Radio-Tartaglia Syndrome

Mendelian MONDO:0859143 Pathograph 34 Show in embeddings browser neurodevelopmental disorder syndromic intellectual disability

Radio-Tartaglia syndrome (RATARS) is an autosomal dominant neurodevelopmental disorder caused by heterozygous truncating, loss-of-function variants in SPEN, a transcriptional repressor gene at 1p36 that lies just centromeric to the proximal 1p36 deletion critical region. It was defined in 2021 from 34 individuals and overlaps clinically with proximal 1p36 deletion syndrome: developmental delay and intellectual disability, autism spectrum disorder, anxiety, aggression and attention deficit, hypotonia, brain and spine anomalies, congenital heart defects, a high or narrow palate, facial dysmorphism, and obesity or increased BMI that is more marked in females. Most variants arise de novo, but familial transmission with variable expressivity is documented. SPEN is the protein through which XIST RNA initiates silencing of one X chromosome, and affected females carry a distinctive X-chromosome DNA methylation episignature in blood; whether that epigenetic change contributes to the clinical features is not established.

Ask OpenScientist

Ask a research question about Radio-Tartaglia Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
7
Pathophys.
28
Phenotypes
3
Gaps
34
Pathograph
1
Genes
3
Variants
2
Medical Actions
2
Differentials
2
Models
1
Deep Research
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
A single heterozygous truncating SPEN variant is sufficient. Most published variants arose de novo; transmission over three generations has been reported in a Chinese family, with milder disease in the transmitting grandmother than in her daughter, and a mother-daughter pair has been reported with a dystonia-predominant presentation.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:41574619 SUPPORT Human Clinical
"Radio-Tartaglia Syndrome (RATARS) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function (LoF) variants in SPEN."
States the dominant mode and the loss-of-function variant class directly.
PMID:41574619 SUPPORT Human Clinical
"Sanger sequencing confirmed the authenticity of the variant and revealed that it was inherited from the mother of the pregnant woman."
Transmission of a heterozygous SPEN frameshift from an affected parent to an affected child, and on to the fetus, is the segregation pattern of a dominant disorder.
PMID:39431794 SUPPORT Human Clinical
"We identified a de novo heterozygous pathogenic variant of SPEN and diagnosed her with RATARS."
A de novo heterozygous variant causing disease is consistent with dominant (haploinsufficient) inheritance.
?

Discussions and Knowledge Gaps

3
Does heterozygous SPEN loss disturb X-chromosome inactivation in human females, and does the female X-chromosome methylation episignature have any consequence for the clinical features or for sex differences such as the female predominance of obesity?
KNOWLEDGE GAP OPEN ratars_x_episignature_function
Attached to
pathophysiology#Female X Chromosome DNA Methylation Episignature pathophysiology#Impaired XIST-SPEN-Mediated X Chromosome Silencing
The X-silencing role of SPEN was shown with complete loss in mouse embryos and stem cells, and in neural progenitors SPEN is not needed to maintain silencing. Patients keep one functional copy. The episignature is the only human observation, measured in blood, and no study has measured X-inactivation skewing or escape-gene expression in patient cells.
Show evidence (1 reference)
PMID:32025035 SUPPORT Model Organism
"SPEN is dispensable for maintenance of XCI in neural progenitors, although it significantly decreases the expression of genes that escape XCI."
The model evidence is for complete loss and shows a maintenance role limited to escape genes, which leaves the human haploinsufficient case open.
Is the obesity and raised BMI of this syndrome caused by the fat-mobilization defect seen in Spen-depleted Drosophila, or by a central (hypothalamic or behavioural) mechanism that the fly model cannot represent?
HUMAN MODEL MISMATCH OPEN ratars_obesity_mechanism
Attached to
pathophysiology#Impaired Fat Mobilization and Fatty Acid Beta-Oxidation phenotypes#Obesity
The only mechanistic evidence comes from invertebrate fat-storage cells and a body-fat correlation in mouse. No human metabolic, lipidomic or energy-expenditure study exists, and the female predominance of obesity in patients is unexplained.
Show evidence (1 reference)
PMID:28640815 SUPPORT Model Organism
"Finally, mouse Spen and Spenito transcript levels scaled directly with body fat in vivo, suggesting a conserved role in fat liberation and catabolism."
The mammalian link is correlational, which is why the human mechanism is open.
Are dystonia and sensorineural hearing loss part of the SPEN-related spectrum, or coincidental findings in single families?
KNOWLEDGE GAP OPEN ratars_phenotype_expansion
Attached to
phenotypes#Dystonia genetic#SPEN
Dystonia is reported in one mother-daughter pair whose other relatives with tremor were not tested. Hearing loss occurred in 3 of 31 of the founding series, but severe congenital sensorineural hearing loss in a premature boy carrying a SPEN variant of uncertain significance, inherited from a healthy father, cannot be attributed to this syndrome. Both need further cases.
Show evidence (2 references)
PMID:40529391 SUPPORT Human Clinical
"who possessed a novel variant of the SPEN gene (discovered by whole exome sequencing), which was inherited from a healthy father, and severe congenital bilateral sensorineural hearing loss. This SPEN gene variant was classified as having unknown significance."
The variant is inherited from an unaffected parent and of uncertain significance, so this case is not counted toward the Hearing impairment phenotype, which rests on the founding series alone.
PMID:41525714 SUPPORT Human Clinical
"While dystonia can be idiopathic or associated with other neurological disorders, it has never been reported in patients with SPEN haploinsufficiency and RTS."
The authors themselves flag dystonia as a single-family finding.
⚙

Pathophysiology

7
SPEN Haploinsufficiency
A heterozygous stop-gain or frameshift variant in SPEN (or, in a broader proximal 1p36 deletion, loss of one SPEN copy) halves the dose of SPEN protein. The founding series consisted entirely of truncating variants; reduced protein was inferred from variant class and was not measured variant by variant in patient cells.
SPEN hgnc:17575 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SPEN (hgnc:17575). hgnc:17575 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Reduced SPEN-Mediated Transcriptional Repression SPEN is a transcriptional repressor, so halving its dose reduces the repressive activity it recruits to target genes.
Impaired XIST-SPEN-Mediated X Chromosome Silencing The X-silencing function of SPEN was established by complete loss of SPEN in mouse cells and embryos. Whether a single remaining SPEN copy is enough for normal X inactivation in human females has not been tested; the female X-chromosome methylation episignature is the only human observation pointing that way.
Show evidence (2 references)
PMID:33596411 SUPPORT Human Clinical
"Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome."
The founding cohort is defined by heterozygous truncating SPEN variants.
PMID:33596411 SUPPORT Human Clinical
"We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions."
Names haploinsufficiency as the disease mechanism.
Reduced SPEN-Mediated Transcriptional Repression
SPEN (also called SHARP or MINT) binds RNA through its RRM domains and, via its C-terminal SPOC domain, recruits the NCoR/SMRT co-repressor and HDAC3 as well as NuRD, m6A and RNA polymerase II machinery. In mouse it also competes with the Notch intracellular domain for RBP-J and so dampens Notch-dependent transactivation. Which developmental target genes are de-repressed in RATARS patients is unknown.
SPEN hgnc:17575 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SPEN (hgnc:17575). hgnc:17575 is a gene from the HUGO Gene Nomenclature Committee.
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. negative regulation of Notch signaling pathway GO:0045746 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of Notch signaling pathway (GO:0045746). GO:0045746 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
Abnormal Neurodevelopment SPEN is needed for several developmental processes, but the de-repressed genes and the neural cell types that carry the defect in patients are not identified.
Impaired Palatal Shelf Development In the mouse, Spen loss reduces palatal mesenchyme proliferation and delays shelf elevation; Spen interacts genetically with the RERE co-repressor in this process. The transcriptional targets involved are not identified.
Impaired Fat Mobilization and Fatty Acid Beta-Oxidation In Drosophila, Spen acts cell-autonomously in fat-storage cells to permit lipid mobilization, and mouse Spen transcript levels track body fat. This is a candidate explanation for the obesity in RATARS, not a demonstrated human mechanism.
Show evidence (2 references)
PMID:32025035 SUPPORT In Vitro
"We identify the protein partners of SPOC, including NCoR/SMRT, the m6A RNA methylation machinery, the NuRD complex, RNA polymerase II and factors involved in the regulation of transcription initiation and elongation."
Identifies the co-repressor and transcription machinery that SPEN recruits, the activity a reduced dose would diminish. Measured in mouse embryonic stem cells.
PMID:12594956 SUPPORT INDIRECT In Vitro
"We found that Msx2-interacting nuclear target protein (MINT) competed with the intracellular region of Notch for binding to a DNA binding protein RBP-J and suppressed the transactivation activity of Notch signaling."
Shows the Notch-repressive activity of mouse SPEN (MINT). Indirect for this disease, since no Notch-pathway change has been measured in RATARS patients.
Impaired XIST-SPEN-Mediated X Chromosome Silencing
XIST RNA recruits SPEN to the future inactive X through SPEN RRM4 and the XIST A-repeat; SPEN then recruits SMRT/HDAC3, histones are deacetylated and RNA polymerase II is excluded, initiating silencing. In mouse, SPEN is essential to initiate X inactivation but dispensable for its maintenance in neural progenitors, where it still dampens expression of escape genes. All of this comes from complete loss of SPEN; the effect of heterozygous loss on human X inactivation is untested.
SPEN hgnc:17575 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SPEN (hgnc:17575). hgnc:17575 is a gene from the HUGO Gene Nomenclature Committee.
dosage compensation by inactivation of X chromosome GO:0009048 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dosage compensation by inactivation of X chromosome (GO:0009048). GO:0009048 is a biological process from the Gene Ontology.
XIST lncRNA binding GO:0106222 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased XIST lncRNA binding, annotated with lncRNA binding (GO:0106222). GO:0106222 is a molecular function from the Gene Ontology.
Downstream
Female X Chromosome DNA Methylation Episignature The episignature is restricted to the X chromosome and to females, which is the pattern expected if SPEN dosage affects the epigenetic state of the inactive X. The link is inferred from that specificity; no study has measured X-inactivation skewing or escape-gene expression in patients.
Show evidence (4 references)
PMID:25915022 SUPPORT In Vitro
"Our results suggest that Xist silences transcription by directly interacting with SHARP, recruiting SMRT, activating HDAC3, and deacetylating histones to exclude Pol II across the X chromosome."
Defines the XIST-SPEN-SMRT-HDAC3 silencing route in mouse embryonic stem cells.
PMID:32025035 SUPPORT Model Organism
"We show that SPEN is essential for initiating gene silencing on the X chromosome in preimplantation mouse embryos and in embryonic stem cells."
Shows SPEN is required to initiate X silencing in vivo.
PMID:32025035 SUPPORT Model Organism
"SPEN is dispensable for maintenance of XCI in neural progenitors, although it significantly decreases the expression of genes that escape XCI."
Limits the claim: in neural progenitors SPEN is not needed to keep the X silent, but it does restrain escape genes, which is relevant to a neurodevelopmental disease.
+ 1 more reference
Female X Chromosome DNA Methylation Episignature
Peripheral-blood DNA from affected females shows a distinctive methylation pattern confined to the X chromosome. The founding paper describes it as an X chromosome-specific episignature that classifies the syndrome; it is a research-stage biomarker from a small number of females and is not reported for affected males. Whether it has any functional consequence for the clinical features, or explains any sex difference in presentation, is not known.
Show evidence (2 references)
PMID:33596411 SUPPORT Human Clinical
"Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females"
Direct statement of the female X-chromosome episignature.
PMID:33596411 SUPPORT Human Clinical
"a paradigm of an X chromosome-specific episignature that classifies syndromic traits"
The authors present the signature as a classifier, which is why it is recorded as a biomarker rather than as a cause of any phenotype.
Abnormal Neurodevelopment
Altered development of the brain underlies the developmental delay, intellectual disability, behavioural and psychiatric features, hypotonia and the structural brain anomalies. Reported neuroimaging findings vary between individuals. The intermediate cell types and the genes that mediate the effect are unresolved.
central nervous system development GO:0007417 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal central nervous system development (GO:0007417). GO:0007417 is a biological process from the Gene Ontology.
Downstream
Global developmental delay
Intellectual disability
Autism spectrum disorder
Anxiety
Aggressive behavior
Attention deficit disorder
Hypotonia
Brain anomalies
Gait disturbance
Delayed speech and language development
Motor delay
Motor stereotypy
Seizure
Abnormal pyramidal signs
Feeding difficulties Inferred via hypotonia and oral-motor dysfunction; not studied directly.
Show evidence (1 reference)
PMID:33596411 SUPPORT Human Clinical
"The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies"
The neurodevelopmental core of the clinical profile.
Impaired Palatal Shelf Development
In Spen-null mouse embryos, proliferation of mesenchymal cells in the medial palatal shelves is reduced at E13.5, delaying shelf elevation and extension and producing cleft palate; ablating Spen only in cranial neural crest cells delays palatal development. In people, a high or narrow palate is common and orofacial clefting occasional, and clefting is more frequent with 1p36 deletions removing both SPEN and RERE.
cranial neural crest cell CL:0000008 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cranial neural crest cell, annotated with migratory cranial neural crest cell (CL:0000008). CL:0000008 is a cell type from the Cell Ontology.
secondary palate development GO:0062009 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased secondary palate development (GO:0062009). GO:0062009 is a biological process from the Gene Ontology. palatal mesenchymal cell proliferation GO:0010463 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased palatal mesenchymal cell proliferation, annotated with mesenchymal cell proliferation (GO:0010463). GO:0010463 is a biological process from the Gene Ontology.
Animal models
Spen-null and neural crest-conditional Spen mouse Mouse partially recapitulates Reproduces a palatal shelf defect, and localizes it to neural crest-derived mesenchyme.
Downstream
High narrow palate Inferred: the mouse shows delayed shelf elevation, and the common human palatal anomaly is a high or narrow palate rather than a cleft.
Orofacial cleft
Show evidence (2 references)
PMID:42456047 SUPPORT Model Organism
"Mesenchymal cell proliferation in the medial halves of the palatal shelves of Spen-null embryos at E13.5 is significantly reduced."
Identifies the cellular defect behind the palatal phenotype in the mouse.
PMID:42456047 SUPPORT Model Organism
"Tissue specific ablation of Spen in the cranial neural crest cells results in delayed palatal development."
Localizes the requirement to cranial neural crest-derived cells.
Impaired Fat Mobilization and Fatty Acid Beta-Oxidation
Spen-depleted Drosophila fat-body cells store excess fat and fail to liberate it, with starvation sensitivity and changes in beta-oxidation enzymes and metabolites; diet alters these effects. A matching human metabolic signature has not been looked for. This node is a model-derived candidate explanation for the obesity and raised BMI in RATARS.
fatty acid beta-oxidation GO:0006635 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased fatty acid beta-oxidation (GO:0006635). GO:0006635 is a biological process from the Gene Ontology.
Animal models
Spen-depleted Drosophila fat body Fruit fly partially recapitulates Supplies the only mechanistic account of why SPEN loss might cause obesity.
Downstream
Obesity Hypothesised: a fat-mobilization defect would favour fat accumulation, but this has not been shown in patients or mammals.
Show evidence (2 references)
PMID:28640815 SUPPORT INDIRECT Model Organism
"Spen-depleted larvae had defects in energy liberation from stores, including starvation sensitivity and major changes in the levels of metabolic enzymes and metabolites, particularly those involved in β-oxidation."
Fly evidence for the impaired-mobilization mechanism; indirect for humans.
PMID:32107279 SUPPORT INDIRECT Model Organism
"Lipid catabolism is impaired in Spen-deficient fat storage cells, accompanied by a compensatory increase in glycolytic flux and protein catabolism."
Follow-up from the same group restating the catabolic defect.
⬡

