SPOP-Related Neurodevelopmental Disorder

Mendelian MONDO:0032942 Pathograph 23 Show in embeddings browser Mendelian neurodevelopmental disorder

SPOP-related neurodevelopmental disorder (Nabais Sa-de Vries syndrome, NSDVS) is an autosomal dominant condition caused by de novo missense variants in SPOP, which encodes the MATH-domain substrate-recognition adaptor of the CUL3-RING E3 ubiquitin ligase. Affected individuals show developmental delay and/or intellectual disability, congenital anomalies, and a recognizable facial gestalt. Functional studies distinguish two variant classes with opposite effects on SPOP-mediated substrate ubiquitination: gain-of-function variants that increase substrate (including BET protein) degradation cause NSDVS type 1 with congenital microcephaly (OMIM:618828, this MONDO term), whereas dominant-negative variants that impair substrate degradation cause NSDVS type 2 with relative macrocephaly and hypertelorism (OMIM:618829, MONDO:0032943). Somatic SPOP mutation is separately a well-known driver of prostate and endometrial cancer; that is a distinct, non-heritable disease process and is contextual background only for this germline disorder.

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1
Inheritance
6
Pathophys.
24
Phenotypes
1
Hypotheses
3
Gaps
23
Pathograph
1
Genes
10
Variants
3
Medical Actions
2
Subtypes
1
Models
1
Deep Research
👪

Inheritance

1
Autosomal dominant (de novo) HP:0000006
All molecularly confirmed individuals reported to date carry heterozygous de novo SPOP variants; no familial transmission has been described.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:36063898 SUPPORT Human Clinical
"Nabais Sa-de Vries syndrome (NSDVS) is an autosomal dominant neurodevelopmental disorder first described in 2020 and is classified into type 1 (NSDVS1) and type 2 (NSDVS2) which encompassed of spectrum of distinct clinical features due to gain-of-function (GOF) and loss-of-function (LOF)..."
States the autosomal dominant inheritance pattern and the two-type classification of the syndrome.
PMID:32109420 SUPPORT Human Clinical
"By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies."
The defining cohort: every pathogenic SPOP variant was de novo, supporting dominant disease from new heterozygous mutations.
◆

Subtypes

2
NSDVS type 1 (microcephaly; gain-of-function) MONDO:0032942
SPOP hgnc:11254 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SPOP (hgnc:11254). hgnc:11254 is a gene from the HUGO Gene Nomenclature Committee.
NSDVS type 1 (OMIM:618828) is caused by gain-of-function SPOP variants (e.g. p.Arg121Gln, p.Asp144Asn) that increase SPOP-mediated substrate degradation. The craniofacial phenotype includes congenital microcephaly, narrow forehead, highly arched eyebrows, and blepharophimosis; hearing loss and ocular abnormalities are recurrent.
Show evidence (2 references)
PMID:32109420 SUPPORT Human Clinical
"Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism."
Defines the microcephalic subgroup that became NSDVS type 1, contrasted with the macrocephalic type 2 subgroup.
PMID:32109420 SUPPORT In Vitro
"The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn), identified in the first two individuals, resulted in a gain of function"
Assigns the microcephalic individuals' variants to the gain-of-function class in cell-based assays.
NSDVS type 2 (relative macrocephaly; dominant-negative) MONDO:0032943
SPOP hgnc:11254 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SPOP (hgnc:11254). hgnc:11254 is a gene from the HUGO Gene Nomenclature Committee.
NSDVS type 2 (OMIM:618829) is caused by dominant-negative SPOP variants (p.Thr25Ala, p.Tyr83Cys, p.Gly132Val, p.Arg138Cys) that impair SPOP-mediated substrate degradation. The phenotype includes relative macrocephaly, hypertelorism, and broad forehead, with or without cardiac or endocrine anomalies (per the MONDO term for this subtype).
Show evidence (1 reference)
PMID:32109420 SUPPORT In Vitro
"the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect"
Assigns the macrocephalic individuals' variants to the dominant-negative class in cell-based assays.
◈

