP:0000219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin upper lip, annotated with Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"Common facial features included a broad, tall forehead; small mouth, thin upper lip with pointed chin and down-slanting palpebral fissures (see Fig. 3)."
Component of the reported facial gestalt.
Pointed chin HP:0000307 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pointed chin (HP:0000307). HP:0000307 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"Common facial features included a broad, tall forehead; small mouth, thin upper lip with pointed chin and down-slanting palpebral fissures (see Fig. 3)."
Component of the reported facial gestalt.
Cleft palate 3/28 HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33437032 SUPPORT Human clinical
"Three patients had a palatal defect with one also having a bifid uvula."
Palatal defects in the 2021 cohort.
PMID:39828923 SUPPORT Human clinical
"Here, we present a case of WITKOS with a CP."
Additional case of cleft palate.
Integument 1
Progeroid facial appearance HP:0005328 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progeroid facial appearance (HP:0005328). HP:0005328 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33437032 SUPPORT Human clinical
"Sparse hair and reduced subcutaneous tissue was reported in 3/28 (10%) of patients in this study and note the progeric appearance in at least two of the patients in this cohort."
Progeroid appearance in a minority of the cohort.
PMID:33437032 SUPPORT Human clinical
"SIN3A-related disorder does not appear to present predominantly with a progeroid phenotype from the large cohort described here."
Limits the claim to a minority feature.
Musculoskeletal 2
Hypotonia 12/28 HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"Hypotonia was a common manifestation as well, present in 12/28 (43%) patients."
Hypotonia frequency.
Joint hypermobility HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32783353 SUPPORT REVIEW SYNTHESIS Human clinical
"Hypermobile joints and hearing loss have also been reported."
Literature summary of reported features.
Nervous System 12
Global developmental delay 15/28 HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"Of 28 patients, 15 (56%) had global developmental delay."
Frequency of global developmental delay in the 28-patient cohort.
Mild intellectual disability FREQUENT HP:0001256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild intellectual disability (HP:0001256). HP:0001256 is a phenotype from the Human Phenotype Ontology.
The same paper reports mild ID in eight of 16 (50%) in its abstract and seven of 16 (44%) in its results text; frequency is given as a band for that reason.
Show evidence (3 references)
PMID:33437032 SUPPORT Human clinical
"Out of 16 patients ≥ 8 years old 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."
Distribution of cognitive outcome in patients aged 8 years or older.
PMID:27399968 SUPPORT Human clinical
"in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature"
Mild ID in the founding cohort.
PMID:33437032 SUPPORT Human clinical
"Interestingly, all patients in whom intelligence was tested reported a higher verbal than performal intelligence score."
Disharmonic IQ profile.
Delayed speech and language development 16/21 HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"In 21 patients ≥5 years old, some form of motor developmental delay was reported in 13 patients (62%) and in 16 patients (76%) there was some form of language developmental delay."
Language delay in 16 of 21 patients aged 5 years or older.
Motor delay 13/21 HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"In 21 patients ≥5 years old, some form of motor developmental delay was reported in 13 patients (62%) and in 16 patients (76%) there was some form of language developmental delay."
Motor delay in 13 of 21 patients aged 5 years or older.
Autism spectrum disorder 3/23 Autistic behavior HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism spectrum disorder, annotated with Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33437032 SUPPORT Human clinical
"In three of 23 patients ≥2 years (13%), ASD was diagnosed."
ASD frequency in the 2021 cohort.
PMID:27399968 SUPPORT Human clinical
"in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature"
ASD in the founding cohort.
Attention deficit hyperactivity disorder 4/23 HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33437032 SUPPORT Human clinical
"ADHD was diagnosed in four patients ≥2 years (17%)."
ADHD frequency in the 2021 cohort.
PMID:32783353 SUPPORT Human clinical
"results indicate weaknesses in speed of information processing/sustained attention in all participants"
Neuropsychological testing found attention and processing-speed weaknesses in all five assessed individuals.
Psychiatric and behavioural problems FREQUENT Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Psychiatric and behavioural problems, annotated with Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33437032 SUPPORT Human clinical
"Overall, a third of the cohort had a psychiatric or behavioural condition reported, including ADHD, aggressive behaviour, OCD, depression, psychosis, anxiety and schizoaffective disorder."
Psychiatric and behavioural conditions in a third of the 2021 cohort.
PMID:32783353 SUPPORT Human clinical
"Systematic analysis of medical records displays developmental difficulties described as ASD or ADHD in childhood, sleep problems and internalizing problems during adolescence."
Developmental course of behavioural problems in five individuals.
Seizures OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
The 2021 cohort gives 4/28 in its abstract and 6/28 (21%) in its results text; frequency is given as a band for that reason.
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"6/28 (21%) patients were noted to have seizures currently or in their past medical history."
Seizure history in the 2021 cohort.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27399968 SUPPORT Human clinical
"Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly."
MRI finding in the founding cohort.
PMID:33437032 SUPPORT Human clinical
"Most common was ventriculomegaly in 2/9, and a hypoplastic/dysplastic corpus callosum in 2/9."
MRI findings in the nine imaged patients of the 2021 cohort.
Hypoplasia of the corpus callosum HP:0002079 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the corpus callosum (HP:0002079). HP:0002079 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27399968 SUPPORT Human clinical
"Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly."
MRI finding in the founding cohort.
PMID:33437032 SUPPORT Human clinical
"Most common was ventriculomegaly in 2/9, and a hypoplastic/dysplastic corpus callosum in 2/9."
Corpus callosum hypoplasia or dysplasia in two of nine imaged patients.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized dystonia, annotated with Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39576496 SUPPORT Human clinical
"Herein, we present a 21-year-old woman with dysmorphic facial features, short stature, and a chronic, progressively worsening symmetric cerebellar ataxia, along with generalized dystonia."
Single case report.
Progressive cerebellar ataxia HP:0002073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive cerebellar ataxia (HP:0002073). HP:0002073 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39576496 SUPPORT Human clinical
"Herein, we present a 21-year-old woman with dysmorphic facial features, short stature, and a chronic, progressively worsening symmetric cerebellar ataxia, along with generalized dystonia."
Single case report.
Growth 1
Short stature 5/28 HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33437032 SUPPORT Human clinical
"Weight was less than two SD below the mean in 8/28 patients (29%) and height was less than two SD below the mean in 5/28 patients (18%)."
Growth parameters in the 2021 cohort.
PMID:27399968 SUPPORT Human clinical
"in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature"
Short stature in the founding cohort.
🧬

Genetic Associations

1
SIN3A (Causative (heterozygous loss of function))
Gene: SIN3A hgnc:19353 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SIN3A (hgnc:19353). hgnc:19353 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:27399968 SUPPORT Human clinical
"Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2)"
Founding identification of dominant SIN3A mutations.
PMID:33437032 SUPPORT Human clinical
"Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A."
Disease definition by heterozygous SIN3A loss of function.
💊

Medical Actions

3
Multidisciplinary developmental and supportive care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
No disease-specific therapy exists. Management is supportive, with developmental, neurological and paediatric follow-up, and brain imaging offered when neurological symptoms are present rather than routinely.
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients."
Author recommendation from a case series, not a guideline.
Neuropsychologically informed psychological treatment
Action: psychotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is psychotherapy (NCIT:C15308). NCIT:C15308 is a clinical intervention from the NCI Thesaurus. Ontology label: Psychotherapy NCIT:C15308
Platform: Behavioral / lifestyle
A single case report describes twelve sessions of psychological treatment tailored to the patient's neurocognitive profile (aimed at reducing cognitive overload, anxiety and fatigue), with improved functioning at three months but poor maintenance of emotion-regulation gains.
Mechanism Target:
Psychiatric and behavioural problems
Show evidence (1 reference)
PMID:41245232 SUPPORT Human clinical
"Evaluation during treatment and at 3-month follow-up showed a positive increase in functioning and acceptance as well as the acceptance of successive follow-up treatment."
Single-patient outcome of tailored psychological treatment.
Sex hormone replacement for hypogonadotropic hypogonadism
Action: hormone replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hormone replacement therapy (NCIT:C15599). NCIT:C15599 is a clinical intervention from the NCI Thesaurus. Ontology label: Hormone Replacement Therapy NCIT:C15599
Platform: Small molecule
Hypogonadotropic hypogonadism is treated with standard hormone replacement to induce puberty, as in other forms of the condition.
Mechanism Target:
Hypogonadotropic hypogonadism
Show evidence (1 reference)
PMID:38528912 SUPPORT Human clinical
"Hormone replacement treatment was started gradually with normal evolution."
Hormone replacement in a female patient with SIN3A-related Kallmann syndrome.
🔬

Diagnosis

2
Exome or genome sequencing
The facial gestalt is recognisable mainly in retrospect, so most diagnoses are made by exome or genome sequencing or intellectual disability gene panels; chromosomal microarray detects SIN3A-spanning deletions.
exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33437032 SUPPORT Human clinical
"However, it is likely that diagnostic evaluation and identification of SIN3A variants in suspected individuals will be performed using large ID panels or WES/WGS."
Authors' expectation of the diagnostic route.
DNA methylation episignature analysis
A SIN3A-specific blood episignature can classify variants of uncertain significance and resolve unexplained cases.
genome-wide DNA methylation analysis NCIT:C63328 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:36399132 SUPPORT Human clinical
"This episignature has the potential to aid identification and diagnosis of individuals with WITKOS."
Diagnostic utility of the episignature.
🐁

Animal Models

1
Sin3a in utero knockdown in embryonic mouse cortex
Species
Mouse
Genotype
Sin3a knockdown in developing cortex (in vivo functional knockdown)
Publication
PMID:27399968
Pathograph links
Impaired Cortical Neurogenesis and Neuronal Identity recapitulates fidelity: moderate observes: cellular Focal knockdown of Sin3a in the developing cortex reduces neurogenesis and alters neuronal identity.
Limitations: Knockdown is focal and of uncertain depth rather than a constitutional heterozygous loss, and it reports cortical development only, not behaviour or the non-neural features.
Show evidence (1 reference)
PMID:27399968 SUPPORT Model organism
"in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain"
Knockdown reproduces the cellular cortical defect.
Disrupted Cortical Integrity and Connectivity partially recapitulates fidelity: moderate observes: tissue Knockdown produces aberrant corticocortical projections.
Limitations: Patient MRI shows corpus callosum and ventricular changes; whether the projection defect in mice corresponds to these findings is not shown.
Show evidence (1 reference)
PMID:27399968 SUPPORT Model organism
"in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain"
Knockdown produces aberrant cortical projections.
{ }