Pathograph

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

Phenotypes

28
Cardiovascular 1
Congenital heart defect OCCASIONAL Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defect, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33596411 SUPPORT Human Clinical
"attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects"
Congenital heart defects are part of the clinical profile; the abstract names no specific lesion, so the general CHD term is bound.
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Congenital heart defect +, Secundum ASD 8/29 (28)"
Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 8 of 29 had a congenital heart defect.
Digestive 2
Feeding difficulties OCCASIONAL HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding/swallowing problems, annotated with Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Feeding/swallowing problems +, Epiglottic malacia 8/30 (27)"
Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 8 of 30 had feeding or swallowing problems; the Korean boy needed fundoplication and gastrostomy.
Gastrointestinal features FREQUENT Abnormality of the gastrointestinal tract HP:0011024 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal features (reflux, constipation), annotated with Abnormality of the gastrointestinal tract (HP:0011024). HP:0011024 is a phenotype from the Human Phenotype Ontology.
Coarse binding: variable spectrum
Show evidence (1 reference)
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Congenital heart defect +, Secundum ASD 8/29 (28) Gastrointestinal feature +, Gastrostomy feeding 13/31 (42)"
Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 13 of 31 had a gastrointestinal feature.
Ear 1
Hearing impairment OCCASIONAL HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing loss, annotated with Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Epiglottic malacia 8/30 (27) Hearing loss - 3/31 (10)"
Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 3 of 31 had hearing loss.
Eye 2
Strabismus OCCASIONAL HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exotropia/strabismus, annotated with Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Exotropia/strabismus +, Exotropia 6/30 (20) Myopia - 6/30 (20)"
Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 6 of 30 had exotropia or strabismus.
Myopia OCCASIONAL HP:0000545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopia (HP:0000545). HP:0000545 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Exotropia 6/30 (20) Myopia - 6/30 (20)"
Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 6 of 30 had myopia.
Head and Neck 3
High narrow palate FREQUENT High palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High/narrow palate, annotated with High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33596411 SUPPORT Human Clinical
"congenital heart defects, high/narrow palate, facial dysmorphisms"
High or narrow palate is part of the clinical profile.
PMID:42456047 SUPPORT BACKGROUND Human Clinical
"Haploinsufficiency of SPEN, a 1p36 gene that encodes a transcriptional repressor, causes Radio-Tartaglia syndrome, a neurodevelopmental syndrome in which high/narrow palates are common, and OFC is occasionally observed."
"Common" supports the FREQUENT band; no count is given in the abstract.
Orofacial cleft OCCASIONAL HP:0000202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Orofacial cleft (HP:0000202). HP:0000202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42456047 SUPPORT BACKGROUND Human Clinical
"Haploinsufficiency of SPEN, a 1p36 gene that encodes a transcriptional repressor, causes Radio-Tartaglia syndrome, a neurodevelopmental syndrome in which high/narrow palates are common, and OFC is occasionally observed."
"Occasionally observed" supports the OCCASIONAL band; the abstract does not say whether the clefts involve lip, palate or both, so the general orofacial cleft term is bound.
Facial dysmorphism VERY_FREQUENT Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33596411 SUPPORT Human Clinical
"congenital heart defects, high/narrow palate, facial dysmorphisms"
Facial dysmorphism is part of the clinical profile.
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Pregnancy history complication - 19/34 (56) Craniofacial dysmorphism + 28/31 (90)"
Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 28 of 31 had craniofacial dysmorphism.
Limbs 1
Brachydactyly OCCASIONAL HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Brachydactyly - 5/30 (17) Toes abnormalities - 4/27 (15)"
Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 5 of 30 had brachydactyly.
Musculoskeletal 3
Hypotonia FREQUENT 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 (2 references)
PMID:39431794 SUPPORT Human Clinical
"RATARS is characterized by developmental delay, hypotonia, and intellectual disability."
Hypotonia is a defining feature.
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Hypotonia + 22/30 (73) Seizures – 3/32 (9)"
Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 22 of 30 had hypotonia.
Kyphosis HP:0002808 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Kyphosis (HP:0002808). HP:0002808 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41574619 SUPPORT Human Clinical
"The 22-year-old pregnant woman presented with neurodevelopmental defects including moderate intellectual disability (ID) and hypotonia, gait abnormalities, behavioural problems, kyphosis and dysmorphic facial features."
Kyphosis reported in an affected adult.
Scoliosis OCCASIONAL HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis/kyphosis, annotated with Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Toes abnormalities - 4/27 (15) Scoliosis/kyphosis +, Scoliosis 5/28 (18)"
Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 5 of 28 had scoliosis or kyphosis; the source does not split the two, so the count is an upper bound for scoliosis alone.
Nervous System 14
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental delay, annotated with Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:33596411 SUPPORT Human Clinical
"The clinical profile of this disease includes developmental delay/intellectual disability"
Developmental delay heads the clinical profile.
PMID:39431794 SUPPORT Human Clinical
"RATARS is characterized by developmental delay, hypotonia, and intellectual disability."
Restates developmental delay as a defining feature.
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Global developmental delay + 32/33 (97) Intellectual disability + 23/24 (96)"
Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 32 of 33 had global developmental delay.
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:39431794 SUPPORT Human Clinical
"RATARS is characterized by developmental delay, hypotonia, and intellectual disability."
Intellectual disability is a defining feature.
PMID:41574619 SUPPORT Human Clinical
"Compared to the proband, the mother has a milder phenotype, mainly manifested as mild ID."
Shows the range of severity within one family carrying the same variant, moderate in the proband and mild in her mother.
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Global developmental delay + 32/33 (97) Intellectual disability + 23/24 (96)"
Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 23 of 24 assessed had intellectual disability.
Autism spectrum disorder FREQUENT 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:33596411 SUPPORT Human Clinical
"The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder"
Autism spectrum disorder is listed in the clinical profile.
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Aggressive behavior – 18/29 (62) Autism spectrum disorder – 18/28 (64)"
Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 18 of 28 assessed had autism spectrum disorder.
Anxiety HP:0000739 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anxiety (HP:0000739). HP:0000739 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33596411 SUPPORT Human Clinical
"autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder"
Anxiety is listed in the clinical profile.
Aggressive behavior FREQUENT HP:0000718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aggressive behavior (HP:0000718). HP:0000718 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33596411 SUPPORT Human Clinical
"autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder"
Aggressive behavior is listed in the clinical profile.
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Aggressive behavior – 18/29 (62) Autism spectrum disorder – 18/28 (64)"
Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 18 of 29 assessed had aggressive behavior.
Attention deficit disorder Attention deficit hyperactivity disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit disorder, annotated with Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33596411 SUPPORT Human Clinical
"autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder"
Attention deficit disorder is listed in the clinical profile. The source wording is kept in preferred_term; the bound HPO term is the attention-deficit hyperactivity disorder class.
Brain anomalies FREQUENT Abnormal brain morphology HP:0012443 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brain anomalies, annotated with Abnormal brain morphology (HP:0012443). HP:0012443 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33596411 SUPPORT Human Clinical
"attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects"
Brain anomalies are part of the clinical profile.
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Hemiparesis – 2/28 (7) Brain anomalies + 14/22 (64)"
Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 14 of 22 imaged individuals had a brain anomaly, a selected imaged denominator.
Gait disturbance HP:0001288 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait abnormalities, annotated with Gait disturbance (HP:0001288). HP:0001288 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41574619 SUPPORT Human Clinical
"The 22-year-old pregnant woman presented with neurodevelopmental defects including moderate intellectual disability (ID) and hypotonia, gait abnormalities, behavioural problems, kyphosis and dysmorphic facial features."
Gait abnormality reported in an affected adult.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cervical and upper-limb dystonia with dystonic tremor, annotated with Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41525714 SUPPORT Human Clinical
"We hereby describe a mother and a daughter with a novel SPEN variant leading to haploinsufficiency presenting with cervical dystonia and dystonic head and upper limb tremor."
Direct report of dystonia in two related carriers of a truncating SPEN variant.
Delayed speech and language development VERY_FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Language delay, annotated with Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Delayed fine motor skills + 23/24 (96) Language delay + 31/32 (97)"
Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 31 of 32 had language delay.
Motor delay VERY_FREQUENT HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed gross and fine motor skills, annotated with Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Delayed gross motor skills + 26/30 (87) Delayed fine motor skills + 23/24 (96)"
Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 26 of 30 had delayed gross motor and 23 of 24 delayed fine motor skills.
Motor stereotypy FREQUENT HP:0000733 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stereotypic behavior, annotated with Motor stereotypy (HP:0000733). HP:0000733 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Autism spectrum disorder – 18/28 (64) Stereotypic behavior – 13/28 (46)"
Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 13 of 28 had stereotypic behavior.
Seizure OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Hypotonia + 22/30 (73) Seizures – 3/32 (9)"
Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 3 of 32 had seizures, so epilepsy is uncommon, unlike in distal 1p36 deletion syndrome.
Abnormal pyramidal signs OCCASIONAL HP:0007256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal pyramidal signs, annotated with Abnormal pyramidal sign (HP:0007256). HP:0007256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.26815/acn.2024.00717 SUPPORT BACKGROUND Human Clinical
"Seizures – 3/32 (9) Abnormal pyramidal signs – 6/24 (25)"
Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 6 of 24 assessed had abnormal pyramidal signs.
Growth 1
Obesity HP:0001513 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obesity/increased BMI, especially in females, annotated with Obesity (HP:0001513). HP:0001513 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33596411 SUPPORT Human Clinical
"facial dysmorphisms, and obesity/increased BMI, especially in females"
States the phenotype and its female predominance.
🧬

Genetic Associations

1
SPEN
Gene: SPEN hgnc:17575 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SPEN (hgnc:17575). hgnc:17575 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant inheritance
Show evidence (2 references)
PMID:33596411 SUPPORT Human Clinical
"Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome."
The founding gene-disease association.
PMID:39431794 SUPPORT Human Clinical
"Radio-Tartaglia syndrome (RATARS) (MIM#619312) is a genetic disorder caused by heterozygous truncating variants of SPEN on chromosome 1p36."
Independent restatement of the causal gene and variant class.
Variants (3)
NM_015001.3:c.6223_6227del p.(Ser2075GlufsTer46) Pathogenic
frameshift variant
Recurrent frameshift; present in the founding series and found de novo in a Japanese girl whose facial features first suggested Down syndrome.
Show evidence (1 reference)
PMID:39431794 SUPPORT Human Clinical
"We performed trio-based whole exome sequencing and identified a recurrent pathogenic variant of SPEN:NM_015001.3:c.6223_6227del, p.(Ser2075GlufsTer46)."
Names the variant, its recurrence and its pathogenic classification.
c.2417_2418dup p.(Arg807Aspfs*3) Pathogenic
frameshift variant
Frameshift transmitted across three generations of a Chinese family, with a milder phenotype in the grandmother than in her daughter; detected prenatally in the fetus.
Show evidence (1 reference)
PMID:41574619 SUPPORT Human Clinical
"WES identified a previously unreported heterozygous frameshift variant (c.2417_2418dup, p.Arg807Aspfs*3) in the SPEN gene."
Reports the variant in the affected proband.
NM_015001.3:c.2170C>T p.(Arg724*) Likely Pathogenic
stop gained
Stop-gain found in a mother and daughter with cervical and upper-limb dystonia; classified likely pathogenic by the reporting authors (PVS1, PM2).
Show evidence (1 reference)
PMID:41525714 SUPPORT Human Clinical
"This approach identified a heterozygous likely pathogenic stop‐gain variant in SPEN (NM_015001.3: c.2170C>T, p.Arg724*)."
Reports the variant and its classification.
🗃️

External Assertions

1
OMIM Radio-Tartaglia syndrome entry
OMIM disease record OMIM:619312
OMIM phenotype entry, as cited (MIM#619312) in PMID:39431794. Recorded as an identifier only.
💊

Medical Actions

2
Clonazepam for dystonia
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: clonazepam CHEBI:3756 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses clonazepam (CHEBI:3756). CHEBI:3756 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Oral clonazepam given for dystonia in one adult patient, together with botulinum toxin injections (and escitalopram for psychiatric symptoms); the report describes some reduction of symptoms at follow-up. There is no disease-modifying treatment for this syndrome; management is otherwise supportive and directed at the individual's developmental, behavioural, cardiac and feeding needs.
Mechanism Target:
Dystonia
Show evidence (1 reference)
PMID:41525714 SUPPORT Human Clinical
"Treatment included clonazepam and botulinum toxin injections for the dystonia and escitalopram for the psychiatric symptoms, with some reduction of the symptoms at follow‐up."
Single-patient report in which clonazepam and botulinum toxin were given together; the benefit cannot be attributed to either agent alone, and this is not a controlled result.
Botulinum toxin injections for dystonia
Action: Botulinum toxin therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Botulinum toxin therapy (NCIT:C157775). NCIT:C157775 is a clinical intervention from the NCI Thesaurus. Ontology label: Botulinum Toxin Therapy NCIT:C157775
Platform: Other
Botulinum toxin injections for cervical and upper-limb dystonia in the same single adult patient, given together with clonazepam; some reduction of symptoms at follow-up.
Mechanism Target:
Dystonia
Show evidence (1 reference)
PMID:41525714 SUPPORT Human Clinical
"Treatment included clonazepam and botulinum toxin injections for the dystonia and escitalopram for the psychiatric symptoms, with some reduction of the symptoms at follow‐up."
Single-patient report in which clonazepam and botulinum toxin were given together; the benefit cannot be attributed to either agent alone, and this is not a controlled result.
🔬