Mechanistic Hypotheses

1
Bidirectional BET protein dysregulation drives the contrasting phenotypes
bet_bidirectional_dysregulation EMERGING
Evidence balance 2 support
The two clinical types track with opposite functional effects of SPOP variants on substrate ubiquitination, measured on BET proteins (BRD2/BRD3/BRD4) in endometrial cancer cell models: gain-of-function variants deplete BET proteins (type 1, microcephaly) while dominant-negative variants stabilize them (type 2, macrocephaly). Whether BET dysregulation itself, or dysregulation of other SPOP substrates, is the proximate driver of abnormal human brain development has not been established in neural cells or in vivo.
Pathograph links
Increased CUL3-SPOP Substrate Degradation -> Reduced BET Protein Abundance DIRECT
Impaired CUL3-SPOP Substrate Degradation -> BET Protein Accumulation DIRECT
Reduced BET Protein Abundance -> Aberrant Neurodevelopment INDIRECT UNKNOWN INTERMEDIATES Inferred step: how reduced BET protein levels (or depletion of other SPOP substrates) perturbs human brain growth has not been demonstrated directly; the association rests on the genotype-phenotype correlation.
Reduced BET Protein Abundance -> Congenital Microcephaly INDIRECT UNKNOWN INTERMEDIATES Head-size correlation for the gain-of-function class: the individuals whose variants deplete BET proteins are the individuals with congenital microcephaly. The intermediate steps are unknown.
BET Protein Accumulation -> Aberrant Neurodevelopment INDIRECT UNKNOWN INTERMEDIATES Inferred step: how BET protein accumulation (or stabilization of other SPOP substrates) perturbs human brain growth has not been demonstrated directly; the association rests on the genotype-phenotype correlation.
BET Protein Accumulation -> Relative Macrocephaly INDIRECT UNKNOWN INTERMEDIATES Head-size correlation for the dominant-negative class: the individuals whose variants stabilize BET proteins are the individuals with (relative) macrocephaly. The intermediate steps are unknown.
Show evidence (2 references)
PMID:32109420 SUPPORT Human Clinical
"Our findings suggest that these opposite functional effects caused by the variants in SPOP result in two distinct and clinically recognizable syndromic forms of intellectual disability with contrasting craniofacial dysmorphisms."
The genotype-phenotype correlation at the core of the hypothesis: opposite biochemical effects segregate with opposite craniofacial phenotypes.
PMID:28805821 SUPPORT In Vitro
"Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants."
Establishes BET proteins as SPOP-CUL3 substrates whose degradation is bidirectionally modulated by SPOP mutation class, the biochemical basis borrowed by the germline model.
?

Discussions and Knowledge Gaps

3
Which SPOP substrates mediate the neurodevelopmental phenotype in vivo, and do the BET protein changes measured in endometrial cancer cell models occur in human neural cells?
KNOWLEDGE GAP OPEN neural_substrate_gap
Attached to
pathophysiology#Reduced BET Protein Abundance pathophysiology#BET Protein Accumulation
The functional classification of NSDVS variants rests on BET protein abundance measured in Ishikawa endometrial cancer cells and patient-derived (non-neural) cell lines. SPOP has many other substrates, and no neural cell model, brain organoid, or in vivo study has yet linked a specific substrate to the abnormal brain growth, so the middle of the causal chain (substrate dysregulation to aberrant neurodevelopment) is inferred from genotype-phenotype correlation.
Show evidence (1 reference)
PMID:32109420 SUPPORT In Vitro
"We measured the effect of SPOP variants on BET protein amounts in human Ishikawa endometrial cancer cells and patient-derived cell lines because we hypothesized that variants would lead to functional divergent effects on BET proteins."
Shows the functional evidence base is cancer cell lines and patient-derived non-neural cells, not neural systems, which is the gap this discussion records.
How do BACK-domain truncations that attenuate SPOP higher-order oligomerization produce mixed type 1/type 2 phenotypes, and should oligomerization state be modeled as a third functional class?
OPEN QUESTION OPEN oligomerization_mixed_phenotype
Attached to
genetic#SPOP pathophysiology#De Novo SPOP Missense Variation
A de novo p.Tyr353Ter BACK-domain truncation was reported with combined type 1 and type 2 features. Because the BACK domain drives higher-order oligomerization that enhances substrate avidity and ubiquitylation efficiency, a truncation could simultaneously reduce degradation of some substrates and dysregulate others, blurring the binary gain/loss model used in this entry's pathophysiology.
Show evidence (2 references)
PMID:36063898 SUPPORT Human Clinical
"We conclude the p.Tyr353Term is a Janus-faced variant which explains the dual NSDVS type 1 and 2 phenotypes in this case."
The mixed-phenotype case motivating the question.
PMID:36063898 SUPPORT In Vitro
"The BACK domain is functionally critical for the SPOP higher-order oligomerization and is shown to increase substrate binding avidity with enhanced ubiquitylation efficiency in vitro."
In vitro basis for expecting BACK-domain truncation to perturb oligomerization-dependent substrate handling.
Does SPOP-dependent GLI3/Hedgehog dysregulation, firmly established in mouse genetics, contribute to the human SPOP neurodevelopmental syndrome?
HUMAN MODEL MISMATCH OPEN gli3_hedgehog_axis_mismatch
Attached to
pathophysiology#Impaired CUL3-SPOP Substrate Degradation animal_models#Spop-null mouse
Mouse studies show that Spop targets the Gli3 repressor for degradation in vivo and that reducing Gli3 dosage rescues the Spop-null skeletal phenotype - unusually strong genetic evidence for a SPOP-GLI3 axis. But the mouse phenotype is predominantly skeletal, Spop-null spinal cord patterning is grossly normal, and no study has examined GLI3 or Hedgehog signaling in patient-derived neural tissue, so the translational validity of this axis for the human microcephaly/macrocephaly and cognitive phenotype is the open question. The BET-protein model (this entry's pathograph) and the GLI3 axis are not mutually exclusive.
Show evidence (2 references)
PMID:27930311 SUPPORT Model Organism
"Consistent with this finding, reducing Gli3 dosage greatly rescued the Spop mutant skeletal defects."
The genetic rescue that establishes GLI3 as the mediator of the mouse Spop-null phenotype, motivating the question of its role in the human syndrome.
PMID:28412462 SUPPORT Model Organism
"Here, we show that loss of Spop does not alter spinal cord patterning, but it suppresses the loss of floor plate and V3 interneuron phenotype of Gli2 mutants, suggesting a negative role of Spop in Gli3 activator activity, Shh signaling and the specification of ventral cell fates in the spinal cord."
Shows the context dependence of the neural Hedgehog effect in the model, part of why fidelity to the human syndrome is uncertain.
⚙