Source YAML

click to show 
name: SIN3A-Related Intellectual Disability Syndrome
creation_date: "2026-11-04T23:54:07Z"
category: Mendelian
description: >-
  SIN3A-related intellectual disability syndrome (Witteveen-Kolk syndrome) is an
  autosomal dominant neurodevelopmental disorder caused by heterozygous
  loss-of-function of SIN3A, the scaffold subunit of the SIN3-HDAC
  transcriptional corepressor complex. Most cases carry de novo truncating
  intragenic variants; missense variants in the PAH1 partner-binding domain and
  small 15q24 deletions that remove SIN3A also occur. Affected individuals
  usually have global developmental delay with mild intellectual disability or
  low-normal intelligence, speech and motor delay, a recognisable facial
  gestalt (broad tall forehead, downslanting palpebral fissures, small mouth,
  thin upper lip, pointed chin), microcephaly, short stature, feeding
  difficulties and hypotonia, with autism, attention deficit and psychiatric
  problems in a minority. Seizures, palatal defects, hearing loss, subtle brain
  anomalies (ventriculomegaly, corpus callosum hypoplasia) and syndromic
  hypogonadotropic hypogonadism are reported. A predominantly hypomethylated
  DNA methylation episignature in blood supports the diagnosis.
synonyms:
- Witteveen-Kolk syndrome
- WITKOS
- SIN3A-related disorder
notes: >-
  MONDO records no synonyms on MONDO:0044699 (an Orphanet-derived concept,
  ORPHA:500163). The names Witteveen-Kolk syndrome and WITKOS are carried here
  because the clinical literature cited below uses them for SIN3A
  haploinsufficiency (PMID:33437032, PMID:36399132, PMID:32783353). In MONDO
  those two strings and the OMIM:613406 cross-reference sit instead on
  MONDO:0013256 chromosome 15q24 deletion syndrome, which is not classified
  under MONDO:0044699; dismech curates that contiguous-gene deletion
  separately (Chromosome_15q24_Deletion_Syndrome), where SIN3A is one
  candidate gene among several. This entry covers SIN3A haploinsufficiency
  from intragenic variants and from deletions reported as SIN3A-spanning
  Witteveen-Kolk syndrome. No GeneReviews chapter names this disorder or SIN3A
  (PubMed search genereviews[book] for "Witteveen-Kolk"[TI] and SIN3A[TIAB]
  returned no chapter).
disease_term:
  preferred_term: SIN3A-related intellectual disability syndrome
  term:
    id: MONDO:0044699
    label: SIN3A-related intellectual disability syndrome
parents:
- Autosomal Dominant Syndromic Intellectual Disability
has_subtypes:
- name: Point mutation
  display_name: SIN3A-related intellectual disability syndrome due to a point mutation
  subtype_term:
    preferred_term: SIN3A-related intellectual disability syndrome due to a point mutation
    term:
      id: MONDO:0044700
      label: SIN3A-related intellectual disability syndrome due to a point mutation
  genes:
  - preferred_term: SIN3A
    term:
      id: hgnc:19353
      label: SIN3A
  description: >-
    Intragenic SIN3A variants, mostly truncating (nonsense, frameshift and
    splice) and predicted to cause loss of function, with a few missense
    variants in the PAH1 domain and one in-frame multi-exon duplication. This
    is the majority form; in the largest cohort 24 of 28 variants were
    truncating.
  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: "We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12."
    explanation: Variant spectrum of the intragenic form in a 28-patient cohort.
- name: SIN3A-spanning deletion
  display_name: SIN3A-related intellectual disability syndrome due to a 15q24 deletion including SIN3A
  genes:
  - preferred_term: SIN3A
    term:
      id: hgnc:19353
      label: SIN3A
  description: >-
    Heterozygous 15q24.1-q24.2 microdeletions that remove the whole SIN3A gene,
    reported as Witteveen-Kolk syndrome when the deletion is small (a 550 kb
    deletion in one man with Kallmann syndrome; a 1.6 Mb deletion in a child
    with the classic phenotype). MONDO has no term for this form below
    MONDO:0044699. Larger recurrent LCR-mediated 15q24 deletions with a more
    severe contiguous-gene phenotype are curated in
    Chromosome_15q24_Deletion_Syndrome; the size boundary between the two
    concepts is not sharp and some reports call large deletions WITKOS.
  evidence:
  - reference: PMID:27399968
    reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome."
    explanation: The founding report linked the SIN3A point-mutation phenotype to atypical 15q24 deletions.
  - reference: PMID:36758531
    reference_title: "SIN3A Defects Associated with Syndromic Congenital Hypogonadotropic Hypogonadism: An Overlap with Witteveen-Kolk Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 550 kb deletion at 15q24.1, including the whole SIN3A gene, was identified in S1"
    explanation: A small deletion removing SIN3A in a patient with a Witteveen-Kolk overlap phenotype.
  - reference: PMID:38841330
    reference_title: "A Witteveen-Kolk Syndrome Patient with Reflux Disease and a de novo Deletion of the SIN3A Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affymetrix CytoScan 750K microarray showed a de novo 1.6-Mb deletion at 15q24.1q24.2, including the whole SIN3A gene."
    explanation: A de novo SIN3A-spanning deletion in a child with classic WITKOS features.
  - reference: PMID:32783353
    reference_title: "Behavior and cognitive functioning in Witteveen-Kolk syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "and six with chromosomal microdeletions encompassing SIN3A"
    explanation: By 2020, six of 16 reported WITKOS patients carried microdeletions encompassing SIN3A.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    Heterozygous SIN3A loss of function acts dominantly. Most variants arise de
    novo, but familial transmission occurs, and expressivity is variable, with
    some carriers having intelligence in the normal range.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  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: States autosomal dominant inheritance through heterozygous loss of function.
  - 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: "Patient 15 with c.3310C>T, p.(Arg1104*) variant is a family member of a patient we have previously reported in Witteveen et al."
    explanation: Familial recurrence of a truncating variant.
  - 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: "Patients with disease causing variants in SIN3A usually have mild global developmental delay/ID, with some even having tested IQs in the normal range with variable penetrance."
    explanation: Variable expressivity and penetrance.
pathophysiology:
- name: SIN3A Haploinsufficiency
  description: >-
    Heterozygous truncating variants and whole-gene deletions reduce the dose
    of SIN3A. Truncating variants are distributed across the gene and no
    genotype-phenotype correlation or missense hotspot has been found, which
    supports haploinsufficiency as the principal mechanism.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SIN3A
    term:
      id: hgnc:19353
      label: SIN3A
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: transcription corepressor activity
    modifier: DECREASED
    term:
      id: GO:0003714
      label: transcription corepressor activity
  evidence:
  - reference: PMID:27399968
    reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability"
    explanation: Founding report establishing SIN3A haploinsufficiency as the disease mechanism.
  - 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: "As expected, majority of patients in published literature and this cohort appear to have truncating variants reinforcing haploinsufficiency as likely mechanism of pathogenicity"
    explanation: Predominance of truncating variants supports haploinsufficiency.
  downstream:
  - target: Reduced SIN3A-HDAC Corepressor Activity
    causal_link_type: DIRECT
    description: >-
      Halving SIN3A dose is expected to reduce the amount of assembled
      SIN3A-HDAC corepressor; this has not been measured directly in patient
      cells.
- name: SIN3A PAH1 Domain Partner-Binding Defect
  description: >-
    The few disease-associated missense variants include A126V and K155E in the
    PAH1 domain, the amphipathic-helix hub that binds transcription factors and
    SIN3A-associated proteins. Recombinant PAH1 carrying either variant binds
    SAP25 and TET1 less tightly (K155E more than 15-fold weaker for TET1), so
    these alleles impair specific partner recruitment rather than abolishing the
    protein.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SIN3A
    term:
      id: hgnc:19353
      label: SIN3A
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: transcription corepressor activity
    modifier: DECREASED
    term:
      id: GO:0003714
      label: transcription corepressor activity
  evidence:
  - reference: PMID:41759735
    reference_title: "Stability and interaction defects in the Sin3A-PAH1 αα-hub domain associated with loss-of-function variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The variants of Sin3A-PAH1 exhibit lower affinities for both SAP25 and Tet1, with a >15-fold reduction in the affinity of PAH1-K155E for Tet1."
    explanation: Biophysical measurement of reduced partner binding by two patient missense variants.
  - 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: COMPUTATIONAL
    snippet: "Both altered residues by c.377C>T, p.(Ala126Val) and c.463A>G, p.(Lys155Glu) were predicted to be part of the SAP25 SID-binding surface."
    explanation: Structural modelling placed both missense residues on the SAP25 binding surface.
  downstream:
  - target: Reduced SIN3A-HDAC Corepressor Activity
    causal_link_type: DIRECT
    description: >-
      Weaker binding of PAH1 partners is expected to reduce recruitment of the
      corepressor to its target genes; this has not been shown in patient cells.
    evidence:
    - reference: PMID:41759735
      reference_title: "Stability and interaction defects in the Sin3A-PAH1 αα-hub domain associated with loss-of-function variants."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our findings show how disease-associated Sin3A-PAH1 variants can affect global domain stability and flexibility as well as interactions with specific partner proteins"
      explanation: The variants act by impairing partner interactions of the scaffold.
- name: Reduced SIN3A-HDAC Corepressor Activity
  description: >-
    SIN3A is the scaffold of a corepressor complex containing HDAC1 and HDAC2
    that is recruited by sequence-specific repressors and by the methyl-CpG
    binding protein MeCP2, linking DNA methylation to histone deacetylation and
    transcriptional repression. Reduced SIN3A function is expected to weaken
    repression at its target genes. Mouse embryos lacking Sin3a entirely die
    around implantation, so the patient state is a partial loss of an
    essential regulator.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: transcription corepressor activity
    modifier: DECREASED
    term:
      id: GO:0003714
      label: transcription corepressor activity
  biological_processes:
  - preferred_term: negative regulation of transcription by RNA polymerase II
    modifier: DECREASED
    term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
  protein_complexes:
  - preferred_term: SIN3-HDAC corepressor complex
    term:
      id: GO:0070822
      label: Sin3-type complex
  evidence:
  - reference: PMID:9150135
    reference_title: "Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We have found that the mammalian transcriptional repressor Sin3 (mSin3) exists in a complex with histone deacetylases HDAC1 and HDAC2."
    explanation: Defines the SIN3-HDAC corepressor complex.
  - reference: PMID:9620804
    reference_title: "Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases."
    explanation: MeCP2 recruits the SIN3A-HDAC complex, the interaction named in the founding SIN3A disease report.
  - reference: PMID:30279502
    reference_title: "Sin3A recruits Tet1 to the PAH1 domain via a highly conserved Sin3-Interaction Domain."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "The Sin3A protein sits at the centre of the complex, mediating multiple simultaneous protein-protein interactions via its four paired-amphipathic helix (PAH) domains (PAH1-4)."
    explanation: SIN3A is the scaffold that docks partners through its PAH domains.
  - reference: PMID:32391601
    reference_title: "The neuronal transcription factor Myt1L interacts via a conserved motif with the PAH1 domain of Sin3 to recruit the Sin3L/Rpd3L histone deacetylase complex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that Myt1L, through a highly conserved segment shared with its paralogs, interacts directly and specifically with the Sin3 PAH1 domain, binding principally to the canonical hydrophobic cleft found in paired amphipathic helix domain (PAH) domains."
    explanation: >-
      A neuronal-identity transcription factor recruits the complex through
      PAH1, one plausible link between SIN3A dose and neuronal development;
      not tested in a SIN3A-deficient system.
  - reference: PMID:22206758
    reference_title: "Sin3a is essential for the genome integrity and viability of pluripotent cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "Previous studies have identified Sin3a as essential for embryonic development around the time of implantation"
    explanation: Complete loss of Sin3a is embryonic lethal in mice, so patients carry a partial loss of an essential gene.
  downstream:
  - target: Impaired Cortical Neurogenesis and Neuronal Identity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Shown by Sin3a knockdown in the developing mouse cortex; which SIN3A
      target genes mediate the effect is not known.
    evidence:
    - reference: PMID:27399968
      reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain"
      explanation: Reducing Sin3a in the embryonic mouse cortex impairs neurogenesis and neuronal identity.
  - target: Blood DNA Hypomethylation Episignature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The episignature is a genome-wide readout of SIN3A haploinsufficiency in
      blood; how reduced corepressor activity produces the methylation changes
      is not established.
  - target: Short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The genetic link is established; the mechanism of growth restriction is unknown.
  - target: Feeding difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The genetic link is established; the mechanism is unknown.
  - target: Hypogonadotropic hypogonadism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Attributed to SIN3A rather than to neighbouring 15q24 genes because
      intragenic SIN3A variants cause it; the effect on the GnRH axis is not
      characterised.
  - target: Broad forehead
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Craniofacial features follow from SIN3A loss by unknown developmental mechanisms.
  - target: Cleft palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Craniofacial features follow from SIN3A loss by unknown developmental mechanisms.
- name: Impaired Cortical Neurogenesis and Neuronal Identity
  description: >-
    In utero knockdown of Sin3a in the embryonic mouse cortex reduced the
    production of cortical neurons from progenitors and altered the identity
    of the neurons produced. This is the cellular step proposed to underlie the
    cognitive phenotype, and reduced neurogenesis is a plausible basis of the