Diagnosis

3
Exome or genome sequencing
The diagnosis is molecular: identification of a heterozygous truncating SPEN variant. Chromosomal microarray detects 1p36 deletions but not the sequence-level truncations that cause most cases, and the clinical picture can resemble other conditions, so exome or genome sequencing (trio where possible) is the effective test.
Show evidence (2 references)
PMID:39431794 SUPPORT Human Clinical
"Microarray analysis revealed no pathogenic aberrations. We performed trio-based whole exome sequencing and identified a recurrent pathogenic variant"
Microarray was uninformative and trio exome sequencing made the diagnosis.
DOI:10.26815/acn.2024.00717 SUPPORT Human Clinical
"A 3-year-old boy was brought to the hospital and underwent whole genome sequencing to evaluate developmental delay and multiple anomalies. This led to the identification of a de novo truncating variant in SPEN."
A second independent diagnosis made by genome sequencing.
Prenatal genetic testing in families with a known variant
Where a familial SPEN variant is known, it can be tested for prenatally by amniocentesis; fetal ultrasound may be unremarkable.
Show evidence (1 reference)
PMID:41574619 SUPPORT Human Clinical
"Prenatal ultrasonography during pregnancy revealed no obvious structural abnormalities. However, prenatal genetic testing revealed the foetus harboured the same SPEN pathogenic variant."
Ultrasound was normal and genetic testing was what identified the affected fetus.
X-chromosome DNA methylation episignature (research)
In affected females a blood DNA methylation episignature restricted to the X chromosome distinguishes cases. It is a research-stage classifier derived from a small number of females, not reported for males, and not a validated stand-alone clinical test.
Show evidence (1 reference)
PMID:33596411 SUPPORT Human Clinical
"a paradigm of an X chromosome-specific episignature that classifies syndromic traits"
The authors present the episignature as a classifier.
📊

Prevalence

1
Published RATARS case literature
Cases In Literature Ultra Rare
The founding series described 34 individuals. Later single-family reports (Japan, China, Slovenia) add a handful of cases. No population-based prevalence or incidence estimate exists, and 34 is a case count, not a rate.
Show evidence (1 reference)
PMID:39431794 SUPPORT Human Clinical
"This syndrome is extremely rare, with only 34 cases reported to date."
Gives the cumulative published case count at the time of the report.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Radio-Tartaglia Syndrome:

Proximal 1p36 deletion syndrome
Overlapping Features The phenotype overlaps considerably with proximal 1p36 deletion syndrome, and SPEN is commonly deleted in it; it also overlaps with distal 1p36 deletions that spare SPEN. Chromosomal microarray separates a multigene deletion from an intragenic SPEN variant; deletions removing both SPEN and RERE carry a higher rate of orofacial clefting.
Show evidence (2 references)
PMID:33596411 SUPPORT Human Clinical
"Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome."
States the clinical overlap that makes this the main differential.
DOI:10.26815/acn.2024.00717 SUPPORT Human Clinical
"However, in all reported Korean cases of 1p36DS, the deletions were distal and did not involve SPEN; despite this, the clinical features of the disorder overlap considerably with those of RTS."
The overlap extends to distal 1p36 deletions that spare SPEN, so a 1p36 phenotype does not by itself implicate SPEN; molecular testing is needed.
Down syndrome
Overlapping Features One reported girl with developmental delay, hypotonia, upslanting palpebral fissures, hypertelorism and epicanthus was first thought to have Down syndrome; cytogenetic testing excluded it.
Show evidence (1 reference)
PMID:39431794 SUPPORT Human Clinical
"We first considered DS as a differential diagnosis based on the developmental delay with hypotonia and facial features, including an upslanted palpebral fissure, hypertelorism, epicanthus folds, and a low nose; however, it was ruled out after cytogenetic testing."
A documented case where Down syndrome was the working diagnosis.
🐁

Animal Models

2
Spen-null and neural crest-conditional Spen mouse
Homozygous Spen-null embryos develop cleft palate from defective palatal shelf elevation and extension; deleting Spen only in cranial neural crest delays palatal development. Rere and Spen interact genetically in palate development.
Species
Mouse
Genotype
Spen homozygous null; Spen conditional deletion in cranial neural crest
Publication
PMID:42456047
Pathograph links
Impaired Palatal Shelf Development partially recapitulates fidelity: moderate observes: tissue Reproduces a palatal shelf defect, and localizes it to neural crest-derived mesenchyme.
Limitations: The model is homozygous null, while patients are heterozygous. The model shows frank cleft palate, which in patients is only occasional, whereas the common human finding, a high or narrow palate, is not what the null mouse displays.
Divergences from the human mechanism
species mismatch qualifying
Palatogenesis timing and the degree of shelf delay that produces a cleft differ between mouse and human, so a cleft in the mouse does not predict a cleft in patients.
Show evidence (1 reference)
PMID:42456047 SUPPORT Model Organism
"We show that Spen-null embryos have abnormal palatal shelf elevation and extension leading to the development of cleft palate."
The model's palatal phenotype.
Spen-depleted Drosophila fat body
Spen depletion in Drosophila fat-storage cells increases fat and impairs energy liberation and beta-oxidation; dietary supplementation changes the outcome in a stage-dependent way.
Species
Fruit fly
Genotype
Spen knockdown in larval fat body
Publication
PMID:28640815
Pathograph links
Impaired Fat Mobilization and Fatty Acid Beta-Oxidation partially recapitulates fidelity: low observes: cellular Supplies the only mechanistic account of why SPEN loss might cause obesity.
Limitations: Invertebrate fat body, not mammalian adipose tissue; no human metabolic measurement exists to compare against, so the model's relevance to the obesity in this syndrome is unconfirmed.
Divergences from the human mechanism
species mismatch qualifying
The Drosophila fat body combines liver and adipose functions, so a fat-body storage defect cannot be assigned to one human tissue.
Show evidence (1 reference)
PMID:28640815 SUPPORT Model Organism
"Spen-depleted larvae had defects in energy liberation from stores, including starvation sensitivity and major changes in the levels of metabolic enzymes and metabolites, particularly those involved in β-oxidation."
The model's metabolic phenotype.
{ }