Pathophysiology

6
De Novo SPOP Missense Variation
Heterozygous de novo missense variants alter SPOP, the MATH-domain substrate-recognition adaptor that docks substrates onto the CUL3-RING E3 ubiquitin ligase. NSDVS variants cluster in and around the MATH substrate-binding domain and split into two functional classes with opposite consequences for substrate turnover.
SPOP hgnc:11254 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SPOP (hgnc:11254). hgnc:11254 is a gene from the HUGO Gene Nomenclature Committee.
ubiquitin ligase-substrate adaptor activity GO:1990756 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves ubiquitin ligase-substrate adaptor activity, annotated with ubiquitin-like ligase-substrate adaptor activity (GO:1990756). GO:1990756 is a molecular function from the Gene Ontology.
CUL3-RING ubiquitin ligase complex GO:0031463 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves CUL3-RING ubiquitin ligase complex (GO:0031463). GO:0031463 is a cellular component from the Gene Ontology.
Downstream
Increased CUL3-SPOP Substrate Degradation Gain-of-function variant class (NSDVS type 1).
Impaired CUL3-SPOP Substrate Degradation Dominant-negative variant class (NSDVS type 2).
Show evidence (2 references)
PMID:32109420 SUPPORT Human Clinical
"By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies."
Identifies de novo SPOP missense variation as the initiating lesion of the disorder.
PMID:19818708 SUPPORT In Vitro
"In the largest E3 ligase subfamily, Cul3 binds a BTB domain, and an associated protein-interaction domain such as MATH recruits substrates for ubiquitination."
Structural basis for SPOP's role: the MATH domain recruits substrates to the CUL3 ligase, so missense change there alters substrate handling.
Increased CUL3-SPOP Substrate Degradation
Gain-of-function variants (NSDVS type 1) enhance SPOP-mediated ubiquitination, accelerating proteasomal degradation of SPOP substrates.
Bidirectional BET protein dysregulation drives the contrasting phenotypes
Genetic context variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Type 1 variants p.Arg121Gln and p.Asp144Asn (and, per later case reports, p.Arg121Trp and p.Met117Ile).
proteasome-mediated degradation of SPOP substrates GO:0043161 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased proteasome-mediated degradation of SPOP substrates, annotated with proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161). GO:0043161 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Reduced BET Protein Abundance Bidirectional BET protein dysregulation drives the contrasting phenotypes
Show evidence (1 reference)
PMID:32109420 SUPPORT In Vitro
"The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn), identified in the first two individuals, resulted in a gain of function"
Direct functional classification of the type 1 variants as gain-of-function toward SPOP substrate handling.
Impaired CUL3-SPOP Substrate Degradation
Dominant-negative variants (NSDVS type 2) interfere with residual wild-type SPOP, repressing ubiquitination and proteasomal degradation of SPOP substrates.
Bidirectional BET protein dysregulation drives the contrasting phenotypes
Genetic context variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE
Type 2 variants p.Thr25Ala, p.Tyr83Cys, p.Gly132Val, and p.Arg138Cys.
proteasome-mediated degradation of SPOP substrates GO:0043161 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased proteasome-mediated degradation of SPOP substrates, annotated with proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161). GO:0043161 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Spop-null mouse Mouse perturbs Genetic Spop ablation removes SPOP-dependent substrate degradation in vivo, an extreme version of the reduced-function state produced by the human dominant-negative class, and identifies GLI3 as an in vivo SPOP substrate.
Downstream
BET Protein Accumulation Bidirectional BET protein dysregulation drives the contrasting phenotypes
Show evidence (1 reference)
PMID:32109420 SUPPORT In Vitro
"the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect"
Direct functional classification of the type 2 variants as dominant-negative toward SPOP substrate handling.
Reduced BET Protein Abundance
Enhanced SPOP activity depletes BET family proteins (BRD2, BRD3, BRD4), chromatin readers broadly required for transcriptional regulation. In the defining study, type 1 patient variants reduced BET protein amounts in endometrial cancer cells and patient-derived cell lines.