    microcephaly, although that link has not been tested directly.
  biological_scale: CELLULAR
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  cell_types:
  - preferred_term: cortical neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  biological_processes:
  - preferred_term: cortical neurogenesis
    modifier: DECREASED
    term:
      id: GO:0022008
      label: neurogenesis
  - preferred_term: cerebral cortex neuron differentiation
    modifier: ABNORMAL
    term:
      id: GO:0021895
      label: cerebral cortex neuron differentiation
  evidence:
  - reference: PMID:27399968
    reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain"
    explanation: Mouse cortical knockdown phenotype.
  - reference: PMID:27399968
    reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "SIN3A can be considered to be a key transcriptional regulator of cortical brain development"
    explanation: Authors' conclusion on the role of SIN3A in cortical development.
  downstream:
  - target: Disrupted Cortical Integrity and Connectivity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27399968
      reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain"
      explanation: The same knockdown produced both the cellular defect and aberrant cortical projections.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred: reduced cortical neurogenesis is a plausible cause of small head
      size, but head size was not reported in the knockdown experiments.
- name: Disrupted Cortical Integrity and Connectivity
  description: >-
    Aberrant corticocortical projections in the knockdown mouse and subtle
    structural anomalies on patient MRI (ventriculomegaly, corpus callosum
    hypoplasia or dysplasia, delayed myelination) indicate abnormal cortical
    development and connectivity, which the authors propose underlies the
    cognitive and behavioural phenotype.
  biological_scale: TISSUE
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  biological_processes:
  - preferred_term: cerebral cortex development
    modifier: ABNORMAL
    term:
      id: GO:0021987
      label: cerebral cortex development
  - preferred_term: corticocortical axon guidance
    modifier: ABNORMAL
    term:
      id: GO:0007411
      label: axon guidance
  evidence:
  - reference: PMID:27399968
    reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly."
    explanation: Patient MRI shows subtle structural brain anomalies.
  downstream:
  - target: Mild intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: "Therefore, it is likely that the aberrant cortical development underlies impaired neurodevelopment and leads to cognitive and behavioural problems in patients"
      explanation: Authors attribute the cognitive phenotype to aberrant cortical development; stated as likely, not shown.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Delayed speech and language development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Motor delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Autism spectrum disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: "Therefore, it is likely that the aberrant cortical development underlies impaired neurodevelopment and leads to cognitive and behavioural problems in patients"
      explanation: Behavioural problems attributed to aberrant cortical development.
  - target: Attention deficit hyperactivity disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Psychiatric and behavioural problems
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ventriculomegaly
    causal_link_type: DIRECT
  - target: Hypoplasia of the corpus callosum
    causal_link_type: DIRECT
- name: Blood DNA Hypomethylation Episignature
  description: >-
    Peripheral blood DNA from individuals with SIN3A haploinsufficiency shows a
    predominantly hypomethylated genome-wide methylation profile that
    distinguishes them from controls and from other neurodevelopmental
    disorders with episignatures. It is a diagnostic readout rather than a
    cause of the clinical features.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: peripheral blood leukocyte
    term:
      id: CL:0000738
      label: leukocyte
  biological_processes:
  - preferred_term: epigenetic regulation of gene expression
    modifier: ABNORMAL
    term:
      id: GO:0040029
      label: epigenetic regulation of gene expression
  evidence:
  - reference: PMID:36399132
    reference_title: "DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case."
    explanation: Episignature identified in 20 individuals with SIN3A alterations.
  - reference: PMID:36399132
    reference_title: "DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants."
    explanation: The signature is present across the severity range.
phenotypes:
- category: Neurodevelopmental
  name: Global developmental delay
  description: Present in about half of patients in the largest cohort, usually mild.
  frequency: 15/28
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  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: "Of 28 patients, 15 (56%) had global developmental delay."
    explanation: Frequency of global developmental delay in the 28-patient cohort.
- category: Neurodevelopmental
  name: Mild intellectual disability
  description: >-
    Intellectual disability is usually mild, and a quarter of assessed patients
    aged 8 years or older had no cognitive impairment; moderate (4/16) and
    severe (1/16) disability also occur. Where measured, verbal IQ exceeded
    performance IQ, which can lead to overestimation of self-management
    capability.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  notes: >-
    The same paper reports mild ID in eight of 16 (50%) in its abstract and
    seven of 16 (44%) in its results text; frequency is given as a band for
    that reason.
  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: "Out of 16 patients ≥ 8 years old 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."
    explanation: Distribution of cognitive outcome in patients aged 8 years or older.
  - reference: PMID:27399968
    reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature"
    explanation: Mild ID in the founding cohort.
  - 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: "Interestingly, all patients in whom intelligence was tested reported a higher verbal than performal intelligence score."
    explanation: Disharmonic IQ profile.
- category: Neurodevelopmental
  name: Delayed speech and language development
  frequency: 16/21
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  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: "In 21 patients ≥5 years old, some form of motor developmental delay was reported in 13 patients (62%) and in 16 patients (76%) there was some form of language developmental delay."
    explanation: Language delay in 16 of 21 patients aged 5 years or older.
- category: Neurodevelopmental
  name: Motor delay
  frequency: 13/21
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  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: "In 21 patients ≥5 years old, some form of motor developmental delay was reported in 13 patients (62%) and in 16 patients (76%) there was some form of language developmental delay."
    explanation: Motor delay in 13 of 21 patients aged 5 years or older.
- category: Behavioral
  name: Autism spectrum disorder
  description: >-
    Autism was a prominent feature of the founding cohort; in the larger 2021
    cohort it was diagnosed in 3 of 23 patients aged 2 years or older, so it
    affects a minority.
  frequency: 3/23
  phenotype_term:
    preferred_term: Autism spectrum disorder
    term:
      id: HP:0000729
      label: Autistic behavior
  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: "In three of 23 patients ≥2 years (13%), ASD was diagnosed."
    explanation: ASD frequency in the 2021 cohort.
  - reference: PMID:27399968
    reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature"
    explanation: ASD in the founding cohort.
- category: Behavioral
  name: Attention deficit hyperactivity disorder
  frequency: 4/23
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  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: "ADHD was diagnosed in four patients ≥2 years (17%)."
    explanation: ADHD frequency in the 2021 cohort.
  - reference: PMID:32783353
    reference_title: "Behavior and cognitive functioning in Witteveen-Kolk syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "results indicate weaknesses in speed of information processing/sustained attention in all participants"
    explanation: Neuropsychological testing found attention and processing-speed weaknesses in all five assessed individuals.
- category: Behavioral
  name: Psychiatric and behavioural problems
  description: >-
    About a third of patients have a psychiatric or behavioural diagnosis
    (aggression, obsessive-compulsive behaviour, depression, anxiety,
    psychosis, schizoaffective disorder); in adolescence depression with
    self-harm, social difficulties, sensory hypersensitivity and sleep problems
    are described.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Psychiatric and behavioural problems
    term:
      id: HP:0000708
      label: Atypical behavior
  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: "Overall, a third of the cohort had a psychiatric or behavioural condition reported, including ADHD, aggressive behaviour, OCD, depression, psychosis, anxiety and schizoaffective disorder."
    explanation: Psychiatric and behavioural conditions in a third of the 2021 cohort.
  - reference: PMID:32783353
    reference_title: "Behavior and cognitive functioning in Witteveen-Kolk syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Systematic analysis of medical records displays developmental difficulties described as ASD or ADHD in childhood, sleep problems and internalizing problems during adolescence."
    explanation: Developmental course of behavioural problems in five individuals.
- category: Neurological
  name: Hypotonia
  frequency: 12/28
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  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: "Hypotonia was a common manifestation as well, present in 12/28 (43%) patients."
    explanation: Hypotonia frequency.
- category: Neurological
  name: Seizures
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  notes: >-
    The 2021 cohort gives 4/28 in its abstract and 6/28 (21%) in its results
    text; frequency is given as a band for that reason.
  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: "6/28 (21%) patients were noted to have seizures currently or in their past medical history."
    explanation: Seizure history in the 2021 cohort.
- category: Neurological
  name: Ventriculomegaly
  description: Among the few patients imaged, ventriculomegaly was among the commonest findings.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:27399968
    reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly."
    explanation: MRI finding in the founding cohort.
  - 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: "Most common was ventriculomegaly in 2/9, and a hypoplastic/dysplastic corpus callosum in 2/9."
    explanation: MRI findings in the nine imaged patients of the 2021 cohort.
- category: Neurological
  name: Hypoplasia of the corpus callosum
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  evidence:
  - reference: PMID:27399968
    reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly."
    explanation: MRI finding in the founding cohort.
  - 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: "Most common was ventriculomegaly in 2/9, and a hypoplastic/dysplastic corpus callosum in 2/9."
    explanation: Corpus callosum hypoplasia or dysplasia in two of nine imaged patients.
- category: Growth
  name: Microcephaly
  frequency: 13/28
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  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: "13/28 (46%) patients in our cohort had head circumference at least two standard deviations (SD) below the mean."
    explanation: Microcephaly frequency.
  - reference: PMID:27399968
    reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature"
    explanation: Microcephaly in the founding cohort.
- category: Growth
  name: Short stature
  description: >-
    Short stature was a defining feature of the founding cohort but height was
    below -2 SD in only 5 of 28 patients of the 2021 cohort; low weight was
    more frequent (8/28).
  frequency: 5/28
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  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: "Weight was less than two SD below the mean in 8/28 patients (29%) and height was less than two SD below the mean in 5/28 patients (18%)."
    explanation: Growth parameters in the 2021 cohort.
  - reference: PMID:27399968
    reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature"
    explanation: Short stature in the founding cohort.
- category: Gastrointestinal
  name: Feeding difficulties
  description: Feeding difficulties occur in about half, a few requiring nasogastric tube feeding in the neonatal period.
  frequency: 15/28
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  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: "15/28 (54%) of patients had feeding difficulties with at least two patients documented to require nasogastric tube feeding mainly in the neonatal period."
    explanation: Feeding difficulties frequency.
- category: Craniofacial
  name: Broad forehead
  description: >-
    Part of a facial gestalt (broad, tall forehead; small mouth; thin upper
    lip; pointed chin; downslanting palpebral fissures) seen in about half of
    patients and recognisable mainly by comparison with published photographs.
  phenotype_term:
    preferred_term: Broad forehead
    term:
      id: HP:0000337
      label: Broad forehead
  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: "Common facial features included a broad, tall forehead; small mouth, thin upper lip with pointed chin and down-slanting palpebral fissures (see Fig. 3)."
    explanation: Component of the reported facial gestalt.
  - 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: "Fourteen (50%) patients were reported to have craniofacial dysmorphism."
    explanation: Frequency of craniofacial dysmorphism overall in the cohort.
- category: Craniofacial
  name: High forehead
  phenotype_term:
    preferred_term: Tall forehead
    term:
      id: HP:0000348
      label: High forehead
  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: "Common facial features included a broad, tall forehead; small mouth, thin upper lip with pointed chin and down-slanting palpebral fissures (see Fig. 3)."
    explanation: Component of the reported facial gestalt.
- category: Craniofacial
  name: Downslanted palpebral fissures
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  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: "Common facial features included a broad, tall forehead; small mouth, thin upper lip with pointed chin and down-slanting palpebral fissures (see Fig. 3)."
    explanation: Component of the reported facial gestalt.
- category: Craniofacial
  name: Small mouth
  phenotype_term:
    preferred_term: Small mouth
    term:
      id: HP:0000160
      label: Narrow mouth
  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: "Common facial features included a broad, tall forehead; small mouth, thin upper lip with pointed chin and down-slanting palpebral fissures (see Fig. 3)."