Source YAML

click to show 
name: Radio-Tartaglia Syndrome
creation_date: "2026-10-09T20:30:00Z"
description: >-
  Radio-Tartaglia syndrome (RATARS) is an autosomal dominant neurodevelopmental
  disorder caused by heterozygous truncating, loss-of-function variants in SPEN,
  a transcriptional repressor gene at 1p36 that lies just centromeric to the
  proximal 1p36 deletion critical region. It was defined in 2021 from 34
  individuals and overlaps clinically with proximal 1p36 deletion syndrome:
  developmental delay and intellectual disability, autism spectrum disorder,
  anxiety, aggression and attention deficit, hypotonia, brain and spine
  anomalies, congenital heart defects, a high or narrow palate, facial
  dysmorphism, and obesity or increased BMI that is more marked in females.
  Most variants arise de novo, but familial transmission with variable
  expressivity is documented. SPEN is the protein through which XIST RNA
  initiates silencing of one X chromosome, and affected females carry a
  distinctive X-chromosome DNA methylation episignature in blood; whether that
  epigenetic change contributes to the clinical features is not established.
category: Mendelian
disease_term:
  preferred_term: Radio-Tartaglia syndrome
  term:
    id: MONDO:0859143
    label: Radio-Tartaglia syndrome
synonyms:
- RATARS
- SPEN-related neurodevelopmental disorder
- SPEN haploinsufficiency syndrome
parents:
- neurodevelopmental disorder
- syndromic intellectual disability
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A single heterozygous truncating SPEN variant is sufficient. Most published
    variants arose de novo; transmission over three generations has been
    reported in a Chinese family, with milder disease in the transmitting
    grandmother than in her daughter, and a mother-daughter pair has been
    reported with a dystonia-predominant presentation.
  evidence:
  - reference: PMID:41574619
    reference_title: "Prenatal Diagnosis of Radio-Tartaglia Syndrome Caused by a Loss-of-Function Variant in SPEN in a Chinese Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radio-Tartaglia Syndrome (RATARS) is a rare autosomal dominant
      neurodevelopmental disorder caused by loss-of-function (LoF) variants in
      SPEN.
    explanation: >-
      States the dominant mode and the loss-of-function variant class directly.
  - reference: PMID:41574619
    reference_title: "Prenatal Diagnosis of Radio-Tartaglia Syndrome Caused by a Loss-of-Function Variant in SPEN in a Chinese Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sanger sequencing confirmed the authenticity of the variant and revealed
      that it was inherited from the mother of the pregnant woman.
    explanation: >-
      Transmission of a heterozygous SPEN frameshift from an affected parent to
      an affected child, and on to the fetus, is the segregation pattern of a
      dominant disorder.
  - reference: PMID:39431794
    reference_title: "Clinical Features of a Japanese Girl With Radio-Tartaglia Syndrome due to a SPEN Truncating Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a de novo heterozygous pathogenic variant of SPEN and
      diagnosed her with RATARS.
    explanation: >-
      A de novo heterozygous variant causing disease is consistent with
      dominant (haploinsufficient) inheritance.
prevalence:
- population: Published RATARS case literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The founding series described 34 individuals. Later single-family reports
    (Japan, China, Slovenia) add a handful of cases. No population-based
    prevalence or incidence estimate exists, and 34 is a case count, not a rate.
  evidence:
  - reference: PMID:39431794
    reference_title: "Clinical Features of a Japanese Girl With Radio-Tartaglia Syndrome due to a SPEN Truncating Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This syndrome is extremely rare, with only 34 cases reported to date.
    explanation: >-
      Gives the cumulative published case count at the time of the report.
pathophysiology:
- name: SPEN Haploinsufficiency
  biological_scale: MOLECULAR
  description: >-
    A heterozygous stop-gain or frameshift variant in SPEN (or, in a broader
    proximal 1p36 deletion, loss of one SPEN copy) halves the dose of SPEN
    protein. The founding series consisted entirely of truncating variants;
    reduced protein was inferred from variant class and was not measured
    variant by variant in patient cells.
  genes:
  - preferred_term: SPEN
    term:
      id: hgnc:17575
      label: SPEN
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    zygosity: HETEROZYGOUS
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we used clinical data from 34 individuals with truncating variants
      in SPEN to define a neurodevelopmental disorder presenting with features
      that overlap considerably with those of proximal del1p36 syndrome.
    explanation: >-
      The founding cohort is defined by heterozygous truncating SPEN variants.
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that SPEN is required for multiple developmental processes and
      SPEN haploinsufficiency is a major contributor to a disorder associated
      with deletions centromeric to the previously established 1p36 critical
      regions.
    explanation: >-
      Names haploinsufficiency as the disease mechanism.
  downstream:
  - target: Reduced SPEN-Mediated Transcriptional Repression
    causal_link_type: DIRECT
    description: >-
      SPEN is a transcriptional repressor, so halving its dose reduces the
      repressive activity it recruits to target genes.
    evidence:
    - reference: PMID:33596411
      reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        SPEN encodes a transcriptional repressor commonly deleted in proximal
        del1p36 syndrome and is located centromeric to the proximal 1p36
        critical region.
      explanation: >-
        Establishes the molecular function that a reduced dose diminishes.
  - target: Impaired XIST-SPEN-Mediated X Chromosome Silencing
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The X-silencing function of SPEN was established by complete loss of SPEN
      in mouse cells and embryos. Whether a single remaining SPEN copy is enough
      for normal X inactivation in human females has not been tested; the
      female X-chromosome methylation episignature is the only human
      observation pointing that way.
    evidence:
    - reference: PMID:33596411
      reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        providing further evidence of a specific contribution of the protein to
        the epigenetic control of this chromosome
      explanation: >-
        The authors read the female episignature as evidence that SPEN dosage
        matters for epigenetic control of the X chromosome in patients.
- name: Reduced SPEN-Mediated Transcriptional Repression
  biological_scale: MOLECULAR
  description: >-
    SPEN (also called SHARP or MINT) binds RNA through its RRM domains and, via
    its C-terminal SPOC domain, recruits the NCoR/SMRT co-repressor and HDAC3
    as well as NuRD, m6A and RNA polymerase II machinery. In mouse it also
    competes with the Notch intracellular domain for RBP-J and so dampens
    Notch-dependent transactivation. Which developmental target genes are
    de-repressed in RATARS patients is unknown.
  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
  - preferred_term: negative regulation of Notch signaling pathway
    modifier: DECREASED
    term:
      id: GO:0045746
      label: negative regulation of Notch signaling pathway
  genes:
  - preferred_term: SPEN
    term:
      id: hgnc:17575
      label: SPEN
  evidence:
  - reference: PMID:32025035
    reference_title: "SPEN integrates transcriptional and epigenetic control of X-inactivation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We identify the protein partners of SPOC, including NCoR/SMRT, the m6A
      RNA methylation machinery, the NuRD complex, RNA polymerase II and factors
      involved in the regulation of transcription initiation and elongation.
    explanation: >-
      Identifies the co-repressor and transcription machinery that SPEN
      recruits, the activity a reduced dose would diminish. Measured in mouse
      embryonic stem cells.
  - reference: PMID:12594956
    reference_title: "Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      We found that Msx2-interacting nuclear target protein (MINT) competed with
      the intracellular region of Notch for binding to a DNA binding protein
      RBP-J and suppressed the transactivation activity of Notch signaling.
    explanation: >-
      Shows the Notch-repressive activity of mouse SPEN (MINT). Indirect for
      this disease, since no Notch-pathway change has been measured in RATARS
      patients.
  downstream:
  - target: Abnormal Neurodevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      SPEN is needed for several developmental processes, but the de-repressed
      genes and the neural cell types that carry the defect in patients are not
      identified.
    evidence:
    - reference: PMID:33596411
      reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We conclude that SPEN is required for multiple developmental processes
      explanation: >-
        Supports SPEN dosage acting on development generally; the specific
        neural intermediates remain unresolved.
  - target: Impaired Palatal Shelf Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In the mouse, Spen loss reduces palatal mesenchyme proliferation and
      delays shelf elevation; Spen interacts genetically with the RERE
      co-repressor in this process. The transcriptional targets involved are
      not identified.
    evidence:
    - reference: PMID:42456047
      reference_title: "SPEN deficiency contributes to the development of orofacial clefts in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results suggest that SPEN is required for normal mammalian palatal
        development, that RERE and SPEN interact in a common pathway during
        palatal development
      explanation: >-
        Places SPEN, a transcriptional repressor, upstream of palatal
        development, in a pathway shared with another 1p36 co-repressor.
  - target: Impaired Fat Mobilization and Fatty Acid Beta-Oxidation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In Drosophila, Spen acts cell-autonomously in fat-storage cells to permit
      lipid mobilization, and mouse Spen transcript levels track body fat. This
      is a candidate explanation for the obesity in RATARS, not a demonstrated
      human mechanism.
    evidence:
    - reference: PMID:28640815
      reference_title: "An autonomous metabolic role for Spen."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        We find that manipulating Spen expression alters larval fat levels in a
        cell-autonomous manner.
      explanation: >-
        Fly evidence that Spen dosage controls fat storage; indirect for the
        human disease.
- name: Impaired XIST-SPEN-Mediated X Chromosome Silencing
  biological_scale: MOLECULAR
  description: >-
    XIST RNA recruits SPEN to the future inactive X through SPEN RRM4 and the
    XIST A-repeat; SPEN then recruits SMRT/HDAC3, histones are deacetylated and
    RNA polymerase II is excluded, initiating silencing. In mouse, SPEN is
    essential to initiate X inactivation but dispensable for its maintenance in
    neural progenitors, where it still dampens expression of escape genes. All
    of this comes from complete loss of SPEN; the effect of heterozygous loss
    on human X inactivation is untested.
  molecular_functions:
  - preferred_term: XIST lncRNA binding
    modifier: DECREASED
    term:
      id: GO:0106222
      label: lncRNA binding
  biological_processes:
  - preferred_term: dosage compensation by inactivation of X chromosome
    modifier: DECREASED
    term:
      id: GO:0009048
      label: dosage compensation by inactivation of X chromosome
  genes:
  - preferred_term: SPEN
    term:
      id: hgnc:17575
      label: SPEN
  evidence:
  - reference: PMID:25915022
    reference_title: "The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our results suggest that Xist silences transcription by directly
      interacting with SHARP, recruiting SMRT, activating HDAC3, and
      deacetylating histones to exclude Pol II across the X chromosome.
    explanation: >-
      Defines the XIST-SPEN-SMRT-HDAC3 silencing route in mouse embryonic stem
      cells.
  - reference: PMID:32025035
    reference_title: "SPEN integrates transcriptional and epigenetic control of X-inactivation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We show that SPEN is essential for initiating gene silencing on the X
      chromosome in preimplantation mouse embryos and in embryonic stem cells.
    explanation: >-
      Shows SPEN is required to initiate X silencing in vivo.
  - reference: PMID:32025035
    reference_title: "SPEN integrates transcriptional and epigenetic control of X-inactivation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      SPEN is dispensable for maintenance of XCI in neural progenitors,
      although it significantly decreases the expression of genes that escape
      XCI.
    explanation: >-
      Limits the claim: in neural progenitors SPEN is not needed to keep the X
      silent, but it does restrain escape genes, which is relevant to a
      neurodevelopmental disease.
  - reference: PMID:38164599
    reference_title: "Dissection of protein and RNA regions required for SPEN binding to XIST A-repeat RNA."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Binding of SPEN to XIST RNA requires RRM 4 of the protein, in contrast to
      the requirement of RRM 3 and RRM 4 for specific binding to SRA RNA.
    explanation: >-
      Maps the human SPEN domain that binds XIST, using purified human
      components.
  downstream:
  - target: Female X Chromosome DNA Methylation Episignature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The episignature is restricted to the X chromosome and to females, which
      is the pattern expected if SPEN dosage affects the epigenetic state of the
      inactive X. The link is inferred from that specificity; no study has
      measured X-inactivation skewing or escape-gene expression in patients.
    evidence:
    - reference: PMID:33596411
      reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Finally, we show that haploinsufficiency of SPEN is associated with a
        distinctive DNA methylation episignature of the X chromosome in affected
        females
      explanation: >-
        The observed female-specific, X-restricted methylation change is the
        downstream readout of this node.
- name: Female X Chromosome DNA Methylation Episignature
  biological_scale: MOLECULAR
  description: >-
    Peripheral-blood DNA from affected females shows a distinctive methylation
    pattern confined to the X chromosome. The founding paper describes it as an
    X chromosome-specific episignature that classifies the syndrome; it is a
    research-stage biomarker from a small number of females and is not reported
    for affected males. Whether it has any functional consequence for the
    clinical features, or explains any sex difference in presentation, is not
    known.
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, we show that haploinsufficiency of SPEN is associated with a
      distinctive DNA methylation episignature of the X chromosome in affected
      females
    explanation: >-
      Direct statement of the female X-chromosome episignature.
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a paradigm of an X chromosome-specific episignature that classifies
      syndromic traits
    explanation: >-
      The authors present the signature as a classifier, which is why it is
      recorded as a biomarker rather than as a cause of any phenotype.
- name: Abnormal Neurodevelopment
  biological_scale: TISSUE
  description: >-
    Altered development of the brain underlies the developmental delay,
    intellectual disability, behavioural and psychiatric features, hypotonia
    and the structural brain anomalies. Reported neuroimaging findings vary
    between individuals. The intermediate cell types and the genes that
    mediate the effect are unresolved.
  biological_processes:
  - preferred_term: central nervous system development
    modifier: ABNORMAL
    term:
      id: GO:0007417
      label: central nervous system development
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical profile of this disease includes developmental delay/intellectual
      disability, autism spectrum disorder, anxiety, aggressive behavior,
      attention deficit disorder, hypotonia, brain and spine anomalies
    explanation: >-
      The neurodevelopmental core of the clinical profile.
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Autism spectrum disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Anxiety
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Aggressive behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Attention deficit disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Brain anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Gait disturbance
    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: Motor stereotypy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal pyramidal signs
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Feeding difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred via hypotonia and oral-motor dysfunction; not studied directly.
- name: Impaired Palatal Shelf Development
  biological_scale: TISSUE
  description: >-
    In Spen-null mouse embryos, proliferation of mesenchymal cells in the
    medial palatal shelves is reduced at E13.5, delaying shelf elevation and
    extension and producing cleft palate; ablating Spen only in cranial neural
    crest cells delays palatal development. In people, a high or narrow palate
    is common and orofacial clefting occasional, and clefting is more frequent
    with 1p36 deletions removing both SPEN and RERE.
  biological_processes:
  - preferred_term: secondary palate development
    modifier: DECREASED
    term:
      id: GO:0062009
      label: secondary palate development
  - preferred_term: palatal mesenchymal cell proliferation
    modifier: DECREASED
    term:
      id: GO:0010463
      label: mesenchymal cell proliferation
  cell_types:
  - preferred_term: cranial neural crest cell
    term:
      id: CL:0000008
      label: migratory cranial neural crest cell
  evidence:
  - reference: PMID:42456047
    reference_title: "SPEN deficiency contributes to the development of orofacial clefts in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mesenchymal cell proliferation in the medial halves of the palatal shelves
      of Spen-null embryos at E13.5 is significantly reduced.
    explanation: >-
      Identifies the cellular defect behind the palatal phenotype in the mouse.
  - reference: PMID:42456047
    reference_title: "SPEN deficiency contributes to the development of orofacial clefts in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Tissue specific ablation of Spen in the cranial neural crest cells results
      in delayed palatal development.
    explanation: >-
      Localizes the requirement to cranial neural crest-derived cells.
  downstream:
  - target: High narrow palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred: the mouse shows delayed shelf elevation, and the common human
      palatal anomaly is a high or narrow palate rather than a cleft.
  - target: Orofacial cleft
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42456047
      reference_title: "SPEN deficiency contributes to the development of orofacial clefts in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We show that Spen-null embryos have abnormal palatal shelf elevation and
        extension leading to the development of cleft palate.
      explanation: >-
        Shows the shelf defect producing cleft palate, in homozygous null mice.
- name: Impaired Fat Mobilization and Fatty Acid Beta-Oxidation
  biological_scale: CELLULAR
  description: >-
    Spen-depleted Drosophila fat-body cells store excess fat and fail to
    liberate it, with starvation sensitivity and changes in beta-oxidation
    enzymes and metabolites; diet alters these effects. A matching human
    metabolic signature has not been looked for. This node is a model-derived
    candidate explanation for the obesity and raised BMI in RATARS.
  biological_processes:
  - preferred_term: fatty acid beta-oxidation
    modifier: DECREASED
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
  evidence:
  - reference: PMID:28640815
    reference_title: "An autonomous metabolic role for Spen."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Spen-depleted larvae had defects in energy liberation from stores,
      including starvation sensitivity and major changes in the levels of
      metabolic enzymes and metabolites, particularly those involved in
      β-oxidation.
    explanation: >-
      Fly evidence for the impaired-mobilization mechanism; indirect for
      humans.
  - reference: PMID:32107279
    reference_title: "Gene-Diet Interactions: Dietary Rescue of Metabolic Effects in spen-Depleted Drosophila melanogaster."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Lipid catabolism is impaired in Spen-deficient fat storage cells,
      accompanied by a compensatory increase in glycolytic flux and protein
      catabolism.
    explanation: >-
      Follow-up from the same group restating the catabolic defect.
  downstream:
  - target: Obesity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hypothesised: a fat-mobilization defect would favour fat accumulation,
      but this has not been shown in patients or mammals.
    evidence:
    - reference: PMID:28640815
      reference_title: "An autonomous metabolic role for Spen."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Finally, mouse Spen and Spenito transcript levels scaled directly with
        body fat in vivo, suggesting a conserved role in fat liberation and
        catabolism.
      explanation: >-
        The mammalian link is a correlation in mouse, so the edge to human
        obesity is a hypothesis.
genetic:
- name: SPEN
  gene_term:
    preferred_term: SPEN
    term:
      id: hgnc:17575
      label: SPEN
  presence: PRESENT
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    No ClinGen gene-disease validity record for SPEN and this disease is in the
    repository's reference cache, so gene_disease_validity is left absent (not
    classified, rather than classified as anything). All defining variants are
    truncating; a missense or inherited variant of uncertain significance
    should not be assumed causal (see the phenotype-expansion knowledge gap).
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  variants:
  - name: NM_015001.3:c.6223_6227del p.(Ser2075GlufsTer46)
    description: >-
      Recurrent frameshift; present in the founding series and found de novo in
      a Japanese girl whose facial features first suggested Down syndrome.
    clinical_significance: PATHOGENIC
    type: frameshift_variant
    evidence:
    - reference: PMID:39431794
      reference_title: "Clinical Features of a Japanese Girl With Radio-Tartaglia Syndrome due to a SPEN Truncating Variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We performed trio-based whole exome sequencing and identified a
        recurrent pathogenic variant of SPEN:NM_015001.3:c.6223_6227del,
        p.(Ser2075GlufsTer46).
      explanation: >-
        Names the variant, its recurrence and its pathogenic classification.
  - name: c.2417_2418dup p.(Arg807Aspfs*3)
    description: >-
      Frameshift transmitted across three generations of a Chinese family, with
      a milder phenotype in the grandmother than in her daughter; detected
      prenatally in the fetus.
    clinical_significance: PATHOGENIC
    type: frameshift_variant
    evidence:
    - reference: PMID:41574619
      reference_title: "Prenatal Diagnosis of Radio-Tartaglia Syndrome Caused by a Loss-of-Function Variant in SPEN in a Chinese Family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        WES identified a previously unreported heterozygous frameshift variant
        (c.2417_2418dup, p.Arg807Aspfs*3) in the SPEN gene.
      explanation: >-
        Reports the variant in the affected proband.
  - name: NM_015001.3:c.2170C>T p.(Arg724*)
    description: >-
      Stop-gain found in a mother and daughter with cervical and upper-limb
      dystonia; classified likely pathogenic by the reporting authors (PVS1,
      PM2).
    clinical_significance: LIKELY_PATHOGENIC
    type: stop_gained
    evidence:
    - reference: PMID:41525714
      reference_title: "Two Cases of SPEN Haploinsufficiency Presenting with Dystonia: Expanding the Genotype and Phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This approach identified a heterozygous likely pathogenic stop‐gain
        variant in SPEN (NM_015001.3: c.2170C>T, p.Arg724*).
      explanation: >-
        Reports the variant and its classification.
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we used clinical data from 34 individuals with truncating variants
      in SPEN to define a neurodevelopmental disorder presenting with features
      that overlap considerably with those of proximal del1p36 syndrome.
    explanation: >-
      The founding gene-disease association.
  - reference: PMID:39431794
    reference_title: "Clinical Features of a Japanese Girl With Radio-Tartaglia Syndrome due to a SPEN Truncating Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radio-Tartaglia syndrome (RATARS) (MIM#619312) is a genetic disorder
      caused by heterozygous truncating variants of SPEN on chromosome 1p36.
    explanation: >-
      Independent restatement of the causal gene and variant class.
phenotypes:
- category: Neurodevelopmental
  name: Global developmental delay
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical profile of this disease includes developmental delay/intellectual
      disability
    explanation: >-
      Developmental delay heads the clinical profile.
  - reference: PMID:39431794
    reference_title: "Clinical Features of a Japanese Girl With Radio-Tartaglia Syndrome due to a SPEN Truncating Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RATARS is characterized by developmental delay, hypotonia, and
      intellectual disability.
    explanation: >-
      Restates developmental delay as a defining feature.
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Global developmental delay + 32/33 (97) Intellectual disability + 23/24 (96)
    explanation: >-
      Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 32 of 33 had global developmental delay.
- category: Neurodevelopmental
  name: Intellectual disability
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:39431794
    reference_title: "Clinical Features of a Japanese Girl With Radio-Tartaglia Syndrome due to a SPEN Truncating Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RATARS is characterized by developmental delay, hypotonia, and
      intellectual disability.
    explanation: >-
      Intellectual disability is a defining feature.
  - reference: PMID:41574619
    reference_title: "Prenatal Diagnosis of Radio-Tartaglia Syndrome Caused by a Loss-of-Function Variant in SPEN in a Chinese Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared to the proband, the mother has a milder phenotype, mainly
      manifested as mild ID.
    explanation: >-
      Shows the range of severity within one family carrying the same variant,
      moderate in the proband and mild in her mother.
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Global developmental delay + 32/33 (97) Intellectual disability + 23/24 (96)
    explanation: >-
      Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 23 of 24 assessed had intellectual disability.
- category: Behavioral
  name: Autism spectrum disorder
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Autism spectrum disorder
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical profile of this disease includes developmental delay/intellectual
      disability, autism spectrum disorder
    explanation: >-
      Autism spectrum disorder is listed in the clinical profile.
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Aggressive behavior – 18/29 (62) Autism spectrum disorder – 18/28 (64)
    explanation: >-
      Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 18 of 28 assessed had autism spectrum disorder.
- category: Behavioral
  name: Anxiety
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      autism spectrum disorder, anxiety, aggressive behavior, attention deficit
      disorder
    explanation: >-
      Anxiety is listed in the clinical profile.
- category: Behavioral