Bidirectional BET protein dysregulation drives the contrasting phenotypes
BRD2 hgnc:1103 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BRD2 (hgnc:1103). hgnc:1103 is a gene from the HUGO Gene Nomenclature Committee. BRD3 hgnc:1104 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BRD3 (hgnc:1104). hgnc:1104 is a gene from the HUGO Gene Nomenclature Committee. BRD4 hgnc:13575 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BRD4 (hgnc:13575). hgnc:13575 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Aberrant Neurodevelopment Inferred step: how reduced BET protein levels (or depletion of other SPOP substrates) perturbs human brain growth has not been demonstrated directly; the association rests on the genotype-phenotype correlation. Bidirectional BET protein dysregulation drives the contrasting phenotypes
Congenital Microcephaly Head-size correlation for the gain-of-function class: the individuals whose variants deplete BET proteins are the individuals with congenital microcephaly. The intermediate steps are unknown. Bidirectional BET protein dysregulation drives the contrasting phenotypes
Show evidence (1 reference)
PMID:32109420 SUPPORT In Vitro
"We measured the effect of SPOP variants on BET protein amounts in human Ishikawa endometrial cancer cells and patient-derived cell lines because we hypothesized that variants would lead to functional divergent effects on BET proteins."
BET protein abundance was the functional readout used to classify the NSDVS variants, including in patient-derived cells.
BET Protein Accumulation
Dominant-negative SPOP variants stabilize BET family proteins (BRD2, BRD3, BRD4) by repressing their ubiquitin-dependent degradation, the opposite cellular state to the type 1 class.
Bidirectional BET protein dysregulation drives the contrasting phenotypes
BRD2 hgnc:1103 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BRD2 (hgnc:1103). hgnc:1103 is a gene from the HUGO Gene Nomenclature Committee. BRD3 hgnc:1104 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BRD3 (hgnc:1104). hgnc:1104 is a gene from the HUGO Gene Nomenclature Committee. BRD4 hgnc:13575 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BRD4 (hgnc:13575). hgnc:13575 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Aberrant Neurodevelopment Inferred step: how BET protein accumulation (or stabilization of other SPOP substrates) perturbs human brain growth has not been demonstrated directly; the association rests on the genotype-phenotype correlation. Bidirectional BET protein dysregulation drives the contrasting phenotypes
Relative Macrocephaly Head-size correlation for the dominant-negative class: the individuals whose variants stabilize BET proteins are the individuals with (relative) macrocephaly. The intermediate steps are unknown. Bidirectional BET protein dysregulation drives the contrasting phenotypes
Show evidence (1 reference)
PMID:28805821 SUPPORT In Vitro
"Conversely, prostate cancer-specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition."
Demonstrates BET protein stabilization by dominant-negative SPOP mutants, the mechanism shared by the NSDVS type 2 variant class.
Aberrant Neurodevelopment
Disturbed brain growth and development producing global developmental delay, intellectual disability, and abnormal head size, with the direction of head-size change tracking the variant class: congenital microcephaly in the gain-of-function type 1 and relative macrocephaly in the dominant-negative type 2.
Downstream
Global Developmental Delay
Intellectual Disability
Language Disorder Delayed language acquisition is part of the developmental expression of the disturbed neurodevelopment.
Show evidence (2 references)
PMID:32109420 SUPPORT Human Clinical
"Our findings suggest that these opposite functional effects caused by the variants in SPOP result in two distinct and clinically recognizable syndromic forms of intellectual disability with contrasting craniofacial dysmorphisms."
Connects the two molecular classes to the two clinically distinct neurodevelopmental syndromes.
PMID:39918173 SUPPORT Human Clinical
"These findings suggest a predominant involvement of the central nervous system in NSDVS and expand the phenotypic spectrum of this syndrome."
Longitudinal phenotyping supports the central nervous system as the primary organ system affected.
⬡