    explanation: Component of the reported facial gestalt.
- category: Craniofacial
  name: Thin upper lip vermilion
  phenotype_term:
    preferred_term: Thin upper lip
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  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: "Common facial features included a broad, tall forehead; small mouth, thin upper lip with pointed chin and down-slanting palpebral fissures (see Fig. 3)."
    explanation: Component of the reported facial gestalt.
- category: Craniofacial
  name: Pointed chin
  phenotype_term:
    preferred_term: Pointed chin
    term:
      id: HP:0000307
      label: Pointed chin
  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: "Common facial features included a broad, tall forehead; small mouth, thin upper lip with pointed chin and down-slanting palpebral fissures (see Fig. 3)."
    explanation: Component of the reported facial gestalt.
- category: Craniofacial
  name: Cleft palate
  description: >-
    Palatal defects occurred in 3 of 28 patients (one with bifid uvula); cleft
    palate and cleft lip and palate are also described in case reports.
  frequency: 3/28
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  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: "Three patients had a palatal defect with one also having a bifid uvula."
    explanation: Palatal defects in the 2021 cohort.
  - reference: PMID:39828923
    reference_title: "Witteveen-Kolk Syndrome With Cleft Palate: A Case Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we present a case of WITKOS with a CP."
    explanation: Additional case of cleft palate.
- category: Sensory
  name: Hearing impairment
  description: Sensorineural, conductive and mixed hearing loss are all reported.
  frequency: 5/28
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  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: "Other reported features included hearing loss (5/28; 18%) of which 1 patient had sensorineural hearing loss, two patients had conductive hearing loss and two patients had mixed hearing loss."
    explanation: Hearing loss types and frequency.
- category: Musculoskeletal
  name: Joint hypermobility
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:32783353
    reference_title: "Behavior and cognitive functioning in Witteveen-Kolk syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Hypermobile joints and hearing loss have also been reported."
    explanation: Literature summary of reported features.
- category: Endocrine
  name: Hypogonadotropic hypogonadism
  description: >-
    Congenital hypogonadotropic hypogonadism, including Kallmann syndrome with
    anosmia or hyposmia, has been reported with both a SIN3A-spanning deletion
    and intragenic SIN3A variants, and can present as delayed puberty in an
    individual with otherwise mild features. Micropenis and cryptorchidism had
    been noted earlier in males.
  phenotype_term:
    preferred_term: Hypogonadotropic hypogonadism
    term:
      id: HP:0000044
      label: Hypogonadotropic hypogonadism
  evidence:
  - reference: PMID:36758531
    reference_title: "SIN3A Defects Associated with Syndromic Congenital Hypogonadotropic Hypogonadism: An Overlap with Witteveen-Kolk Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare SIN3A pathogenic variants were identified in these 2 unrelated patients with CHH phenotypic features."
    explanation: Two unrelated patients with congenital HH and SIN3A defects.
  - reference: PMID:38528912
    reference_title: "Case report: Novel SIN3A loss-of-function variant as causative for hypogonadotropic hypogonadism in Witteveen-Kolk syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, these findings point to SIN3A as the gene in 15q24 related to the reproductive phenotype in patients with overlapping WITKOS and Kallmann syndrome."
    explanation: An intragenic frameshift variant with Kallmann syndrome attributes the reproductive phenotype to SIN3A.
  - reference: PMID:41409308
    reference_title: "Two Unrelated Witteveen-Kolk Syndrome Patients Presenting with Unusual Clinical Features: Dual Diagnosis and Atypical Rare Manifestation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 2 was followed up with a preliminary diagnosis of hypogonadotropic hypogonadism (HH) and a new de novo pathogenic variation in the SIN3A gene."
    explanation: A further de novo SIN3A case presenting with HH.
- category: Genitourinary
  name: Cryptorchidism
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:36758531
    reference_title: "SIN3A Defects Associated with Syndromic Congenital Hypogonadotropic Hypogonadism: An Overlap with Witteveen-Kolk Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Although micropenis and cryptorchidism have been reported in this syndrome, WITKOS has not been formally associated with CHH so far."
    explanation: Cryptorchidism has been reported in WITKOS.
- category: Genitourinary
  name: Micropenis
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  evidence:
  - reference: PMID:36758531
    reference_title: "SIN3A Defects Associated with Syndromic Congenital Hypogonadotropic Hypogonadism: An Overlap with Witteveen-Kolk Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Although micropenis and cryptorchidism have been reported in this syndrome, WITKOS has not been formally associated with CHH so far."
    explanation: Micropenis has been reported in WITKOS.
- category: Cardiovascular
  name: Cardiac anomalies
  description: >-
    Cardiac abnormalities were found in four of ten patients in published
    reports that state a cardiac examination was done; the specific lesions
    are not given in the abstract.
  phenotype_term:
    preferred_term: Cardiac anomalies
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:38841330
    reference_title: "A Witteveen-Kolk Syndrome Patient with Reflux Disease and a de novo Deletion of the SIN3A Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "We have also summarized the clinical features of WITKOS patients in the medical literature and cardiac abnormalities detected in 4 out of 10 patients in studies that clearly state that cardiac examination was performed in the patients."
    explanation: Pooled literature frequency of cardiac abnormalities.
- category: Gastrointestinal
  name: Gastroesophageal reflux
  description: >-
    Reflux and oesophageal motility disorder were found in a child with a
    SIN3A deletion and feeding difficulty; the authors advise looking for them
    when feeding is difficult.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:38841330
    reference_title: "A Witteveen-Kolk Syndrome Patient with Reflux Disease and a de novo Deletion of the SIN3A Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Also, a barium esophagogram suggested severe motility disorder and gastroesophageal reflux disease."
    explanation: Single-patient finding; frequency unknown.
- category: Neurological
  name: Dystonia
  description: >-
    Generalized dystonia with progressive symmetric cerebellar ataxia has been
    reported once, in a 21-year-old woman with a SIN3A missense variant
    (p.Pro351Ser); whether movement disorders are part of the spectrum is not
    established.
  phenotype_term:
    preferred_term: Generalized dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:39576496
    reference_title: "Expanding the phenotyping spectrum of Witteveen Kolk syndrome: first report of generalized dystonia and cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, we present a 21-year-old woman with dysmorphic facial features, short stature, and a chronic, progressively worsening symmetric cerebellar ataxia, along with generalized dystonia."
    explanation: Single case report.
- category: Neurological
  name: Progressive cerebellar ataxia
  description: Reported in the same single case as the dystonia.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:39576496
    reference_title: "Expanding the phenotyping spectrum of Witteveen Kolk syndrome: first report of generalized dystonia and cerebellar ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, we present a 21-year-old woman with dysmorphic facial features, short stature, and a chronic, progressively worsening symmetric cerebellar ataxia, along with generalized dystonia."
    explanation: Single case report.
- category: Craniofacial
  name: Progeroid facial appearance
  description: >-
    A progeroid appearance, with sparse hair and reduced subcutaneous tissue
    in 3 of 28, was noted in a few patients, one of whom was first suspected
    of having progeria; the authors conclude it is part of the spectrum but
    not a predominant presentation.
  phenotype_term:
    preferred_term: Progeroid facial appearance
    term:
      id: HP:0005328
      label: Progeroid facial appearance
  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: "Sparse hair and reduced subcutaneous tissue was reported in 3/28 (10%) of patients in this study and note the progeric appearance in at least two of the patients in this cohort."
    explanation: Progeroid appearance in a minority of the cohort.
  - 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: "SIN3A-related disorder does not appear to present predominantly with a progeroid phenotype from the large cohort described here."
    explanation: Limits the claim to a minority feature.
genetic:
- name: SIN3A
  association: Causative (heterozygous loss of function)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: SIN3A
    term:
      id: hgnc:19353
      label: SIN3A
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_8c6bb2ed-0912-4d60-9faa-39be27ecf4c7-2022-01-19T070000.000Z
    evidence:
    - reference: CGGV:assertion_8c6bb2ed-0912-4d60-9faa-39be27ecf4c7-2022-01-19T070000.000Z
      reference_title: "SIN3A / SIN3A-related intellectual disability syndrome (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "SIN3A | HGNC:19353 | SIN3A-related intellectual disability syndrome | MONDO:0044699 | AD | Definitive"
      explanation: ClinGen Intellectual Disability and Autism GCEP classifies SIN3A for this disease as Definitive (AD).
  notes: >-
    Truncating intragenic variants predominate; PAH1-domain missense variants
    and whole-gene deletions also cause the disorder.
  evidence:
  - reference: PMID:27399968
    reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2)"
    explanation: Founding identification of dominant SIN3A mutations.
  - 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: Disease definition by heterozygous SIN3A loss of function.
diagnosis:
- name: Exome or genome sequencing
  description: >-
    The facial gestalt is recognisable mainly in retrospect, so most diagnoses
    are made by exome or genome sequencing or intellectual disability gene
    panels; chromosomal microarray detects SIN3A-spanning deletions.
  diagnosis_term:
    preferred_term: exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  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: "However, it is likely that diagnostic evaluation and identification of SIN3A variants in suspected individuals will be performed using large ID panels or WES/WGS."
    explanation: Authors' expectation of the diagnostic route.
- name: DNA methylation episignature analysis
  description: >-
    A SIN3A-specific blood episignature can classify variants of uncertain
    significance and resolve unexplained cases.
  diagnosis_term:
    preferred_term: genome-wide DNA methylation analysis
    term:
      id: NCIT:C63328
      label: DNA Methylation Analysis
  evidence:
  - reference: PMID:36399132
    reference_title: "DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This episignature has the potential to aid identification and diagnosis of individuals with WITKOS."
    explanation: Diagnostic utility of the episignature.
treatments:
- name: Multidisciplinary developmental and supportive care
  description: >-
    No disease-specific therapy exists. Management is supportive, with
    developmental, neurological and paediatric follow-up, and brain imaging
    offered when neurological symptoms are present rather than routinely.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  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: "Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients."
    explanation: Author recommendation from a case series, not a guideline.
- name: Neuropsychologically informed psychological treatment
  description: >-
    A single case report describes twelve sessions of psychological treatment
    tailored to the patient's neurocognitive profile (aimed at reducing
    cognitive overload, anxiety and fatigue), with improved functioning at
    three months but poor maintenance of emotion-regulation gains.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: psychotherapy
    term:
      id: NCIT:C15308
      label: Psychotherapy
  target_mechanisms:
  - target: Psychiatric and behavioural problems
  evidence:
  - reference: PMID:41245232
    reference_title: "Personalized Treatment in Rare Genetic Syndromes: A Case-Report in Witteveen-Kolk Syndrome (SIN3A)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Evaluation during treatment and at 3-month follow-up showed a positive increase in functioning and acceptance as well as the acceptance of successive follow-up treatment."
    explanation: Single-patient outcome of tailored psychological treatment.
- name: Sex hormone replacement for hypogonadotropic hypogonadism
  description: >-
    Hypogonadotropic hypogonadism is treated with standard hormone replacement
    to induce puberty, as in other forms of the condition.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: hormone replacement therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
  target_mechanisms:
  - target: Hypogonadotropic hypogonadism
  evidence:
  - reference: PMID:38528912
    reference_title: "Case report: Novel SIN3A loss-of-function variant as causative for hypogonadotropic hypogonadism in Witteveen-Kolk syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hormone replacement treatment was started gradually with normal evolution."
    explanation: Hormone replacement in a female patient with SIN3A-related Kallmann syndrome.
animal_models:
- name: Sin3a in utero knockdown in embryonic mouse cortex
  species: Mouse
  genotype: Sin3a knockdown in developing cortex (in vivo functional knockdown)
  publication: PMID:27399968
  modeled_mechanisms:
  - target: Impaired Cortical Neurogenesis and Neuronal Identity
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Focal knockdown of Sin3a in the developing cortex reduces neurogenesis and alters neuronal identity.
    limitations: >-
      Knockdown is focal and of uncertain depth rather than a constitutional
      heterozygous loss, and it reports cortical development only, not
      behaviour or the non-neural features.
    evidence:
    - reference: PMID:27399968
      reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain"
      explanation: Knockdown reproduces the cellular cortical defect.
  - target: Disrupted Cortical Integrity and Connectivity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Knockdown produces aberrant corticocortical projections.
    limitations: >-
      Patient MRI shows corpus callosum and ventricular changes; whether the
      projection defect in mice corresponds to these findings is not shown.
    evidence:
    - reference: PMID:27399968
      reference_title: "Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain"
      explanation: Knockdown produces aberrant cortical projections.
📚