  name: Aggressive behavior
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      autism spectrum disorder, anxiety, aggressive behavior, attention deficit
      disorder
    explanation: >-
      Aggressive behavior is listed in the clinical profile.
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Aggressive behavior – 18/29 (62) Autism spectrum disorder – 18/28 (64)
    explanation: >-
      Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 18 of 29 assessed had aggressive behavior.
- category: Behavioral
  name: Attention deficit disorder
  phenotype_term:
    preferred_term: Attention deficit disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      autism spectrum disorder, anxiety, aggressive behavior, attention deficit
      disorder
    explanation: >-
      Attention deficit disorder is listed in the clinical profile. The source
      wording is kept in preferred_term; the bound HPO term is the
      attention-deficit hyperactivity disorder class.
- category: Neuromuscular
  name: Hypotonia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:39431794
    reference_title: "Clinical Features of a Japanese Girl With Radio-Tartaglia Syndrome due to a SPEN Truncating Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RATARS is characterized by developmental delay, hypotonia, and
      intellectual disability.
    explanation: >-
      Hypotonia is a defining feature.
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Hypotonia + 22/30 (73) Seizures – 3/32 (9)
    explanation: >-
      Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 22 of 30 had hypotonia.
- category: Neurological
  name: Brain anomalies
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Brain anomalies
    term:
      id: HP:0012443
      label: Abnormal brain morphology
  description: >-
    The founding paper reports brain and spine anomalies without, in its
    abstract, naming a characteristic lesion; imaging findings vary between
    individuals and some patients have a normal brain MRI.
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      attention deficit disorder, hypotonia, brain and spine anomalies,
      congenital heart defects
    explanation: >-
      Brain anomalies are part of the clinical profile.
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Hemiparesis – 2/28 (7) Brain anomalies + 14/22 (64)
    explanation: >-
      Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 14 of 22 imaged individuals had a brain anomaly, a selected imaged denominator.
- category: Neurological
  name: Gait disturbance
  phenotype_term:
    preferred_term: Gait abnormalities
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: PMID:41574619
    reference_title: "Prenatal Diagnosis of Radio-Tartaglia Syndrome Caused by a Loss-of-Function Variant in SPEN in a Chinese Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 22-year-old pregnant woman presented with neurodevelopmental defects
      including moderate intellectual disability (ID) and hypotonia, gait
      abnormalities, behavioural problems, kyphosis and dysmorphic facial
      features.
    explanation: >-
      Gait abnormality reported in an affected adult.
- category: Neurological
  name: Dystonia
  phenotype_term:
    preferred_term: Cervical and upper-limb dystonia with dystonic tremor
    term:
      id: HP:0001332
      label: Dystonia
  description: >-
    Reported so far in one family: a mother with cervical dystonia, dystonic
    head tremor and upper-limb dystonic tremor, and her daughter with milder
    upper-limb dystonia. The authors note dystonia had not been reported before
    in this syndrome.
  evidence:
  - reference: PMID:41525714
    reference_title: "Two Cases of SPEN Haploinsufficiency Presenting with Dystonia: Expanding the Genotype and Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We hereby describe a mother and a daughter with a novel SPEN variant
      leading to haploinsufficiency presenting with cervical dystonia and
      dystonic head and upper limb tremor.
    explanation: >-
      Direct report of dystonia in two related carriers of a truncating SPEN
      variant.
- category: Cardiovascular
  name: Congenital heart defect
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      attention deficit disorder, hypotonia, brain and spine anomalies,
      congenital heart defects
    explanation: >-
      Congenital heart defects are part of the clinical profile; the abstract
      names no specific lesion, so the general CHD term is bound.
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Congenital heart defect +, Secundum ASD 8/29 (28)
    explanation: >-
      Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 8 of 29 had a congenital heart defect.
- category: Craniofacial
  name: High narrow palate
  frequency: FREQUENT
  phenotype_term:
    preferred_term: High/narrow palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      congenital heart defects, high/narrow palate, facial dysmorphisms
    explanation: >-
      High or narrow palate is part of the clinical profile.
  - reference: PMID:42456047
    reference_title: "SPEN deficiency contributes to the development of orofacial clefts in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Haploinsufficiency of SPEN, a 1p36 gene that encodes a transcriptional
      repressor, causes Radio-Tartaglia syndrome, a neurodevelopmental syndrome
      in which high/narrow palates are common, and OFC is occasionally observed.
    explanation: >-
      "Common" supports the FREQUENT band; no count is given in the abstract.
- category: Craniofacial
  name: Orofacial cleft
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Orofacial cleft
    term:
      id: HP:0000202
      label: Orofacial cleft
  evidence:
  - reference: PMID:42456047
    reference_title: "SPEN deficiency contributes to the development of orofacial clefts in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Haploinsufficiency of SPEN, a 1p36 gene that encodes a transcriptional
      repressor, causes Radio-Tartaglia syndrome, a neurodevelopmental syndrome
      in which high/narrow palates are common, and OFC is occasionally observed.
    explanation: >-
      "Occasionally observed" supports the OCCASIONAL band; the abstract does
      not say whether the clefts involve lip, palate or both, so the general
      orofacial cleft term is bound.
- category: Craniofacial
  name: Facial dysmorphism
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  description: >-
    The gestalt overlaps proximal 1p36 deletion syndrome; one reported girl had
    upslanting palpebral fissures, hypertelorism, epicanthus and a low nose that
    first suggested Down syndrome.
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      congenital heart defects, high/narrow palate, facial dysmorphisms
    explanation: >-
      Facial dysmorphism is part of the clinical profile.
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Pregnancy history complication - 19/34 (56) Craniofacial dysmorphism + 28/31 (90)
    explanation: >-
      Counts from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 28 of 31 had craniofacial dysmorphism.
- category: Musculoskeletal
  name: Kyphosis
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
  evidence:
  - reference: PMID:41574619
    reference_title: "Prenatal Diagnosis of Radio-Tartaglia Syndrome Caused by a Loss-of-Function Variant in SPEN in a Chinese Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 22-year-old pregnant woman presented with neurodevelopmental defects
      including moderate intellectual disability (ID) and hypotonia, gait
      abnormalities, behavioural problems, kyphosis and dysmorphic facial
      features.
    explanation: >-
      Kyphosis reported in an affected adult.
- category: Metabolic
  name: Obesity
  phenotype_term:
    preferred_term: Obesity/increased BMI, especially in females
    term:
      id: HP:0001513
      label: Obesity
  description: >-
    The founding paper reports obesity or increased BMI, more marked in
    affected females. The sex bias is stated in the abstract; the counts behind
    it are not, so no frequency is recorded.
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      facial dysmorphisms, and obesity/increased BMI, especially in females
    explanation: >-
      States the phenotype and its female predominance.
- category: Neurodevelopmental
  name: Delayed speech and language development
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Language delay
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Delayed fine motor skills + 23/24 (96) Language delay + 31/32 (97)
    explanation: >-
      Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 31 of 32 had language delay.
- category: Neurodevelopmental
  name: Motor delay
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed gross and fine motor skills
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Delayed gross motor skills + 26/30 (87) Delayed fine motor skills + 23/24 (96)
    explanation: >-
      Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 26 of 30 had delayed gross motor and 23 of 24 delayed fine motor skills.
- category: Behavioral
  name: Motor stereotypy
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Stereotypic behavior
    term:
      id: HP:0000733
      label: Motor stereotypy
  evidence:
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Autism spectrum disorder – 18/28 (64) Stereotypic behavior – 13/28 (46)
    explanation: >-
      Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 13 of 28 had stereotypic behavior.
- category: Neurological
  name: Seizure
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Hypotonia + 22/30 (73) Seizures – 3/32 (9)
    explanation: >-
      Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 3 of 32 had seizures, so epilepsy is uncommon, unlike in distal 1p36 deletion syndrome.
- category: Gastrointestinal
  name: Feeding difficulties
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Feeding/swallowing problems
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Feeding/swallowing problems +, Epiglottic malacia 8/30 (27)
    explanation: >-
      Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 8 of 30 had feeding or swallowing problems; the Korean boy needed fundoplication and gastrostomy.
- category: Ophthalmological
  name: Strabismus
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Exotropia/strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Exotropia/strabismus +, Exotropia 6/30 (20) Myopia - 6/30 (20)
    explanation: >-
      Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 6 of 30 had exotropia or strabismus.
- category: Ophthalmological
  name: Myopia
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Exotropia 6/30 (20) Myopia - 6/30 (20)
    explanation: >-
      Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 6 of 30 had myopia.
- category: Musculoskeletal
  name: Brachydactyly
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Brachydactyly - 5/30 (17) Toes abnormalities - 4/27 (15)
    explanation: >-
      Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 5 of 30 had brachydactyly.
- category: Musculoskeletal
  name: Scoliosis
  frequency: OCCASIONAL
  description: >-
    The source counts scoliosis and kyphosis together; kyphosis reported in a later family is recorded separately.
  phenotype_term:
    preferred_term: Scoliosis/kyphosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Toes abnormalities - 4/27 (15) Scoliosis/kyphosis +, Scoliosis 5/28 (18)
    explanation: >-
      Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 5 of 28 had scoliosis or kyphosis; the source does not split the two, so the count is an upper bound for scoliosis alone.
- category: Auditory
  name: Hearing impairment
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hearing loss
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Epiglottic malacia 8/30 (27) Hearing loss - 3/31 (10)
    explanation: >-
      Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 3 of 31 had hearing loss.
- category: Gastrointestinal
  name: Gastrointestinal features
  frequency: FREQUENT
  description: >-
    The source counts any gastrointestinal feature together; its footnote gives
    gastro-oesophageal reflux and constipation as examples without separate
    counts. Kept apart from feeding and swallowing problems, which the same
    table counts separately (8/30).
  phenotype_term:
    preferred_term: Gastrointestinal features (reflux, constipation)
    term:
      id: HP:0011024
      label: Abnormality of the gastrointestinal tract
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Congenital heart defect +, Secundum ASD 8/29 (28) Gastrointestinal
      feature +, Gastrostomy feeding 13/31 (42)
    explanation: >-
      Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 13 of 31 had a gastrointestinal feature.
- category: Neurological
  name: Abnormal pyramidal signs
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormal pyramidal signs
    term:
      id: HP:0007256
      label: Abnormal pyramidal sign
  evidence:
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Seizures – 3/32 (9) Abnormal pyramidal signs – 6/24 (25)
    explanation: >-
      Count from the founding Radio et al. series as re-tabulated in this paper's Table 2 (positives over individuals assessed for the feature); 6 of 24 assessed had abnormal pyramidal signs.
diagnosis:
- name: Exome or genome sequencing
  description: >-
    The diagnosis is molecular: identification of a heterozygous truncating
    SPEN variant. Chromosomal microarray detects 1p36 deletions but not the
    sequence-level truncations that cause most cases, and the clinical picture
    can resemble other conditions, so exome or genome sequencing (trio where
    possible) is the effective test.
  evidence:
  - reference: PMID:39431794
    reference_title: "Clinical Features of a Japanese Girl With Radio-Tartaglia Syndrome due to a SPEN Truncating Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microarray analysis revealed no pathogenic aberrations. We performed
      trio-based whole exome sequencing and identified a recurrent pathogenic
      variant
    explanation: >-
      Microarray was uninformative and trio exome sequencing made the
      diagnosis.
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 3-year-old boy was brought to the hospital and underwent whole genome
      sequencing to evaluate developmental delay and multiple anomalies. This
      led to the identification of a de novo truncating variant in SPEN.
    explanation: >-
      A second independent diagnosis made by genome sequencing.
- name: Prenatal genetic testing in families with a known variant
  description: >-
    Where a familial SPEN variant is known, it can be tested for prenatally by
    amniocentesis; fetal ultrasound may be unremarkable.
  evidence:
  - reference: PMID:41574619
    reference_title: "Prenatal Diagnosis of Radio-Tartaglia Syndrome Caused by a Loss-of-Function Variant in SPEN in a Chinese Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prenatal ultrasonography during pregnancy revealed no obvious structural
      abnormalities. However, prenatal genetic testing revealed the foetus
      harboured the same SPEN pathogenic variant.
    explanation: >-
      Ultrasound was normal and genetic testing was what identified the
      affected fetus.
- name: X-chromosome DNA methylation episignature (research)
  description: >-
    In affected females a blood DNA methylation episignature restricted to the
    X chromosome distinguishes cases. It is a research-stage classifier derived
    from a small number of females, not reported for males, and not a validated
    stand-alone clinical test.
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a paradigm of an X chromosome-specific episignature that classifies
      syndromic traits
    explanation: >-
      The authors present the episignature as a classifier.
differential_diagnoses:
- name: Proximal 1p36 deletion syndrome
  description: >-
    The phenotype overlaps considerably with proximal 1p36 deletion syndrome,
    and SPEN is commonly deleted in it; it also overlaps with distal 1p36
    deletions that spare SPEN. Chromosomal microarray separates a
    multigene deletion from an intragenic SPEN variant; deletions removing both
    SPEN and RERE carry a higher rate of orofacial clefting.
  evidence:
  - reference: PMID:33596411
    reference_title: "SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we used clinical data from 34 individuals with truncating variants
      in SPEN to define a neurodevelopmental disorder presenting with features
      that overlap considerably with those of proximal del1p36 syndrome.
    explanation: >-
      States the clinical overlap that makes this the main differential.
  - reference: DOI:10.26815/acn.2024.00717
    reference_title: "Identification of De Novo Radio-Tartaglia Syndrome and Comparison of Clinical and Molecular Characteristics with Those of 1p36 Deletion Syndrome"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, in all reported Korean cases of 1p36DS, the deletions were
      distal and did not involve SPEN; despite this, the clinical features of
      the disorder overlap considerably with those of RTS.
    explanation: >-
      The overlap extends to distal 1p36 deletions that spare SPEN, so a 1p36
      phenotype does not by itself implicate SPEN; molecular testing is needed.
- name: Down syndrome
  description: >-
    One reported girl with developmental delay, hypotonia, upslanting
    palpebral fissures, hypertelorism and epicanthus was first thought to have
    Down syndrome; cytogenetic testing excluded it.
  evidence:
  - reference: PMID:39431794
    reference_title: "Clinical Features of a Japanese Girl With Radio-Tartaglia Syndrome due to a SPEN Truncating Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We first considered DS as a differential diagnosis based on the
      developmental delay with hypotonia and facial features, including an
      upslanted palpebral fissure, hypertelorism, epicanthus folds, and a low
      nose; however, it was ruled out after cytogenetic testing.
    explanation: >-
      A documented case where Down syndrome was the working diagnosis.
treatments:
- name: Clonazepam for dystonia
  description: >-
    Oral clonazepam given for dystonia in one adult patient, together with
    botulinum toxin injections (and escitalopram for psychiatric symptoms); the
    report describes some reduction of symptoms at follow-up. There is no
    disease-modifying treatment for this syndrome; management is otherwise
    supportive and directed at the individual's developmental, behavioural,
    cardiac and feeding needs.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: clonazepam
      term:
        id: CHEBI:3756
        label: clonazepam
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Dystonia
  evidence:
  - reference: PMID:41525714
    reference_title: "Two Cases of SPEN Haploinsufficiency Presenting with Dystonia: Expanding the Genotype and Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment included clonazepam and botulinum toxin injections for the
      dystonia and escitalopram for the psychiatric symptoms, with some
      reduction of the symptoms at follow‐up.
    explanation: >-
      Single-patient report in which clonazepam and botulinum toxin were given
      together; the benefit cannot be attributed to either agent alone, and
      this is not a controlled result.
- name: Botulinum toxin injections for dystonia
  description: >-
    Botulinum toxin injections for cervical and upper-limb dystonia in the same
    single adult patient, given together with clonazepam; some reduction of
    symptoms at follow-up.
  notes: >-
    therapeutic_agent is left unbound. The report says "botulinum toxin"
    without a serotype; CHEBI codes only type A (CHEBI:3160), and NCIT's
    generic NCIT:C163032 Botulinum Toxin is outside the ChemicalEntityTerm
    roots, so the only bindable agent would assert a serotype the source does
    not give. therapeutic_modality is OTHER because the toxin is a large
    bacterial protein, neither a small molecule nor a peptide.
  treatment_term:
    preferred_term: Botulinum toxin therapy
    term:
      id: NCIT:C157775
      label: Botulinum Toxin Therapy
  therapeutic_modality: OTHER
  target_mechanisms:
  - target: Dystonia
  evidence:
  - reference: PMID:41525714
    reference_title: "Two Cases of SPEN Haploinsufficiency Presenting with Dystonia: Expanding the Genotype and Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment included clonazepam and botulinum toxin injections for the
      dystonia and escitalopram for the psychiatric symptoms, with some
      reduction of the symptoms at follow‐up.
    explanation: >-
      Single-patient report in which clonazepam and botulinum toxin were given
      together; the benefit cannot be attributed to either agent alone, and
      this is not a controlled result.
animal_models:
- name: Spen-null and neural crest-conditional Spen mouse
  species: Mouse
  genotype: Spen homozygous null; Spen conditional deletion in cranial neural crest
  publication: PMID:42456047
  description: >-
    Homozygous Spen-null embryos develop cleft palate from defective palatal
    shelf elevation and extension; deleting Spen only in cranial neural crest
    delays palatal development. Rere and Spen interact genetically in palate
    development.
  modeled_mechanisms:
  - target: Impaired Palatal Shelf Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reproduces a palatal shelf defect, and localizes it to neural
      crest-derived mesenchyme.
    limitations: >-
      The model is homozygous null, while patients are heterozygous. The model
      shows frank cleft palate, which in patients is only occasional, whereas
      the common human finding, a high or narrow palate, is not what the null
      mouse displays.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Palatogenesis timing and the degree of shelf delay that produces a
        cleft differ between mouse and human, so a cleft in the mouse does not
        predict a cleft in patients.
    evidence:
    - reference: PMID:42456047
      reference_title: "SPEN deficiency contributes to the development of orofacial clefts in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We show that Spen-null embryos have abnormal palatal shelf elevation and
        extension leading to the development of cleft palate.
      explanation: >-
        The model's palatal phenotype.
- name: Spen-depleted Drosophila fat body
  species: Fruit fly
  genotype: Spen knockdown in larval fat body
  publication: PMID:28640815
  description: >-
    Spen depletion in Drosophila fat-storage cells increases fat and impairs
    energy liberation and beta-oxidation; dietary supplementation changes the
    outcome in a stage-dependent way.
  modeled_mechanisms:
  - target: Impaired Fat Mobilization and Fatty Acid Beta-Oxidation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Supplies the only mechanistic account of why SPEN loss might cause
      obesity.
    limitations: >-
      Invertebrate fat body, not mammalian adipose tissue; no human metabolic
      measurement exists to compare against, so the model's relevance to the
      obesity in this syndrome is unconfirmed.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The Drosophila fat body combines liver and adipose functions, so a
        fat-body storage defect cannot be assigned to one human tissue.
    evidence:
    - reference: PMID:28640815
      reference_title: "An autonomous metabolic role for Spen."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Spen-depleted larvae had defects in energy liberation from stores,
        including starvation sensitivity and major changes in the levels of
        metabolic enzymes and metabolites, particularly those involved in
        β-oxidation.
      explanation: >-
        The model's metabolic phenotype.
discussions:
- discussion_id: ratars_x_episignature_function
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does heterozygous SPEN loss disturb X-chromosome inactivation in human
    females, and does the female X-chromosome methylation episignature have any
    consequence for the clinical features or for sex differences such as the
    female predominance of obesity?
  attaches_to:
  - pathophysiology#Female X Chromosome DNA Methylation Episignature
  - pathophysiology#Impaired XIST-SPEN-Mediated X Chromosome Silencing
  rationale: >-
    The X-silencing role of SPEN was shown with complete loss in mouse embryos
    and stem cells, and in neural progenitors SPEN is not needed to maintain
    silencing. Patients keep one functional copy. The episignature is the only
    human observation, measured in blood, and no study has measured
    X-inactivation skewing or escape-gene expression in patient cells.
  status: OPEN
  evidence:
  - reference: PMID:32025035
    reference_title: "SPEN integrates transcriptional and epigenetic control of X-inactivation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      SPEN is dispensable for maintenance of XCI in neural progenitors,
      although it significantly decreases the expression of genes that escape
      XCI.
    explanation: >-
      The model evidence is for complete loss and shows a maintenance role
      limited to escape genes, which leaves the human haploinsufficient case
      open.
- discussion_id: ratars_obesity_mechanism
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Is the obesity and raised BMI of this syndrome caused by the
    fat-mobilization defect seen in Spen-depleted Drosophila, or by a central
    (hypothalamic or behavioural) mechanism that the fly model cannot
    represent?
  attaches_to:
  - pathophysiology#Impaired Fat Mobilization and Fatty Acid Beta-Oxidation
  - phenotypes#Obesity
  rationale: >-
    The only mechanistic evidence comes from invertebrate fat-storage cells and
    a body-fat correlation in mouse. No human metabolic, lipidomic or
    energy-expenditure study exists, and the female predominance of obesity in
    patients is unexplained.
  status: OPEN
  evidence:
  - reference: PMID:28640815
    reference_title: "An autonomous metabolic role for Spen."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Finally, mouse Spen and Spenito transcript levels scaled directly with
      body fat in vivo, suggesting a conserved role in fat liberation and
      catabolism.
    explanation: >-
      The mammalian link is correlational, which is why the human mechanism is
      open.
- discussion_id: ratars_phenotype_expansion
  kind: KNOWLEDGE_GAP
  prompt: >-
    Are dystonia and sensorineural hearing loss part of the SPEN-related
    spectrum, or coincidental findings in single families?
  attaches_to:
  - phenotypes#Dystonia
  - genetic#SPEN
  rationale: >-
    Dystonia is reported in one mother-daughter pair whose other relatives with
    tremor were not tested. Hearing loss occurred in 3 of 31 of the founding
    series, but severe congenital sensorineural hearing loss in a premature boy
    carrying a SPEN variant of uncertain significance, inherited from a healthy
    father, cannot be attributed to this syndrome. Both need further cases.
  status: OPEN
  evidence:
  - reference: PMID:40529391
    reference_title: "Syndromic congenital hypoacusis associated with premature birth and a variant of the SPEN gene: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      who possessed a novel variant of the SPEN gene (discovered by whole exome
      sequencing), which was inherited from a healthy father, and severe
      congenital bilateral sensorineural hearing loss. This SPEN gene variant
      was classified as having unknown significance.
    explanation: >-
      The variant is inherited from an unaffected parent and of uncertain
      significance, so this case is not counted toward the Hearing impairment
      phenotype, which rests on the founding series alone.
  - reference: PMID:41525714
    reference_title: "Two Cases of SPEN Haploinsufficiency Presenting with Dystonia: Expanding the Genotype and Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While dystonia can be idiopathic or associated with other neurological
      disorders, it has never been reported in patients with SPEN
      haploinsufficiency and RTS.
    explanation: >-
      The authors themselves flag dystonia as a single-family finding.
external_assertions:
- name: OMIM Radio-Tartaglia syndrome entry
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:619312
  url: https://omim.org/entry/619312
  description: >-
    OMIM phenotype entry, as cited (MIM#619312) in PMID:39431794. Recorded as
    an identifier only.
notes: >-
  No GeneReviews chapter exists for this disease (PubMed searches for
  "Radio-Tartaglia syndrome" and for SPEN restricted to genereviews[book]
  returned no records).