Pathograph

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

24
Cardiovascular 3
Congenital Heart Disease Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart disease, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42147571 SUPPORT Human Clinical
"A medical genetic evaluation was initiated at one week of age due to congenital heart disease."
Documents congenital heart disease as the presenting anomaly in a type 1 patient.
Patent Ductus Arteriosus HP:0001643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patent ductus arteriosus (HP:0001643). HP:0001643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42147571 SUPPORT Human Clinical
"Findings included a patent ductus arteriosus, a patent foramen ovale, and pulmonary hypertension, which added to minor dysmorphic features and warranted a medical genetic evaluation."
Names the specific neonatal cardiac lesions in a type 1 patient.
Cardiovascular Anomalies Abnormality of the cardiovascular system HP:0001626 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiovascular anomalies, annotated with Abnormality of the cardiovascular system (HP:0001626). HP:0001626 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42147571 SUPPORT Human Clinical
"The second phenotype is also associated with systemic manifestations such as short stature and failure to thrive, as well as cardiovascular and endocrinological anomalies, epilepsy, and sleep disorders, demonstrating pleiotropy"
Literature synthesis (summarizing the founding cohort) attributing cardiovascular anomalies to the type 2 phenotype.
Ear 1
Hearing Impairment 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)
PMID:35892095 SUPPORT Human Clinical
"Similar to other individuals with NSDVS1, he had features of congenital microcephaly, developmental delay, behavioral abnormalities, hearing loss, and facial dysmorphisms."
Hearing loss is listed among the recurrent type 1 features.
Eye 4
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32109420 SUPPORT Human Clinical
"Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism."
Hypertelorism co-defined the type 2 subgroup in the original cohort.
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35892095 SUPPORT Human Clinical
"Ocular and periorbital manifestations in this patient included thick high-arched eyebrows, mild synophrys, long eyelashes, ptosis, and downslanting palpebral fissures; comparable to features described in other individuals with NSDVS1."
Ptosis is listed among the recurrent periorbital manifestations of type 1.
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35892095 SUPPORT Human Clinical
"In addition, this patient had esotropia that required multiple strabismus surgeries and a refractive error that required the use of corrective lenses."
Documents esotropia requiring surgery in a type 1 patient.
PMID:39918173 SUPPORT Human Clinical
"Along with a global developmental delay, she showed microcephaly, dysmorphic features (such as narrow forehead, highly arched eyebrows, and blepharophimosis), moderate intellectual disability, adaptive difficulties, language disorder, and several neurovisual signs and symptoms (such as..."
Independent case documenting strabismus among the neurovisual features.
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39918173 SUPPORT Human Clinical
"Along with a global developmental delay, she showed microcephaly, dysmorphic features (such as narrow forehead, highly arched eyebrows, and blepharophimosis), moderate intellectual disability, adaptive difficulties, language disorder, and several neurovisual signs and symptoms (such as..."
Documents nystagmus among the neurovisual signs in a type 1 patient.
Head and Neck 3
Relative Macrocephaly HP:0004482 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Relative macrocephaly (HP:0004482). HP:0004482 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32109420 SUPPORT Human Clinical
"Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism."
(Relative) macrocephaly defined the type 2 subgroup in the original cohort.
PMID:36259278 SUPPORT Human Clinical
"A 7-month-old boy presented with an enlarged head circumference, widened eye distance, and a protruding nose."
Case with a novel SPOP variant showing enlarged head circumference, the type 2-like head-size phenotype.
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 (1 reference)
PMID:32109420 SUPPORT Human Clinical
"By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies."
Facial dysmorphism was present across the defining cohort, supporting the VERY_FREQUENT band.
Downslanted Palpebral Fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35892095 SUPPORT Human Clinical
"Ocular and periorbital manifestations in this patient included thick high-arched eyebrows, mild synophrys, long eyelashes, ptosis, and downslanting palpebral fissures; comparable to features described in other individuals with NSDVS1."
Downslanting palpebral fissures are among the recurrent periorbital features.
Nervous System 7
Global Developmental Delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32109420 SUPPORT Human Clinical
"By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies."
Developmental delay was a defining feature in all seven individuals of the original cohort, supporting the VERY_FREQUENT band.
PMID:42147571 SUPPORT Human Clinical
"She currently has delayed neurodevelopment and language acquisition, as well as microcephaly, low weight and height, and normal hearing."
Case-level documentation of delayed neurodevelopment in a type 1 patient.
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 (1 reference)
PMID:39918173 SUPPORT Human Clinical
"To date, only 10 cases have been described presenting with intellectual disability, neurological signs and symptoms, and a variable association of dysmorphic features."