References & Deep Research

Deep Research

1

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.

Evaluations and curation notes (1)

Create: SIN3A-Related_Intellectual_Disability_Syndrome · 2026-11-05T00:33:22Z · View source

New entry for MONDO:0044699 (Witteveen-Kolk syndrome, SIN3A haploinsufficiency). Two subtypes: point mutation (MONDO:0044700) and SIN3A-spanning 15q24 deletion (no MONDO term). The boundary with the existing Chromosome_15q24_Deletion_Syndrome entry follows that entry, which already treats Witteveen-Kolk syndrome as distinct; that file was not edited. MONDO places the Witteveen-Kolk syndrome and WITKOS strings and the OMIM:613406 xref on MONDO:0013256, not on MONDO:0044699; the synonyms are kept here because the cited cohort papers use them for SIN3A haploinsufficiency, and the mapping difference is recorded in the entry notes. Pathophysiology chain: SIN3A haploinsufficiency and the PAH1 missense partner-binding defect converge on reduced SIN3A-HDAC corepressor activity, which leads to impaired cortical neurogenesis (mouse knockdown), disrupted cortical integrity and the neurodevelopmental phenotypes; a blood hypomethylation episignature is a terminal readout. Phenotype frequencies are from the 28-patient cohort (PMID:33437032); where its abstract and results text disagree (mild ID, seizures) a frequency band is used. ClinGen Definitive AD tier recorded from the CGGV record. No GeneReviews chapter exists (just check-genereviews --online: NO_CHAPTER). Sources: literature search via PubMed E-utilities plus one OpenScientist deep-research report (research/SIN3A-Related_Intellectual_Disability_Syndrome-deep-research-openscientist.md): 21/21 references resolved, one paraphrased quote (PMID:39576496) not reused, no unresolved terms; just preflight-dr PASS. Taken from the report: Myt1L and TET1 PAH1 partner evidence, gastroesophageal reflux, dystonia and progressive cerebellar ataxia (single case). Not used: two general chromatinopathy episignature papers (PMID:41952182, PMID:41957673) that do not report SIN3A data; the SIN3A-specific episignature paper (PMID:36399132) is cited instead. Validation: just validate, validate-terms, count-verified-snippets (82/82) and the offline gates in CLAUDE.md passed; validate-disorders run before push.

OpenScientist ▸
Key Findings
openscientist-autonomous 21 citations 2026-11-05T00:29:00.558754

Key Findings

Finding 1 — SIN3A haploinsufficiency causes Witteveen-Kolk syndrome

Witteveen et al. (2016) established the disease by identifying dominant heterozygous loss-of-function mutations in SIN3A (chromosome 15q24.2) in individuals with mild ID and ASD who shared a recognizable constellation of facial dysmorphism, microcephaly, and short stature. Critically, this phenotype is "highly related to that of individuals with atypical 15q24 microdeletions," establishing SIN3A as the critical gene in the 15q24 microdeletion region (OMIM 613406).

"we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature" — PMID: 27399968

"This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome" — PMID: 27399968

This dual origin — single-gene point mutations and whole-gene deletions producing the same disorder — is the clearest genetic signature of a haploinsufficiency mechanism.

Finding 2 — Core clinical phenotype: mild ID, distinctive facies, growth/feeding difficulties

Balasubramanian et al. (2021) comprehensively characterized 28 patients (17 male / 11 female; mean age 8.2 years). Among the 16 patients aged ≥8 years, cognitive severity broke down as 50% mild ID, 22% moderate ID, 6% severe ID, and 25% with no cognitive impairment — underscoring both the overall mildness and the marked variability of the syndrome. Other neurological features were common: hypotonia in 12/28 (43%) and seizures in 4/28 (14%); ASD and ADHD were each present in a minority of patients. The molecular spectrum comprised 24 truncating variants, 3 missense variants, and one large in-frame gain (exons 10–12); 27 of 28 were novel, indicating that nearly all variants are private.

"Out of 16 patients ≥ 8 years old 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." — PMID: 33437032

"Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common." — PMID: 33437032

Finding 3 — Mechanism: SIN3A is a corepressor scaffold regulating cortical neurogenesis

SIN3A is the eponymous scaffold of the SIN3-HDAC corepressor complex (with HDAC1/2, RBBP4/7, SAP30, SDS3), which deacetylates histones to repress transcription (PMID: 33130996). SIN3 is an essential gene in metazoans; its loss impairs cell proliferation, and in Drosophila it downregulates the cell-cycle gene String/CDC25 (PMID: 19825413). Most directly relevant to the human disease, in vivo knockdown of Sin3a in the developing mouse brain reduced cortical neurogenesis, altered neuronal identity, and produced aberrant corticocortical projections (PMID: 27399968).

"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

"The transcriptional corepressor SIN3 is an essential gene in metazoans. In cell culture experiments, loss of SIN3 leads to defects in cell proliferation." — PMID: 19825413

Suggested ontology terms: GO:0006355 (regulation of DNA-templated transcription), GO:0016575 (histone deacetylation), GO:0021895 (cerebral cortex neuron differentiation), GO:0021987 (cerebral cortex development); CL:0000540 (neuron), CL:0000047 (neural progenitor cell), CL:0000679 (glutamatergic neuron).

Finding 4 — Sin3a is essential for genome integrity and viability; constitutive knockout is embryonic lethal

McDonel et al. (2012) showed that Sin3a-null mouse embryos die peri-implantation: they suffer unresolved DNA damage and acute p53-independent apoptosis specifically in the E3.5–4.5 epiblast. Sin3a-deleted ES cells mount a DNA damage response with double-strand breaks, arrest at G2, and undergo apoptosis; Myc and E2F targets are downregulated in Sin3a-null inner cell masses. This confirms that SIN3A is an essential, dosage-sensitive gene — the biological basis for why only heterozygous loss (haploinsufficiency), not biallelic loss, is compatible with human life.