  The cached record of the founding 34-person paper (PMID:33596411) is
  abstract-only. Phenotype frequency bands are taken from Table 2 of the
  Korean case report (DOI:10.26815/acn.2024.00717), which re-tabulates the
  founding series' counts with denominators of individuals assessed; those
  evidence items carry quote_role BACKGROUND because the counts were produced
  by the earlier study. Frequencies for features not in that table are left
  unset.
📚

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: Radio-Tartaglia_Syndrome · 2026-10-09T21:23:27Z · View source

New entry for Radio-Tartaglia syndrome (MONDO:0859143; SPEN, hgnc:17575). Deep-research source: the Perplexity report in research/ (reference validation 12/13 resolved). The one unresolved reference, DOI:10.1371/journal.pgen.1008333&type=printable, is a malformed URL fragment; the underlying DOI resolves via eutils to PMID:31537017, a general Xist review, which was not cited because primary papers (PMID:25915022, PMID:32025035, PMID:38164599) support the same XIST-SPEN claims. Report items without a quotable PubMed or DOI source (OMIM/Orphanet/ClinVar/panel pages, neural conditional knockout mouse brain phenotype) were not used. preflight-dr could not run (no local mondo.db); the report was checked manually and is consistently about SPEN/RATARS. Founding paper PMID:33596411 is cached abstract-only, so phenotype frequency bands come from Table 2 of DOI:10.26815/acn.2024.00717, which re-tabulates the founding cohort's counts; those items carry quote_role BACKGROUND. The female X-chromosome DNA methylation episignature is recorded as a biomarker node with an inferred edge from impaired XIST-SPEN silencing, using only what the abstract states; its functional consequence is a KNOWLEDGE_GAP. Obesity mechanism is a fly-model hypothesis (HUMAN_MODEL_MISMATCH). Hearing loss from a VUS case (PMID:40529391) is a discussion, not a phenotype. No GeneReviews chapter (PubMed genereviews[book] and just check-genereviews: NO_CHAPTER). No ClinGen record cached, so gene_disease_validity absent. Validation: validate-disorders passed, 84/84 snippets verified, terms passed, entity refs, causal targets, coarse phenotypes, snippet ratchets clean; 18/26 phenotypes causally connected. In self-review, five downstream edges from Reduced SPEN-Mediated Transcriptional Repression (to congenital heart defect, facial dysmorphism, kyphosis, scoliosis and brachydactyly) were removed because no source specifies a mechanism for them; those phenotypes, plus strabismus, myopia and hearing impairment, are deliberately left unconnected.

Perplexity ▸
Radio–Tartaglia syndrome: disease-characteristics research report
sonar-deep-research 55 citations 2026-10-09T20:59:35.928708

Radio–Tartaglia syndrome: disease-characteristics research report

Radio–Tartaglia syndrome (RATARS; MONDO:0859143) is a rare, autosomal-dominant, SPEN-related neurodevelopmental disorder. Its best-established molecular cause is a heterozygous truncating SPEN variant consistent with haploinsufficiency. Developmental and speech delay, intellectual disability, hypotonia, behavioral differences, and variable congenital anomalies define the clinical picture. The principal human evidence remains a study of 34 affected individuals from 33 families; consequently, many frequencies below are observations among assessed people, not population estimates. [63][27][16][2]

Evidence convention. “Human” denotes affected-person observations; “mouse,” “fly,” and “in vitro” denote experimental evidence that must not be treated as proof of the corresponding mechanism or treatment effect in patients. Percentages retain their published denominators. This is an aggregated disease-level report, not an individual-patient EHR extract. [16][31]

1. Disease information and identifiers

Identifier or name Value and interpretation
Preferred name Radio–Tartaglia syndrome; abbreviation RATARS. [2]
Alternative name SPEN-related neurodevelopmental disorder. SHARP and MINT are names for the protein, not separate disease names. [63][44]
MONDO MONDO:0859143. [63]
OMIM phenotype 619312; SPEN gene OMIM 613484. [27]
Orphanet ORPHA:662234. [27][63]
MedGen Concept C5543339; UID 1778557. [62]
MeSH No syndrome-specific descriptor verified. D065886, sometimes cross-referenced from disease resources, means the broader category Neurodevelopmental Disorders. [64][77]
ICD-10/ICD-11 No syndrome-specific code verified. ICD-10-CM Q87.89 is a general “other specified congenital malformation syndromes” category, not an established RATARS-specific mapping; an ICD-11-specific mapping was not established. [80][86]

In the foundational paper’s abstract, the authors describe “34 individuals with truncating variants in SPEN” and a disorder overlapping proximal 1p36 deletion syndrome (Radio et al., electronically published 16 February 2021, PMID 33596411, DOI 10.1016/j.ajhg.2021.01.015). [45][16]