Intellectual disability is reported across the described cases, supporting the VERY_FREQUENT band.
Behavioral Abnormalities Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Behavioral abnormalities, annotated with Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35892095 SUPPORT Human Clinical
"Similar to other individuals with NSDVS1, he had features of congenital microcephaly, developmental delay, behavioral abnormalities, hearing loss, and facial dysmorphisms."
Behavioral abnormalities are listed among the recurrent type 1 features.
Language Disorder Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Language disorder, annotated with Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42147571 SUPPORT Human Clinical
"She currently has delayed neurodevelopment and language acquisition, as well as microcephaly, low weight and height, and normal hearing."
Documents delayed language acquisition in a type 1 patient.
Epilepsy Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epilepsy, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42147571 SUPPORT Human Clinical
"The second phenotype is also associated with systemic manifestations such as short stature and failure to thrive, as well as cardiovascular and endocrinological anomalies, epilepsy, and sleep disorders, demonstrating pleiotropy"
Literature synthesis (summarizing the founding cohort) attributing epilepsy to the type 2 phenotype.
Sleep Disturbance HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep disorders, annotated with Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42147571 SUPPORT Human Clinical
"The second phenotype is also associated with systemic manifestations such as short stature and failure to thrive, as well as cardiovascular and endocrinological anomalies, epilepsy, and sleep disorders, demonstrating pleiotropy"
Literature synthesis (summarizing the founding cohort) attributing sleep disorders to the type 2 phenotype.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36259278 SUPPORT Human Clinical
"Brain magnetic resonance imaging showed enlargement of the bilateral lateral ventricles and the third ventricle, with the frontal horn of the bilateral lateral ventricles and the anterior part of the body obviously deformed."
MRI documentation of ventriculomegaly in a reported infant.
Growth 2
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42147571 SUPPORT Human Clinical
"The second phenotype is also associated with systemic manifestations such as short stature and failure to thrive, as well as cardiovascular and endocrinological anomalies, epilepsy, and sleep disorders, demonstrating pleiotropy"
Literature synthesis (summarizing the founding cohort) attributing short stature to the type 2 phenotype.
Failure to Thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42147571 SUPPORT Human Clinical
"The second phenotype is also associated with systemic manifestations such as short stature and failure to thrive, as well as cardiovascular and endocrinological anomalies, epilepsy, and sleep disorders, demonstrating pleiotropy"
Literature synthesis (summarizing the founding cohort) attributing failure to thrive to the type 2 phenotype.
Other 4
Congenital Microcephaly Primary microcephaly HP:0011451 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital microcephaly, annotated with Primary microcephaly (HP:0011451). HP:0011451 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32109420 SUPPORT Human Clinical
"Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism."
Congenital microcephaly defined the type 1 subgroup in the original cohort.
PMID:35892095 SUPPORT Human Clinical
"Similar to other individuals with NSDVS1, he had features of congenital microcephaly, developmental delay, behavioral abnormalities, hearing loss, and facial dysmorphisms."
Independent case confirming congenital microcephaly as a recurrent type 1 feature.
Blepharophimosis HP:0000581 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Blepharophimosis (HP:0000581). HP:0000581 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39918173 SUPPORT Human Clinical
"Along with a global developmental delay, she showed microcephaly, dysmorphic features (such as narrow forehead, highly arched eyebrows, and blepharophimosis), moderate intellectual disability, adaptive difficulties, language disorder, and several neurovisual signs and symptoms (such as..."
Documents blepharophimosis within the type 1 facial gestalt.
Patent Foramen Ovale HP:0001655 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patent foramen ovale (HP:0001655). HP:0001655 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42147571 SUPPORT Human Clinical
"Findings included a patent ductus arteriosus, a patent foramen ovale, and pulmonary hypertension, which added to minor dysmorphic features and warranted a medical genetic evaluation."
Documents patent foramen ovale in the type 1 proband.
PMID:36259278 SUPPORT Human Clinical
"An echocardiography revealed a patent foramen ovale and tricuspid regurgitation"
Independent infant case with patent foramen ovale.
Endocrine Anomalies Abnormality of the endocrine system HP:0000818 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Endocrinological anomalies, annotated with Abnormality of the endocrine system (HP:0000818). HP:0000818 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42147571 SUPPORT Human Clinical
"The second phenotype is also associated with systemic manifestations such as short stature and failure to thrive, as well as cardiovascular and endocrinological anomalies, epilepsy, and sleep disorders, demonstrating pleiotropy"
Literature synthesis (summarizing the founding cohort) attributing endocrinological anomalies to the type 2 phenotype.
🧬