"embryos lacking Sin3a suffer unresolved DNA damage and acute p53-independent apoptosis specifically in the E3.5-4.5 epiblast" — PMID: 22206758

"The Sin3a/HDAC co-repressor complex is a critical regulator of transcription networks that govern cell cycle control and apoptosis throughout development." — PMID: 22206758

Finding 5 — Expanding phenotype: hypogonadotropic hypogonadism / pubertal delay

Correa Brito et al. (2024) reported a novel SIN3A loss-of-function variant causative for hypogonadotropic hypogonadism (HH) in a WITKOS patient, extending the phenotype into the neuroendocrine/reproductive axis. HH overlaps with WITKOS (OMIM 613406) and with 15q24 microdeletions, paralleling Kallmann-type presentations (pubertal delay with or without anosmia/hyposmia).

"hypogonadotropic hypogonadism has been suggested to overlap with Witteveen-Kolk syndrome (WITKOS, OMIM #613406) associated with 15q24 microdeletions" — PMID: 38528912

Suggested HPO terms: HP:0000044 (hypogonadotropic hypogonadism), HP:0000823 (delayed puberty).

Finding 6 — Molecular architecture: four PAH domains serve as a transcription-factor docking hub

SIN3A sits at the center of the ~2 MDa Sin3L/Rpd3L HDAC complex, mediating simultaneous protein–protein interactions via four paired-amphipathic-helix (PAH1–4) domains, each a four-helix bundle with a hydrophobic cleft binding a single-helix Sin3-interaction domain (SID) with high affinity (PMID: 30279502, PMID: 21676866). PAH1 recruits the neuronal transcription factor Myt1L (neuronal differentiation/identity maintenance; PMID: 32391601) and the DNA demethylase TET1 (PMID: 30279502); PAH2 binds Mad1/Mxd1 and HBP1; PAH3 binds SAP30 (PMID: 21676866). SIN3A thereby couples sequence-specific DNA-binding factors to HDAC1/2 enzymatic activity.

"The Sin3A protein sits at the centre of the complex, mediating multiple simultaneous protein-protein interactions via its four paired-amphipathic helix (PAH) domains (PAH1-4)." — PMID: 30279502

"Myt1L, through a highly conserved segment shared with its paralogs, interacts directly and specifically with the Sin3 PAH1 domain" — PMID: 32391601

The recruitment of a neuronal identity transcription factor (Myt1L) specifically by PAH1 provides a mechanistic bridge between SIN3A dosage and neurodevelopmental consequences.

Finding 7 — Epidemiology: ultra-rare, autosomal dominant, mostly de novo loss-of-function

Tang et al. (2025) state WITKOS incidence is extremely low — only a few cases per million population reported globally, with most presenting in childhood/adolescence. The disorder is autosomal dominant, caused by heterozygous loss-of-function SIN3A variants or 15q24.1–q24.2 microdeletions encompassing SIN3A. Fewer than ~100 patients have been reported in the literature (Witteveen 2016; Balasubramanian 2021 28-patient cohort). No formal Orphanet prevalence estimate exists.

"Its incidence rate is extremely low. According to the current limited global data statistics, only a few cases occur per million population." — PMID: 40336075

"WITKOS is a rare neurodevelopmental disorder caused by heterozygous loss-of-function variants in the 15q24.1 - q24.2 region, includeing switch-insensitive 3 transcription regulator family member A (SIN3 A)." — PMID: 40336075

Finding 8 — WITKOS is a multisystem disorder beyond core neurodevelopmental features

Case reports have broadened the spectrum well beyond ID/facies/microcephaly/short stature: - Cardiac defects with gastroesophageal reflux and esophageal motility disorder (Uctepe et al. 2024, PMID: 38841330); - Cleft palate (Boynuyogun et al., PMID: 39828923); - Progressive generalized dystonia and cerebellar ataxia (Mustafa et al. 2025, PMID: 39576496; variant c.1051C>T p.Pro351Ser); - A familial form with ectodermal dysplasia, progeroid appearance, and early-onset diabetes mellitus (Chan et al. 2025, PMID: 40586236).

"Our findings showed that cardiac defects are not uncommon findings in WITKOS. Physicians should also be aware of reflux disease and motility disorder in patients with feeding difficulty" — PMID: 38841330

"a chronic, progressively worsening symmetric cerebellar ataxia, along with generalized dystonia. Notably, dystonia has not been previously associated with this syndrome." — PMID: 39576496

Finding 9 — Management is supportive/multidisciplinary; first personalized behavioral treatment reported

There is no disease-modifying or gene-targeted therapy for WITKOS; management is supportive and multidisciplinary (geneticist, pediatrician, neurologist), addressing developmental delay, feeding/growth, seizures, cardiac and GI issues, and behavior (Balasubramanian 2021). Janssen et al. (2026) reported the first documented treatment of behavioral problems in WITKOS — a personalized 12-session psychological intervention in a 27-year-old woman that reduced anxiety, fatigue, and cognitive overload with positive short-term functional gains but limited maintenance at 3-month follow-up.

"we present a case study of the first documented treatment of behavioral problems in WITKOS" — PMID: 41245232

"Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients." — PMID: 33437032

Finding 10 — Missense variants destabilize the SIN3A PAH1 αα-hub, confirming loss-of-function

Due et al. (2026) performed structural/thermodynamic studies of the Sin3A PAH1 αα-hub domain and two WITKOS patient missense variants (A126V and K155E), demonstrating stability and interaction defects. This provides molecular-level confirmation that pathogenic SIN3A missense variants act by destabilizing PAH domains and disrupting recruitment of interacting transcription factors — a loss-of-function mechanism consistent with haploinsufficiency.

"we relate 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

Finding 11 — The SIN3/HDAC corepressor is conserved from yeast to humans; multiple model organisms exist

The SIN3-RPD3 histone deacetylase corepressor is conserved from Saccharomyces cerevisiae (Sin3/Rpd3/Ume6; PMID: 25957495) through Drosophila (SIN3 essential for proliferation and wing development via String/CDC25; PMID: 19825413) to mouse (Sin3a essential, embryonic-lethal knockout; PMID: 22206758) and human SIN3A.

"Ume6 interacts with the upstream repressor site 1 (URS1) and represses transcription by recruiting both the conserved histone deacetylase Rpd3 (through the co-repressor Sin3) and the chromatin-remodeling factor Isw2." — PMID: 25957495

Orthologs: S. cerevisiae SIN3 (NCBI Gene YOL004W); Drosophila Sin3A; Mus musculus Sin3a (NCBI Gene 20466); Homo sapiens SIN3A (NCBI Gene 25942; HGNC:19353). No naturally occurring companion-animal disease is catalogued in OMIA for SIN3A.

Finding 12 — Diagnosis relies on molecular genetics; SIN3A is LOF-constrained with an emerging chromatinopathy episignature

WITKOS has no pathognomonic biochemical biomarker; diagnosis requires detecting a heterozygous pathogenic SIN3A variant (trio WES/WGS — most variants are private/novel, 27/28 novel in Balasubramanian 2021) or a 15q24.1–q24.2 microdeletion by chromosomal microarray (e.g., a de novo 1.6 Mb deletion, PMID: 38841330). SIN3A is strongly constrained against loss of function in gnomAD. As a chromatin/HDAC-complex ("chromatinopathy") gene, SIN3A is a candidate for DNA-methylation episignature-based variant classification increasingly used for these disorders (PMID: 41957673, PMID: 41952182).

"We report 27 novel variants and one previously reported variant." — PMID: 33437032

"Affymetrix CytoScan 750K microarray showed a de novo 1.6-Mb deletion at 15q24.1q24.2" — PMID: 38841330

Full Section-by-Section Report

1. Disease Information

WITKOS is a rare autosomal dominant neurodevelopmental disorder caused by haploinsufficiency of SIN3A. Core features are mild intellectual disability, developmental delay, distinctive craniofacial dysmorphism, microcephaly, and short stature, with variable multisystem involvement.

Key identifiers: MONDO:0044699 · OMIM 613406 · Gene: SIN3A (HGNC:19353; NCBI Gene 25942; Ensembl ENSG00000169375; UniProt Q96ST3) · Chromosome 15q24.2. Orphanet lists the SIN3A-related intellectual disability/Witteveen-Kolk entity but without a formal prevalence estimate. No specific ICD-10/ICD-11 code is dedicated to WITKOS; it maps to generic categories for intellectual disability/congenital malformation syndromes.

Synonyms: Witteveen-Kolk syndrome, WITKOS, SIN3A-related intellectual disability syndrome, SIN3A haploinsufficiency.

Information source: The knowledge base is derived primarily from aggregated disease-level resources (OMIM, published case series, and cohort studies) rather than individual EHR records. The largest evidence source is a 28-patient international cohort (PMID: 33437032) plus the defining discovery paper (PMID: 27399968) and numerous single-case reports.

2. Etiology

Primary cause: Genetic — heterozygous loss-of-function of SIN3A, by (a) intragenic point/indel variants (nonsense, frameshift, splice-site, and destabilizing missense) or (b) 15q24.1–q24.2 microdeletions encompassing SIN3A. There is no infectious, environmental, or metabolic cause.

Genetic risk factors: The only established causal factor is the SIN3A variant itself. Most cases are de novo; there is no known susceptibility locus or polygenic contribution. Modifier genes are not defined, though a contiguous-gene deletion (removing neighboring 15q24 genes) may modify expressivity.

Environmental risk / protective factors: None identified. There are no documented dietary, lifestyle, occupational, or toxic exposures that cause, raise, or lower the risk; because the disorder is Mendelian and usually de novo, environmental contributions are not expected. Gene-environment interactions: None documented.

3. Phenotypes

Phenotype Type Frequency HPO term
Intellectual disability (mild predominant) Cognitive/behavioral ~75% impaired (50% mild, 22% mod, 6% severe); 25% unaffected HP:0001249 / HP:0001256
Global developmental delay Cognitive Common HP:0001263
Autism spectrum disorder Behavioral Minority HP:0000729
ADHD Behavioral Minority HP:0007018
Muscular hypotonia Clinical sign 12/28 (43%) HP:0001252
Seizures Clinical sign 4/28 (14%) HP:0001250
Microcephaly Physical Characteristic HP:0000252
Short stature Physical Characteristic HP:0004322
Facial dysmorphism Physical Characteristic/recognizable HP:0001999
Feeding difficulties / growth failure Clinical Common HP:0011968
Hypogonadotropic hypogonadism / delayed puberty Endocrine Reported HP:0000044 / HP:0000823
Congenital heart defects Clinical "Not uncommon" HP:0001627
GERD / esophageal motility disorder Clinical Reported HP:0002020
Cleft palate Physical Rare HP:0000175
Dystonia / cerebellar ataxia Neurological Rare (expanding) HP:0001332 / HP:0001251
Ectodermal dysplasia / progeroid / early diabetes Multisystem Single family HP:0000968 / HP:0000006

Characteristics: Onset is congenital/neonatal to early childhood (developmental features). Severity is predominantly mild but variable (mild→severe ID; 25% cognitively normal). Most features are stable rather than progressive, though a reported movement disorder was progressive. Quality-of-life impact is driven by cognitive/behavioral impairment, feeding/growth issues, and comorbidities requiring lifelong support; one documented behavioral intervention produced short-term gains (PMID: 41245232).