2. Etiology, risks, protection, and gene–environment interaction

Factor Disease-specific evidence and interpretation
Primary cause Heterozygous, predominantly de novo, protein-truncating variants of SPEN at 1p36.21–p36.13. Familial transmission from an affected parent establishes autosomal-dominant inheritance. Loss of function/haploinsufficiency is the supported disease model; individual variants in the original series were not all functionally tested. [27][22][30]
Chromosomal contribution A proximal 1p36 deletion encompassing SPEN can contribute to overlapping findings, but a multigene deletion is not interchangeable with an isolated SPEN variant. Distal 1p36 deletions can also produce overlapping findings without deleting SPEN. [16][31]
Other genetic risks or modifiers No established susceptibility locus, severity-modifying allele, founder variant, or protective human allele was identified in the reviewed RATARS studies. Variant position did not show a clear genotype–phenotype relationship in the 34-person series. [27][16]
Sex and age effects These affect observed expression, not proven risk of acquiring the mutation: obesity occurred in 6/16 assessed females versus 0/15 males; BMI generally rose after approximately age four. [16]
Environmental, lifestyle, or infectious causes None established for this Mendelian syndrome. In particular, no toxin, infection, smoking exposure, or dietary pattern has been shown to cause RATARS. [27][16]
Protective factors and gene–environment interaction No protective intervention is validated in humans. In Drosophila with experimental Spen depletion, diet changed metabolic outcomes: extra yeast partly rescued larval adiposity/development, while effects differed in adults. This is an experimental gene–diet interaction, not a patient dietary recommendation (Gillette et al., online 27 February 2020, PMID 32107279). [119]

3. Phenotypes

How to read the table: “Frequency” is the count among people evaluated for that feature in the original 34-person cohort, as tabulated in the 2024 Korean case comparison. A later case does not change those original denominators. Proposed HPO labels/IDs are annotation suggestions, not a claim that each has been independently validated as a syndrome-specific association. Most developmental findings arise in infancy or childhood; cohort-wide, feature-specific severity and progression were generally not measured. Functional impacts are clinical implications, not measured EQ-5D, SF-36, or PROMIS results. [31][16]

Phenotype and type Onset, severity, course and frequency Function or quality-of-life relevance Suggested HPO term
Global developmental delay; clinical sign Childhood; variable impairment; 32/33 (97%) in the detailed 2024 comparison. The original paper’s broader combined delay/intellectual-disability category is 33/33. [31][16] Developmental and educational support needs. Global developmental delay HP:0001263. [61]
Intellectual disability; clinical sign Childhood; mild to severe in the cohort; 23/24 (96%) assessed separately. [31][16] Variable lifelong learning and adaptive-function needs. Intellectual disability HP:0001249. [61]
Delayed speech/language; clinical sign Childhood; 31/32 (97%); the original report described language delay as nearly universal. [31][16] Communication and educational access. Delayed speech and language development HP:0000750. [61]
Delayed gross and fine motor skills; clinical signs Childhood; 26/30 (87%) gross and 23/24 (96%) fine motor; severity variable. [31] Mobility, play, self-care, handwriting. Gross motor delay; fine motor delay—verify exact HPO IDs before database entry.
Hypotonia; clinical sign Usually evident early; 22/30 (73%). Oral-motor hypotonia: 12/28 (43%). [16][31] Posture, motor milestones, feeding. Hypotonia HP:0001252; oral-motor hypotonia—ID to verify. [61]
Behavioral differences; behavioral signs Childhood onward; broad abnormal-behavior category 22/30 (73%). The original narrative also reports behavioral and/or psychiatric findings in 81%, using a different definition. [31][16] Social participation and caregiver support; individual impact unquantified. Aggressive behavior HP:0000718 where applicable. [61]
Autism-spectrum features; behavioral sign 18/28 (64%) evaluated; variable expression. [31] Communication, sensory and social-support needs vary. Autistic behavior HP:0000729. [61]
Aggressive behavior; behavioral sign 18/29 (62%) in the detailed comparison. [31] May complicate daily functioning and support. Aggressive behavior HP:0000718. [61]
Motor stereotypy; behavioral sign 13/28 (46%); course not characterized. [31] Variable; cannot infer impairment from presence alone. Motor stereotypy HP:0000733. [61]
Gait imbalance; clinical sign 14/27 (52%); childhood motor difficulty. [16] Walking and fall risk may be affected. Gait imbalance HP:0002141. [61]
Abnormal pyramidal signs; neurological sign 6/24 (25%); progression not established. [31] May add motor-management needs. Abnormal pyramidal signs—ID to verify.
Seizures; symptom/sign 3/32 (9%) in the original cohort; episodic when present. [31] Safety and seizure-care burden for affected individuals. Seizure HP:0001250. [61]
Brain/spine anomalies; imaging signs 14/22 (64%) imaged had a reported CNS anomaly, including polymicrogyria, heterotopia, cerebellar atrophy, periventricular white-matter changes, callosal agenesis, or tethered cord. This is a selected imaged denominator, not a birth prevalence. [16] Consequences depend on the specific lesion; not quantified. Annotate the specific demonstrated lesion, rather than assigning every lesion to every patient.
Craniofacial differences; physical signs 28/31 (90%) had dysmorphism in the detailed comparison. Reported examples include bitemporal narrowing 39%, epicanthus 39%, synophrys 33%, and a broad/bulbous nose or prominent tip 52%. [31][22] Mainly diagnostic relevance; quality-of-life effect not established. Epicanthus HP:0000286; specific remaining facial terms require ID verification. [61]
Congenital heart defect; physical/imaging sign 8/29 (28%) for specifically classified CHD in the detailed comparison. VSD, patent ductus arteriosus, and other findings occur. A broader original-table category, “cardiac features/CHD,” is 14/22 (64%); do not equate the two rates. [31][16] Depends on cardiac lesion and hemodynamic significance. Specific defect term after echocardiographic confirmation.
Gastrointestinal features; clinical signs 13/31 (42%); includes reflux or constipation. Feeding/swallowing difficulty separately occurred in 8/30 (27%). [31][16] Nutrition, aspiration risk, and daily feeding needs in some patients. Specific reflux, constipation, or feeding-difficulty term, as documented.
Hearing loss; clinical sign 3/31 (10%) in the original series; type and individual severity vary. [16] Communication and educational access. Hearing impairment—ID to verify.
Ocular involvement; clinical sign 6/30 (20%); findings include strabismus; the detailed comparison separately records myopia 6/30 (20%). [31] Vision and learning access. Specific documented ocular finding.
Brachydactyly; physical sign 5/30 (17%); congenital/nonprogressive morphology. Toe abnormalities: 4/27 (15%). [16] Functional impact usually requires individual assessment. Brachydactyly; specific toe anomaly—IDs to verify.
Scoliosis/kyphosis; physical sign 5/28 (18%) radiographically supported in the original comparison; subsequent course unknown. [16] Posture and mobility if clinically significant. Specific confirmed spinal-deformity term.
Precocious puberty; endocrine sign 4/18 (22%) assessed; timing is early by definition, but age-specific natural history is unavailable. [16] May require endocrine evaluation. Precocious puberty—ID to verify.
Increased BMI/obesity; clinical sign Age-related tendency, especially females: 6/16 females obese versus 0/15 males among those assessed; raised BMI 10/16 females versus 3/15 males. [16] Potential longer-term metabolic and psychosocial effects have not been quantified specifically for RATARS. Obesity; increased body mass index—IDs to verify.

Frequency caution: the 2024 comparison reports 8/29 CHD, whereas the original cohort’s broader cardiac-features/CHD table reports 14/22. Those are different ascertainment and phenotype definitions, not evidence that the underlying heart-defect rate changed. Likewise, syndrome-page percentages without clear denominators should not replace the primary study counts. [31][16]

4. Genetic and molecular information

SPEN (HGNC:17575; NCBI Gene:23013; OMIM:613484) encodes a nuclear transcriptional repressor also called SHARP/MINT. It has RNA-recognition motifs and a C-terminal SPOC region involved in corepressor interactions. Disease-associated variants in the foundational series are germline-consistent heterozygous stop-gain or frameshift variants; fibroblast testing in three people supported a non-blood-restricted origin. The reported variants were absent from the gnomAD dataset examined at publication, which must not be interpreted as a newly verified 2026 allele frequency. [44][16][27]

Variant evidence or class Findings and interpretation
Foundational cohort variant set 32 distinct truncating changes in 34 people, distributed across SPEN; the published Table 1 supplies each HGVS change, domain, inheritance observation, and original gnomAD check. Of the 34 individuals, a subsequent comparison summarizes 28 de novo, three familial, and three unknown. These are observed cases, not penetrance estimates. [16][31]
Recurrent stop-gain example NM_015001.3:c.5806C>T, p.(Arg1936Ter) occurred in the original cohort and independently in the Korean boy; the latter was de novo, classified pathogenic, and absent from gnomAD in that report. Predicted nonsense-mediated decay was not directly demonstrated for that patient. [16][31]
Recurrent frameshift example NM_015001.3:c.6223_6227del, p.(Ser2075GlufsTer46) occurred in the original series and a Japanese girl; the latter’s variant was de novo and described as pathogenic (Nishi et al., online 21 October 2024, PMID 39431794, DOI 10.1002/ajmg.a.63910). [16][34]
Familial evidence The original cohort included inheritance from an affected mother for p.(Arg1936Ter) and from an affected father for p.(Glu2443GlyfsTer17) in two siblings. An independently de novo p.(Arg1936Ter) demonstrates that the same coding change can have different family histories. [16][31]
Missense variants and uncertain findings The defining 34-person study contained truncating, not missense, variants. A rare SPEN missense finding should not automatically be called causal for RATARS: apply variant-specific ACMG/AMP interpretation and phenotype/segregation evidence. [16][27]
Copy-number changes Deletions including SPEN may contribute to a multigene proximal 1p36 deletion phenotype; evaluate deleted genes and breakpoints rather than labeling every 1p36 deletion isolated RATARS. No recurrent RATARS-specific translocation, inversion, aneuploidy, or repeat expansion is established. [16][31]
Modifier genes and epigenetics No clinically established modifier. In seven affected females versus six batch-matched female controls, blood-DNA analysis yielded an X-chromosome methylation signature; the 11-patient initial genome-wide comparison did not show substantial global methylation change. Affected males were not reliably distinguished by that X-specific classifier. [16]

5. Environmental and infectious information

No infectious agent, toxic exposure, radiation exposure, occupational hazard, or lifestyle behavior is established as a cause or trigger of RATARS. The disease’s genetic cause should not be confused with factors that can influence general health or with the experimental Spen–diet effects observed in flies. Consequently, CTD-style chemical–disease causation, a pathogen taxon, and a disease-preventive CHEBI exposure should not be populated without new evidence. [27][119]

6. Mechanism and pathophysiology

Ordered causal chain

  1. Initiating lesion: A germline heterozygous truncating SPEN variant leads to predicted reduced functional SPEN dosage; the aggregate genetic evidence supports haploinsufficiency, although variant-by-variant protein loss was not measured in the original patients. [27][16]
  2. Upstream molecular branch—transcription: Reduced SPEN is inferred to lead to altered recruitment or action of transcriptional corepressors during development. SPEN’s transcription-repressor function is experimentally supported, but the exact disrupted developmental targets in RATARS patients have not been established. [44][132]
  3. Epigenetic/X-chromosome branch: Reduced SPEN leads to an observed, female-specific blood X-chromosome DNA-methylation episignature. Its relationship to silencing of particular genes in patients, and to their individual symptoms, remains inferred. [16]
  4. Experimental explanation of that branch: In cellular and mouse systems, XIST/Xist RNA recruits SPEN/SHARP, which promotes corepressor/HDAC3-dependent chromatin repression and X-linked gene silencing. Whether altered X inactivation itself causes the full RATARS phenotype is not demonstrated. [46][47][54]
  5. Neurodevelopmental branch: Perturbed developmental gene regulation is inferred to result in altered nervous-system development and neuronal maintenance, leading to developmental, motor, speech, cognitive, and behavioral manifestations. Human clinical associations and mouse neural-knockout phenotypes support this chain, but its intermediate human cell types and target genes remain unresolved. [16][92]
  6. Additional organ branches: Altered developmental transcription is inferred to contribute to congenital cardiac and other structural findings; separate altered energy regulation might contribute to later obesity. The cardiac-development and fat-metabolism mechanisms derive chiefly from mouse and fly models, respectively, and are not demonstrated patient-level causal chains. [92][100][16]

Mechanistic detail and annotation suggestions

Mechanism or evidence type What has actually been shown; limits Suggested annotations
XIST–SPEN binding; human proteins, in vitro A 2024 primary biochemical study found that SPEN RRM4 was needed for high-affinity binding to XIST A-repeat RNA; at least four repeat units supported high-affinity binding under its experimental conditions. This establishes binding determinants, not an assay of RATARS patient variants (Button et al., RNA, March 2024, PMID 38164599, DOI 10.1261/rna.079713.123). Its abstract states: “Binding of SPEN to XIST RNA requires RRM 4 of the protein.” [54] Protein: SPEN; RNA: XIST. GO biological-process suggestions: X-chromosome inactivation; negative regulation of transcription. NCBI annotates SPEN to these processes and to the nucleus/nucleoplasm. [44]
Chromatin repression; cell and mouse evidence McHugh et al. showed XIST–SHARP/SPEN interaction and implicated SMRT/HDAC3-mediated transcriptional silencing (2015, PMID 25915022). Dossin et al. found SPEN required to initiate X silencing in mouse preimplantation embryos and embryonic stem cells, but dispensable for its maintenance in neural progenitors (2020, PMID 32025035). This distinction matters when interpreting a developmental syndrome. [46][47] GO suggestions: random X-chromosome inactivation; negative regulation of transcription by RNA polymerase II; regulatory-ncRNA-mediated heterochromatin formation. GO cellular component: nucleus/nucleoplasm, transcription-repressor complex. [44]
Human methylomics; affected-person biomarker research Blood DNA from 11 affected people was assayed with the MethylationEPIC array. The informative female X-chromosome analysis selected 122 probes and separated tested affected females from controls; the genome-wide difference was not substantial, and the autosomal classifier did not generalize robustly across batches. Research-stage classification evidence, not a validated stand-alone clinical diagnostic test. [16] Biospecimen: peripheral-blood leukocyte DNA; compartment implicated: nuclear chromatin. Do not annotate tissue-specific brain methylation as measured.
Neural development; expression and mouse model Analyses of existing human developing-brain bulk and single-cell RNA data placed SPEN expression in early cortical development, including the transition from ventricular radial glia to intermediate progenitors. Neural conditional Spen knockout mice showed reduced cortex/hippocampus and enlarged ventricles; these are not human single-cell RATARS profiles. [16][92] Suggested CL labels: radial glial cell, neural intermediate progenitor, neuron—cell involvement is inferred, not a demonstrated patient-cell lesion. GO: neurogenesis; anatomical terms: cerebral cortex, hippocampus, brain.
Notch/RBP-J and development; experimental In mouse work, MINT/SPEN opposed Notch-dependent RBP-J transactivation; null mutants had embryonic lethality and altered B-cell differentiation (Kuroda et al., 2003, PMID 12594956). A specific Notch-driven immune deficiency in patients has not been demonstrated. [132] GO: Notch signaling pathway; use B-cell annotations only for the mouse experiment, not a patient immune phenotype. [44]
Metabolism; fly model Spen-depleted Drosophila fat-storage cells had impaired lipid mobilization and β-oxidation-associated metabolic changes, including reduced free carnitine/acylcarnitines (Hazegh et al., 2017, PMID 28640815). A corresponding human metabolic signature, enzyme deficiency, or carnitine treatment indication has not been established. [100][94][16] Suggested process: fatty-acid β-oxidation; chemical-entity suggestion: L-carnitine, with its CHEBI identifier verified before entry. Fly tissue: fat body—not a proven human target tissue.