Genetic Associations

1
SPOP (Heterozygous de novo missense (and rare truncating) variants in SPOP cause both types of Nabais Sa-de Vries syndrome; the functional class of the variant determines the type.)
Gene: SPOP hgnc:11254 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SPOP (hgnc:11254). hgnc:11254 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (1 reference)
PMID:32109420 SUPPORT Human Clinical
"By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies."
Establishes de novo SPOP variants as the cause of the disorder.
Variants (10)
SPOP p.Arg121Gln (c.362G>A)
Gain-of-function variant; NSDVS type 1 (congenital microcephaly). Also a recurrent endometrial cancer somatic mutation.
Show evidence (1 reference)
PMID:32109420 SUPPORT In Vitro
"The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn), identified in the first two individuals, resulted in a gain of function"
Functional classification of this variant as gain-of-function.
SPOP p.Asp144Asn (c.430G>A)
Gain-of-function variant; NSDVS type 1.
Show evidence (1 reference)
PMID:32109420 SUPPORT In Vitro
"The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn), identified in the first two individuals, resulted in a gain of function"
Functional classification of this variant as gain-of-function.
SPOP p.Thr25Ala (c.73A>G)
Dominant-negative variant; NSDVS type 2.
Show evidence (1 reference)
PMID:32109420 SUPPORT In Vitro
"the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect"
Functional classification of this variant as dominant-negative.
SPOP p.Tyr83Cys (c.248A>G)
Dominant-negative variant; NSDVS type 2.
Show evidence (1 reference)
PMID:32109420 SUPPORT In Vitro
"the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect"
Functional classification of this variant as dominant-negative.
SPOP p.Gly132Val (c.395G>T)
Dominant-negative variant; NSDVS type 2.
Show evidence (1 reference)
PMID:32109420 SUPPORT In Vitro
"the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect"
Functional classification of this variant as dominant-negative.
SPOP p.Arg138Cys (c.412C>T)
Dominant-negative variant; NSDVS type 2.
Show evidence (1 reference)
PMID:32109420 SUPPORT In Vitro
"the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect"
Functional classification of this variant as dominant-negative.
SPOP p.Arg121Trp (c.361C>T)
Later-reported missense at the Arg121 hotspot; classified as NSDVS type 1.
Show evidence (1 reference)
PMID:39918173 SUPPORT Human Clinical
"The girl, followed-up from the first months of life to 11 years of age, presented with a de novo heterozygous missense in Exon 5 of the SPOP gene (NM_001007228.2:c.361C>T, p.Arg121Trp) and, thus, classified as NSDVS Type 1."
Reports this novel variant and its type 1 classification.
SPOP p.Met117Ile (c.351G>T)
Later-reported missense classified in silico as gain-of-function (NSDVS type 1).
Show evidence (2 references)
PMID:42147571 SUPPORT Human Clinical
"Exome sequencing revealed a heterozygous missense variant: NM_001007228.2(SPOP):c.351G>T(p.Met117Ile)."
Reports this novel variant in a patient diagnosed with NSDVS type 1.
PMID:42147571 SUPPORT Computational
"In silicotesting classifies this variant as likely pathogenic with protein gain of function, which confirms the diagnosis of NSDVS type 1."
In silico (not experimental) classification of the variant as gain-of-function.
SPOP p.Tyr353Ter (BACK-domain truncation)
De novo nonsense variant truncating the BACK domain, reported with mixed type 1 and type 2 features; proposed to act by attenuating SPOP higher-order oligomerization.
Show evidence (1 reference)
PMID:36063898 SUPPORT Human Clinical
"Here, we report a novel and de novo heterozygous nonsense pathogenic variant, p.Tyr353Term at the BACK domain in a patient with neurodevelopmental delay plus mixed phenotypes of NSDVS type 1 and 2 using trio exome analysis."
Reports the truncating variant and its mixed-type presentation.
SPOP p.Cys23Arg (c.67T>C)
De novo missense near the MATH domain in an infant with an enlarged head circumference (type 2-like presentation); showed decreased mutant mRNA and protein expression in transfected cells.
Show evidence (2 references)
PMID:36259278 SUPPORT Human Clinical
"Trio-whole exome sequencing was used to identify the SPOP mutation c.67 T > C (p.Cys23Arg)."
Reports the novel variant in an infant with a neurodevelopmental disorder.
PMID:36259278 SUPPORT In Vitro
"Analysis via qPCR and WB experiments indicated decreased mutant mRNA and protein expression levels."
Cell-based expression data for the variant, consistent with reduced SPOP function.
💊