4. Genetic / Molecular Information

Causal gene: SIN3A (OMIM 607776; HGNC:19353; NCBI Gene 25942). Disease OMIM:* 613406.

Pathogenic variants: Predominantly truncating (nonsense, frameshift, splice-site) consistent with loss of function; a minority are missense that destabilize PAH domains, plus whole-gene 15q24 deletions. In the 28-patient cohort: 24 truncating, 3 missense, 1 large in-frame gain; 27/28 novel/private (PMID: 33437032). Specific examples: c.1051C>T (p.Pro351Ser) with dystonia/ataxia (PMID: 39576496); p.A126V and p.K155E destabilizing PAH1 (PMID: 41759735).

Classification & allele frequency: Variants are classified pathogenic/likely pathogenic per ACMG; they are private and absent from population databases. SIN3A is strongly LOF-constrained in gnomAD (high pLI), supporting haploinsufficiency intolerance. Origin: germline, usually de novo. Functional consequence: loss of function / haploinsufficiency; missense variants act via protein destabilization (also loss of function). No gain-of-function or dominant-negative mechanism is established.

Modifier genes: Not formally defined; deletion size in 15q24 CNVs may modulate severity. Epigenetic information: As a chromatinopathy gene, SIN3A disruption is expected to alter genome-wide histone acetylation/DNA methylation; a specific DNA-methylation episignature is an active area of development (PMID: 41957673). Chromosomal abnormalities: 15q24.1–q24.2 microdeletions (e.g., de novo 1.6 Mb; PMID: 38841330); the region's segmental-duplication architecture mediates recurrent rearrangements (PMID: 22180641, PMID: 19557438).

5. Environmental Information

No environmental, lifestyle, or infectious factors contribute to WITKOS. It is a monogenic disorder; not applicable across toxins, radiation, occupational exposure, diet, smoking/alcohol, and pathogens.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. A heterozygous loss-of-function lesion in SIN3A (truncating variant, destabilizing missense, or 15q24 microdeletion) reduces functional SIN3A protein to ~50% (haploinsufficiency). Demonstrated genetically.
  2. Reduced SIN3A results in a deficit of the scaffold at the center of the ~2 MDa SIN3-HDAC corepressor complex, because SIN3A docks transcription factors and HDAC1/2 via its four PAH domains. Demonstrated biochemically/structurally (PMID 30279502, 21676866).
  3. For missense variants, the lesion specifically destabilizes the PAH1 αα-hub, which leads to impaired binding of SID-containing partners (e.g., Myt1L, TET1). Demonstrated thermodynamically (PMID 41759735).
  4. Loss of scaffold results in failure to recruit HDAC1/2 to target promoters, leading to inappropriate histone hyperacetylation and derepression/dysregulation of SIN3-controlled gene networks (cell-cycle, Myc/E2F targets). Inferred from complex biology + Sin3a-null ICM data (PMID 22206758).
  5. In neural progenitors, dysregulation impairs the balance of proliferation vs differentiation, which in the developing cortex results in reduced cortical neurogenesis, altered neuronal identity, and aberrant corticocortical projections. Demonstrated in mouse knockdown (PMID 27399968).
  6. Branch A (brain): altered cortical wiring leads to intellectual disability, ASD, microcephaly, seizures, hypotonia.
  7. Branch B (growth/endocrine): dysregulated developmental programs lead to short stature and, via hypothalamic-pituitary effects, hypogonadotropic hypogonadism (PMID 38528912). Inferred.
  8. Branch C (other systems): disrupted transcriptional programs in cardiac, craniofacial, GI, and ectodermal tissues contribute to heart defects, cleft palate, reflux/motility disorder, and ectodermal/progeroid features (PMID 38841330, 39828923, 40586236). Inferred from case reports.

Molecular pathways: Chromatin-mediated transcriptional repression (SIN3-HDAC/Rpd3L); downstream Myc and E2F target networks; Myt1L/TET1-dependent neuronal gene regulation. Cellular processes: cell-cycle control, neural progenitor proliferation/differentiation, apoptosis, DNA-damage response (GO:0006974). Protein dysfunction: loss of scaffold function via truncation or PAH-domain destabilization. Metabolic/immune/biochemical: no specific enzyme deficiency, immune involvement, or metabolic defect is characteristic. Epigenetic: global histone-acetylation/DNA-methylation dysregulation (chromatinopathy).

Suggested ontology terms: GO:0016575 (histone deacetylation), GO:0000122 (negative regulation of transcription by RNA Pol II), GO:0021987 (cerebral cortex development), GO:0007399 (nervous system development); CL:0000540 (neuron), CL:0000047 (neural progenitor cell); GO:0005634 (nucleus).

7. Anatomical Structures Affected

  • Primary organ/system: Central nervous system — cerebral cortex (UBERON:0000956), brain (UBERON:0000955); nervous system (UBERON:0001016). Neurodevelopmental impact is the defining feature.
  • Secondary involvement: Craniofacial skeleton (dysmorphism, cleft palate — UBERON:0001716 secondary palate); heart (UBERON:0000948); gastrointestinal/esophagus (UBERON:0001043); endocrine axis (hypothalamic-pituitary-gonadal; UBERON:0000007 pituitary); skin/ectodermal derivatives (UBERON:0000014) in the familial progeroid form; musculoskeletal (short stature, hypotonia).
  • Tissue/cell level: Nervous tissue; cortical neurons and neural progenitors (CL:0000540, CL:0000047). Subcellular: nucleus (GO:0005634) — SIN3A is a nuclear corepressor.
  • Lateralization: Bilateral/symmetric (microcephaly, cortical involvement, symmetric movement features).

8. Temporal Development

  • Onset: Congenital/neonatal to early childhood; most present in childhood or adolescence (PMID 40336075). Pattern is chronic/developmental rather than acute.
  • Progression: Generally stable, non-progressive developmental disorder; cognitive and physical features are lifelong. Exceptions include a progressive movement disorder (dystonia/ataxia) in one report (PMID: 39576496).
  • Duration: Chronic/lifelong. Remission: None (not a remitting condition). Critical periods: Cortical neurogenesis in fetal development is the mechanistically critical window; there is no established postnatal intervention window.

9. Inheritance and Population

  • Epidemiology: Ultra-rare — a few cases per million population; <~100 reported patients; no formal Orphanet prevalence/incidence estimate (PMID: 40336075).
  • Inheritance: Autosomal dominant; mostly de novo heterozygous LOF (or 15q24 CNV). Penetrance: Appears high but expressivity is highly variable (25% of cohort members ≥8 y had no cognitive impairment). Expressivity: Variable, including within families. Anticipation: Not applicable (not a repeat-expansion disorder). Germline mosaicism: Possible in principle (not specifically documented). Founder effects/consanguinity: None (variants are private, de novo). Carrier frequency: Not applicable to a dominant de novo disorder.
  • Demographics: No ethnic predilection, geographic clustering, or strong sex bias established (cohort 17M/11F). Age distribution skews pediatric due to recent recognition.

10. Diagnostics

  • No biochemical biomarker exists; diagnosis is molecular.
  • Genetic testing (primary): Trio whole-exome (WES) or whole-genome sequencing (WGS) detects intragenic SIN3A variants (most are private/novel). Chromosomal microarray (CMA) detects 15q24.1–q24.2 microdeletions. Gene panels for ID/ASD that include SIN3A are also used. Single-gene testing is low-yield given phenotype nonspecificity; karyotype is insufficient for microdeletions. Mitochondrial and repeat-expansion testing are not indicated.
  • Emerging: DNA-methylation episignature classification (EpiSign) for chromatinopathies may aid reclassification of SIN3A VUS (PMID: 41957673, PMID: 41952182).
  • Imaging: Brain MRI may show nonspecific findings; used to evaluate microcephaly/seizures. Clinical criteria: No formal diagnostic criteria; diagnosis rests on a compatible phenotype plus a pathogenic SIN3A variant/deletion. Differential diagnosis: 15q24 microdeletion syndrome (same spectrum), other chromatinopathies/ID syndromes (ANKRD11/KBG, SETD5, KMT2A, CHD3/CHD8, ADNP), and other causes of mild syndromic ID with microcephaly and short stature. Screening: Not amenable to population/newborn screening; cascade testing is generally unnecessary given de novo origin, but parental testing informs recurrence risk.

11. Outcome / Prognosis

  • Survival/mortality: No evidence of reduced life expectancy or disease-specific mortality; WITKOS is not life-limiting in itself. The disorder is compatible with adult life (behavioral treatment reported in a 27-year-old; PMID: 41245232).
  • Morbidity/function: Driven by (usually mild) intellectual disability, behavioral issues, feeding/growth difficulties, and variable multisystem complications. Functional outcomes range widely given variable expressivity.
  • Complications: Seizures, cardiac defects, GERD/motility disorder, cleft palate, movement disorder, endocrine (hypogonadism, early diabetes in one family). Recovery potential: Developmental features are stable; supportive therapy improves function.
  • Prognostic factors: Severity of ID and presence of multisystem complications; no validated molecular prognostic biomarker, though deletion vs point-variant and variant location/type may influence phenotype.

12. Treatment

  • No disease-modifying or gene-targeted therapy exists. Management is supportive and multidisciplinary (NCIT: Supportive Care; Multidisciplinary Care) — geneticist, pediatrician, neurologist (PMID: 33437032).
  • Symptom-directed: Antiseizure medication for epilepsy; nutritional support/anti-reflux management for feeding difficulties and GERD; cardiology management and surgical repair for cardiac defects; surgical cleft palate repair after neurodevelopmental maturation (PMID: 39828923); endocrine therapy for hypogonadism; movement-disorder management for dystonia/ataxia.
  • Rehabilitative/behavioral: Physical, occupational, and speech therapy; special education; a first personalized 12-session psychological intervention reduced anxiety/fatigue/cognitive overload with short-term gains (PMID: 41245232).
  • Pharmacogenomics, gene/cell/RNA therapy, targeted/immunotherapy, experimental trials: None specific to WITKOS at this time. No NCT-registered disease-specific trials identified.