There is no established RATARS-specific patient proteomic, metabolomic, lipidomic, spatial-transcriptomic, single-cell atlas, multi-omics integration, or CRISPR-screen signature. The human developmental single-cell data above are expression-context analyses, not single-cell sequencing of affected patients. No primary evidence supports adding ischemia, fibrosis, chronic inflammation, apoptosis, mTOR, PI3K–AKT, or mitochondrial enzyme deficiency as a demonstrated RATARS mechanism. [16][54]

7. Anatomical structures affected

Level Supported sites, localization, and ontology suggestions
Organ/system Central nervous system, heart, and variable gastrointestinal, musculoskeletal, ocular, auditory, and endocrine involvement are clinically reported. Suggested verified broad UBERON anchors: brain UBERON:0000955 and heart UBERON:0000948; choose specific anatomical terms only when the patient has that finding. [16][31]
CNS structures Reported lesions include cerebral cortex polymicrogyria, neuronal heterotopia, cerebellar atrophy, periventricular white matter changes, corpus-callosum agenesis, and tethered cord. These are alternatives observed across patients, not a uniform anatomical lesion. [16]
Tissues/cells Developing neural tissue is strongly implicated by clinical and model evidence; radial glial cells, intermediate progenitors, and neurons are research-relevant candidate populations. Cardiac developmental cells are plausible but not resolved as patient-specific targets. Assign precise CL identifiers only after ontology lookup. [16][92]
Subcellular compartment SPEN acts principally in the nucleus/nucleoplasm and transcription-repressor complexes; the X-chromosome chromatin branch is pertinent in females. Fly mitochondrial fatty-acid metabolism is a downstream model observation, not evidence that SPEN is primarily a mitochondrial protein in patients. [44][54][94]
Lateralization No characteristic unilateral, bilateral, or asymmetric pattern is established for RATARS. [16]

8. Temporal development

Onset is developmental: hypotonia and feeding problems can be apparent in infancy, while speech, learning, behavior, and some structural findings become apparent as the child grows. In the foundational series, ages at last assessment ranged from fetal life to 24 years 6 months. Increased BMI tended to emerge after about age four. These observations do not establish formal early/intermediate/end-stage categories or a common progressive neurological course. [16]

A Korean boy’s longitudinal case illustrates variability rather than a universal trajectory: axial hypotonia was present in infancy; at 28 months developmental testing showed substantial delays; at five years he could walk with support and combine two words. The study’s abstract describes his diagnosis as resulting from “whole genome sequencing” (Kim et al., published online 16 December 2024, DOI 10.26815/acn.2024.00717). No standardized remission pattern, disease duration estimate beyond its developmental nature, or validated critical treatment window has been published. [31]

9. Inheritance and population

Population or inheritance measure Best-supported answer
Inheritance Autosomal dominant. Most original cases were de novo; 28 de novo, three familial, three unknown is the published retrospective accounting. [27][31]
Penetrance and expressivity Expressivity is variable. Penetrance has not been quantified in an unbiased carrier series; ascertainment of affected families cannot establish complete penetrance. [16][27]
Anticipation, mosaicism, founder effect, consanguinity, carrier frequency Not established as RATARS features; unaffected carrier frequency and parental germline-mosaicism frequency cannot be estimated from the available reports. [16][27]
Prevalence and incidence No reliable population-based cases-per-100,000 or annual incidence estimate. “34” is the size of the landmark cohort, not prevalence or a complete count of all affected people. [16][34]
Sex and ages Original cohort: 17 female and 17 male; ages at last examination fetus to 24 years 6 months. A 1:1 reported-cohort split is not a population sex ratio. [16]
Ancestry/geography A Korean boy and a Japanese girl were subsequently reported; no ancestry-specific risk, endemic region, or geographic variant distribution is established. [31][34]

10. Diagnostics

The diagnostic anchor is molecular identification and interpretation of a plausible heterozygous SPEN loss-of-function variant in the appropriate clinical setting. Phenotypic findings alone are insufficiently specific to separate RATARS from 1p36 deletion syndrome or other neurodevelopmental disorders. [27][31][34]

Diagnostic approach Utility and limitation
Clinical evaluation Developmental and neurologic assessment, speech/feeding evaluation, growth/BMI and pubertal review; cardiac, hearing, vision, and renal evaluation guided by findings. No published RATARS-specific clinical scoring criteria or laboratory enzyme assay exists. [16][31]
Exome sequencing Appropriate for heterogeneous developmental-delay presentations; trio WES identified the Japanese girl’s recurrent SPEN frameshift after cytogenetics and microarray did not explain her findings. [34]
Genome sequencing Trio WGS identified de novo SPEN c.5806C>T in the Korean boy after a normal 46,XY karyotype. Its abstract says: “A 3-year-old boy ... underwent whole genome sequencing.” WGS can also aid evaluation of other candidate variant types, but a disease-specific comparative diagnostic yield is unavailable. [31]
Multigene panel or targeted test A neurodevelopmental-disorder/intellectual-disability panel including SPEN is a reasonable option; targeted familial-variant testing is appropriate when a causal variant is already known. The Korean investigators specifically recommended including SPEN in relevant genetic testing. [45][31]
Chromosomal microarray; karyotype/FISH CMA addresses 1p36 copy-number deletions and other CNVs, not typical sequence-level SPEN truncations. Karyotyping helped exclude trisomy 21 in the Japanese case but was not the molecular RATARS test. FISH is not routinely established for isolated sequence variants. [34][31]
Imaging and functional tests Brain MRI when indicated can characterize reported anomalies; echocardiography identifies heart defects. Audiology, ophthalmology, swallow assessment, and EEG if clinically indicated address associated manifestations. There is no characteristic diagnostic MRI, EEG, biochemical, biopsy, or pathology result. [16][31]
Methylation/other omics Female X-chromosome blood methylation classification is a research finding with batch and sex limitations; RNA-seq, proteomics, metabolomics, liquid biopsy, and mitochondrial or repeat-expansion testing are not established RATARS diagnostic tests. [16]
Differential diagnosis Proximal or distal 1p36 deletion syndrome: determine deletion boundaries by CMA/sequence analysis; overlap alone does not show SPEN deletion. Down syndrome: assess cytogenetics when clinically suspected; the Japanese case initially resembled it, but cytogenetics and CMA did not identify the cause and trio WES found SPEN. Broader neurodevelopmental disorders require variant-led evaluation. [31][34]
Asymptomatic screening No established population newborn or universal carrier-screening program. Once a familial pathogenic variant is known, offer genetics-led evaluation and targeted cascade testing where appropriate; these are practice implications, not outcome-tested RATARS programs. [27]

11. Outcome and prognosis

Survival probability, mortality rate, life expectancy, and validated prognostic biomarkers are unknown. The original series included individuals assessed into young adulthood, but its ascertainment and follow-up cannot generate a survival estimate. Developmental, speech, behavioral, mobility, feeding, cardiac, and sometimes weight-related needs contribute to morbidity; no disease-specific EQ-5D, SF-36, or PROMIS results, formal disability distribution, or reliable treatment-response rate were established in the cited cohort. Variant location did not yield a clear severity predictor. Recovery probabilities, including a treated-versus-untreated comparison, are unavailable. [16][27]

Potential complications should be recorded patient by patient, not assumed: for example, aspiration and poor growth in the Korean child required substantial feeding support. The original cohort observed seizures in only 3/32, so epilepsy should not be represented as inevitable or as a demonstrated major mortality cause. [31][16]

12. Treatment and real-world implementation

There is no demonstrated disease-modifying treatment for RATARS. Care is individualized around documented developmental and organ-specific needs; the interventions below are management suggestions or reported care, not syndrome-specific efficacy claims. No RATARS drug-response rates, pharmacogenomic rule, approved gene/RNA/cell therapy, immunotherapy, or RATARS-specific NCT trial was established in the reviewed evidence. Suggested NCIT intervention labels are provided for knowledge-base matching; NCIT codes require independent terminology verification. [16][31]

Treatment or intervention Clinical role and evidence boundary Suggested NCIT intervention term
Developmental, speech-language, occupational, and physical therapies Reasonable functional support for documented developmental, communication, and motor needs; RATARS-specific comparative outcomes unavailable. [16] Speech Therapy; Occupational Therapy; Physical Therapy.
Feeding/swallowing and nutritional support Assess aspiration and growth individually. In the Korean case, fundoplication and gastrostomy at four months addressed poor weight gain/recurrent aspiration; tube feeding continued until age three. A single case does not establish routine surgical indications. [31] Nutritional Support; Gastrostomy; Fundoplication.
Cardiac, neurologic, behavioral, and endocrine management Assess and manage a confirmed heart defect, seizures, behavioral condition, precocious puberty, or elevated BMI according to that manifestation. No RATARS-specific drug, combination regimen, response rate, or adverse-event series is available. [16][31] Cardiac Assessment; Seizure Management; Behavioral Therapy; Endocrine Evaluation—term/code validation needed.
Diet modification proposed from fly experiments Extra yeast or sugar altered outcomes of Spen-depleted flies; neither is an established patient treatment, and extra sugar increased adiposity in that model. [119] Do not annotate as a validated RATARS intervention.
Gene editing, gene replacement, ASOs, cell therapy, or methylation-directed treatment Experimental concepts only in this disease context; the cited human studies report no therapeutic implementation or outcome. [16][31] No established disease-specific NCIT treatment annotation.

13. Prevention and counseling

Primary prevention of a spontaneous de novo SPEN variant is not known. No vaccine, antimicrobial prophylaxis, toxin-avoidance program, or lifestyle change prevents RATARS. Genetics-led counseling can explain autosomal-dominant transmission, the distinction between de novo and inherited variants, and reproductive options after a familial variant is established; a de novo result does not by itself quantify possible parental germline mosaicism. Targeted familial testing and, where desired, reproductive testing are individualized options, not population screening. [27][31]

Secondary and tertiary prevention means recognizing developmental and organ-specific issues early and addressing complications—for example, aspiration or a clinically important cardiac defect—rather than preventing the genetic disorder itself. There is no validated RATARS risk score, prophylactic medication, or disease-specific public-health/environmental intervention. [16][31]

14. Other species and natural disease

Species and taxonomy Ortholog or natural-disease evidence Veterinary/transmission interpretation
Human, Homo sapiens (NCBI Taxon:9606) RATARS is the naturally described human disease; SPEN NCBI Gene 23013. [16][44] Inherited genetic condition, not infectious or zoonotic.
Mouse, Mus musculus (NCBI Taxon:10090) Ortholog Spen, NCBI Gene:56381; MGI:1891706. Experimental mutant phenotypes exist, but naturally occurring veterinary RATARS has not been established. [106][92] No demonstrated breed-specific natural disease or cross-species transmission.
Fruit fly, Drosophila melanogaster (NCBI Taxon:7227) Experimental Spen depletion reveals conserved transcription/metabolic research questions; this is not a reported natural animal RATARS diagnosis. [100][119] No breed identifier or zoonotic relevance.
Zebrafish, Danio rerio (NCBI Taxon:7955) A spen ortholog is catalogued in ZFIN, which reports no experimentally associated RATARS model data on the cited gene page. [65] No established natural disease or transmission.

15. Model organisms and model limitations

Model system Manipulation and recapitulated findings What it can—and cannot—establish
Mouse, Spen null or conditional knockout Null embryos have developmental and cardiac abnormalities and embryonic lethality; neural conditional deletion produced reduced brain weight/cortical thickness and hippocampal size with enlarged ventricles. MGI catalogs Spen mutant alleles, including a conditional-ready targeted allele. Primary mouse Notch/B-cell evidence: PMID 12594956; conditional-allele publication: PMID 17457934. [92][106][108][132][129] Useful for developmental requirements and cell-restricted mechanisms. Biallelic/conditional loss is not equivalent to the typical human heterozygous truncation; full RATARS behavior, penetrance, and treatment response are not established by these models. [16][92]
Mouse embryos and embryonic stem cells Spen perturbation impairs initiation of X-chromosome silencing; neural progenitor maintenance findings differ (Dossin et al., PMID 32025035). [47] Tests an upstream epigenetic function, not proof that altered X inactivation alone produces every human symptom.
Drosophila larval fat body; RNAi knockdown Increased fat storage and impaired energy mobilization/β-oxidation-associated measures; diet-modification experiments show stage-dependent partial rescue (PMIDs 28640815, 32107279). [100][119] Tests a candidate metabolic branch and gene–diet interaction; does not validate fly diets, carnitine, or obesity mechanisms as patient treatments.
Purified human SPEN/XIST components; in vitro RNA-binding/domain and XIST A-repeat experiments quantify an upstream interaction (PMID 38164599). [54] Mechanistically precise, but lacks intact human tissues, affected-patient variants, and clinical outcomes.
Human affected-person samples Clinical genotypes/phenotypes and female blood-DNA methylation constitute human disease evidence, not an established patient-derived organoid, iPSC, or gene-corrected model. [16] Most directly relevant to annotation, but small, ascertained cohorts and limited longitudinal follow-up constrain causal and prognostic inference.

Knowledge-base priority: enter the SPEN–RATARS loss-of-function association and the denominator-qualified human phenotypes as established; label the X-chromosome methylation signature as a female-biased research biomarker; and keep Notch, neural-cell-specific, and fatty-acid-metabolism explanations tagged to their experimental evidence type rather than asserting them as proven patient mechanisms. [16][31][47][100]

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 13
Resolved 12
Unresolved (possible confabulation) 1
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 12
On topic 5
Off topic 0

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

  • DOI:10.1371/journal.pgen.1008333&type=printable (2 mentions) - Identifier did not resolve to a record

Term Validation

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

Outcome Count
Terms checked 23
Resolved 13
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 10

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, Gene, OMIM, Taxon, MGI.

13 of 23 terms resolved to a current term; the rest could not be looked up either way.