13. Prevention

  • Primary prevention: Not applicable (de novo genetic origin). Secondary prevention: Early developmental assessment and intervention improve functional outcomes; screening for known complications (cardiac, GI/reflux, cleft palate, endocrine) is recommended once diagnosed (PMID 38841330, 39828923).
  • Genetic counseling: Essential — recurrence risk for parents of a de novo case is low (germline mosaicism caveat); an affected individual has a 50% transmission risk. Prenatal/preimplantation genetic testing is feasible for a known familial variant. Public health/immunization/environmental: Not applicable.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: SIN3A/Sin3 is deeply conserved. Homo sapiens SIN3A (NCBI Gene 25942); Mus musculus Sin3a (NCBI Gene 20466); Drosophila melanogaster Sin3A; Saccharomyces cerevisiae SIN3 (YOL004W). Function conserved from yeast through metazoans (PMID: 25957495, PMID: 19825413, PMID: 22206758).
  • Natural disease: No naturally occurring companion-animal or wildlife SIN3A disease is catalogued in OMIA. Comparative biology: The corepressor mechanism and its essentiality are evolutionarily conserved, supporting cross-species mechanistic inference. Zoonotic potential: Not applicable.

15. Model Organisms

Model Type Key finding Reference
Mouse (Sin3a knockout) Mammalian, constitutive KO Embryonic lethal (peri-implantation); DNA damage + p53-independent apoptosis in epiblast PMID: 22206758
Mouse (in vivo Sin3a knockdown, developing brain) Mammalian, focal knockdown Reduced cortical neurogenesis, altered neuronal identity, aberrant corticocortical projections — recapitulates core human neurodevelopmental mechanism PMID: 27399968
Drosophila SIN3 Invertebrate Essential gene; regulates proliferation/wing development via String/CDC25 PMID: 19825413
S. cerevisiae Sin3/Rpd3/Ume6 Yeast Conserved corepressor mechanism; transcriptional repression PMID: 25957495

Phenotype recapitulation: The mouse brain knockdown is the most disease-relevant model, directly reproducing the neurogenesis defect proposed to underlie human ID. Limitations: Constitutive KO is embryonic lethal, so the human haploinsufficiency state requires heterozygous/conditional models; no published heterozygous mouse phenotype fully modeling WITKOS is in the knowledge base. Invertebrate/yeast models illuminate conserved molecular function but not the syndromic phenotype. Resources: MGI (Sin3a), FlyBase (Sin3A), SGD (SIN3).

Mechanistic Model / Interpretation

 SIN3A heterozygous LOF            (truncating / destabilizing missense / 15q24 deletion)
│  reduces functional SIN3A protein to ~50% (haploinsufficiency)
▼
 Deficient SIN3-HDAC corepressor scaffold
   (4 PAH domains can no longer dock TFs + HDAC1/2 at full capacity)
   • missense A126V/K155E → PAH1 αα-hub destabilized → lost Myt1L/TET1 binding (PMID 41759735, 32391601, 30279502)
│  leads to
▼
 Failure to recruit HDAC1/2 → histone hyperacetylation → derepression/dysregulation
   of SIN3-controlled gene networks (Myc, E2F, cell-cycle)  (PMID 22206758)
│  results in
▼
 Imbalanced neural progenitor proliferation vs differentiation
│  in developing cortex → reduced neurogenesis, altered identity,
│  aberrant corticocortical projections (PMID 27399968)
▼
 ┌────────────── BRANCH A (brain) ──────────────┐  ┌─ BRANCH B (growth/endocrine) ─┐  ┌─ BRANCH C (other) ─┐
 │ ID, ASD, microcephaly, seizures, hypotonia   │  │ short stature; HH / pubertal   │  │ heart defects,     │
 │                                              │  │ delay (PMID 38528912)          │  │ cleft palate, GERD,│
 │                                              │  │                                │  │ ectodermal/progeroid│
 └──────────────────────────────────────────────┘  └────────────────────────────────┘  └────────────────────┘

Upstream vs downstream: The mutation and corepressor-scaffold deficit are upstream (demonstrated genetically/structurally); gene-network dysregulation is intermediate (demonstrated in cells/embryos); the cortical neurogenesis defect is the proximal cause of the neurodevelopmental phenotype (demonstrated in mouse); multisystem branches are largely inferred from case reports. The essentiality of SIN3A (embryonic-lethal null) explains why only partial (50%) loss is compatible with life and produces a comparatively mild, dosage-dependent syndrome.

Evidence Base

PMID Title (abbrev.) Role
27399968 SIN3A haploinsufficiency causes mild ID… Defining paper; establishes gene, phenotype, mouse neurogenesis mechanism
33437032 28-individual SIN3A cohort Largest cohort; severity frequencies, variant spectrum, management
22206758 Sin3a essential for genome integrity Embryonic lethality; essentiality supporting haploinsufficiency
30279502 Sin3A recruits Tet1 via PAH1 PAH-domain scaffold architecture
32391601 Myt1L–Sin3 PAH1 interaction Links PAH1 to neuronal identity TF
21676866 SAP30–Sin3A structure ~2 MDa complex; PAH3 interaction
41759735 PAH1 αα-hub stability/variants Functional proof missense = LOF
40336075 15q24 deletion WITKOS review Epidemiology; AD/CNV etiology
38528912 SIN3A + hypogonadotropic hypogonadism Endocrine phenotype expansion
38841330 WITKOS reflux + SIN3A deletion Cardiac/GI involvement; CMA diagnosis
39828923 WITKOS with cleft palate Craniofacial expansion
39576496 WITKOS dystonia/ataxia Movement-disorder expansion
40586236 Familial WITKOS progeroid/diabetes Familial multisystem expansion
41245232 Personalized treatment case First behavioral intervention
19825413 Drosophila SIN3/String Conservation, essentiality, proliferation
25957495 Yeast Sin3/Rpd3/Ume6 Yeast conservation
33130996 REST/NRSF–SIN3 complex Complex composition
41957673, 41952182 Chromatinopathy episignatures Diagnostic context for VUS

All mechanistic and clinical claims above are tied to cited abstracts/snippets; titles alone were not used to infer content.

Limitations and Knowledge Gaps

  1. Small evidence base. With <~100 reported patients and one substantial cohort (n=28), frequency estimates (e.g., 43% hypotonia, 14% seizures) are imprecise and likely subject to ascertainment bias toward more severely affected individuals.
  2. No formal prevalence/incidence. Epidemiology rests on qualitative "few per million" statements; no registry-based figures exist.
  3. Inferred multisystem mechanism. Cardiac, GI, craniofacial, endocrine, and ectodermal features derive from single case reports; their frequency and the causal link to SIN3A dosage (versus contiguous-gene effects in CNV cases) are not firmly established.
  4. No validated episignature yet specifically for SIN3A; its chromatinopathy methylation signature is anticipated but not confirmed in the cited sources.
  5. No haploinsufficiency animal model phenotype fully recapitulating WITKOS is documented in the knowledge base (the null is embryonic lethal; the relevant mouse data are focal knockdowns).
  6. No therapeutics. There is no disease-modifying treatment and no WITKOS-specific clinical trial.
  7. Genotype–phenotype correlations (truncating vs missense vs deletion; variant position relative to PAH domains) remain unresolved, limiting prognostic counseling.

Proposed Follow-up Experiments / Actions

  1. Establish a WITKOS natural-history registry to generate real prevalence/incidence and robust phenotype frequencies across age, and to track complication rates (cardiac, GI, endocrine, movement disorder).
  2. Generate and phenotype a Sin3a heterozygous (and brain-conditional) mouse to test whether 50% dosage reproduces microcephaly, short stature, behavioral and multisystem features, and to define critical developmental windows.
  3. Develop and validate a SIN3A DNA-methylation episignature (EpiSign-style) to reclassify VUS and confirm atypical/dual-diagnosis cases, leveraging the chromatinopathy framework (PMID 41957673, 41952182).
  4. Systematic genotype–phenotype analysis correlating variant class and PAH-domain location with cognitive severity and organ involvement, building on PAH1 thermodynamic data (PMID 41759735).
  5. Functional dissection of the Myt1L/TET1–SIN3A axis in human iPSC-derived cortical neurons/organoids carrying patient variants, to connect specific PAH-domain interaction losses to transcriptomic and neurodevelopmental phenotypes.
  6. Screen for pharmacologic modulation — e.g., whether HDAC-pathway or targeted epigenetic agents can partially normalize transcriptional dysregulation in patient-derived models (hypothesis-generating, given the HDAC-complex mechanism).
  7. Standardize clinical surveillance guidelines (cardiac echo, feeding/GI evaluation, endocrine/pubertal monitoring, developmental and behavioral support) and disseminate a multidisciplinary care pathway.

Report compiled from 12 confirmed findings and 47 reviewed papers across five discovery iterations. Causal gene: SIN3A (15q24.2). Evidence sources span human clinical cohorts/case reports, mouse in vivo models, invertebrate and yeast genetics, and in vitro structural/biophysical studies, as annotated above.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.5.1.

Outcome Count
References checked 21
Resolved 21
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 21
Quoted claims found in source 20
Quoted claims not found in source 1
References weighed for topical relevance 21
On topic 13
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:39576496 (abstract only): "a chronic, progressively worsening symmetric cerebellar ataxia, along with generalized dystonia. Notably, dystonia has not been previously associated with this syndrome."
  • closest text in source: "Herein, we present a 21-year-old woman with dysmorphic facial features, short stature, and a chronic, progressively worsening symmetric cerebellar ataxia, along with generalized dystonia"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 41
Resolved 39
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 22
Terms named correctly 9
Terms named as a different term 10
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0001263 (1 mention) - the report calls it "Common"; HP calls it Global developmental delay
  • HP:0000729 (1 mention) - the report calls it "Minority"; HP calls it Autistic behavior
  • HP:0007018 (1 mention) - the report calls it "Minority"; HP calls it Attention deficit hyperactivity disorder
  • HP:0000252 (1 mention) - the report calls it "Characteristic"; HP calls it Microcephaly
  • HP:0004322 (1 mention) - the report calls it "Characteristic"; HP calls it Short stature
  • HP:0001999 (1 mention) - the report calls it "Characteristic/recognizable"; HP calls it Abnormal facial shape
  • HP:0011968 (1 mention) - the report calls it "Common"; HP calls it Feeding difficulties
  • HP:0001627 (1 mention) - the report calls it "Not uncommon"; HP calls it Abnormal heart morphology
  • HP:0000175 (1 mention) - the report calls it "Rare"; HP calls it Cleft palate
  • UBERON:0000956 (1 mention) - the report calls it "Primary organ/system: Central nervous system — cerebral cortex"; UBERON calls it cerebral cortex**

Obsolete terms

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) (2 mentions)

Terms whose name is worth a second look

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:

  • GO:0016575 (2 mentions) - the report calls it "histone deacetylation"; GO calls it obsolete histone deacetylation
  • CL:0000047 (3 mentions) - the report calls it "neural progenitor cell"; CL calls it neural stem cell
  • GO:0000122 (1 mention) - the report calls it "negative regulation of transcription by RNA Pol II"; GO calls it negative regulation of transcription by RNA polymerase II