Medical Actions

3
Rehabilitation and Developmental Therapy
Action: rehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is rehabilitation (NCIT:C15315). NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Management is supportive; early rehabilitation training addresses motor, language, and adaptive delays. No disease-specific therapy exists.
Show evidence (1 reference)
PMID:36259278 SUPPORT Human Clinical
"Prompt testing will provide more accurate diagnoses, which in turn offers evidence to assist in the formulation of rehabilitation training plans, and genetic counseling for patients' families."
Rehabilitation training is the management step enabled by molecular diagnosis in this ultrarare disorder.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling for families follows molecular confirmation; because all reported variants are de novo, recurrence risk for parents is low.
Show evidence (1 reference)
PMID:36259278 SUPPORT Human Clinical
"Prompt testing will provide more accurate diagnoses, which in turn offers evidence to assist in the formulation of rehabilitation training plans, and genetic counseling for patients' families."
Genetic counseling is a core management component after diagnosis.
Multidisciplinary Supportive Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Multidisciplinary follow-up (developmental, ophthalmological, audiological, cardiological) matches the multi-system phenotype.
Show evidence (1 reference)
PMID:42147571 SUPPORT Human Clinical
"This case report of a Mexican girl contributes to the expansion of the phenotypic spectrum of NSDVS and supports the implementation of improved multidisciplinary follow-up for affected patients."
Supports multidisciplinary follow-up as the recommended model of care.
🔬

Diagnosis

1
Trio Exome Sequencing
Diagnosis is molecular. There are no consensus clinical diagnostic criteria, and the facial gestalt has low specificity in infancy, so the diagnosis rests on identifying a de novo pathogenic SPOP variant - typically by trio (proband plus parents) exome sequencing with Sanger confirmation, which also establishes the de novo origin needed for counseling.
trio whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:36259278 SUPPORT Human Clinical
"Trio-whole exome sequencing of the patient's family was performed, and a variant was identified by bioinformatics analysis and further verified by Sanger sequencing."
The diagnostic route actually used: trio exome sequencing with Sanger confirmation.
PMID:36259278 SUPPORT Human Clinical
"Our findings suggest that genetic testing should be performed as soon as possible for children with NDD showing low phenotypic specificity."
States the diagnostic strategy for this low-specificity presentation: early genetic testing rather than clinical criteria.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Approximately 10-13 molecularly confirmed cases had been published as of 2025-2026; the syndrome was first described in 2020.
Show evidence (1 reference)
PMID:39918173 SUPPORT Human Clinical
"To date, only 10 cases have been described presenting with intellectual disability, neurological signs and symptoms, and a variable association of dysmorphic features."
Documents the extreme rarity of the syndrome as a literature case count.
🐁

Animal Models

1
Spop-null mouse
Spop-null mice model complete loss of Spop function rather than the heterozygous missense classes seen in patients. They show skeletal defects (brachydactyly, osteopenia, impaired chondrocyte/osteoblast differentiation) driven by GLI3-repressor accumulation, and grossly normal spinal cord dorsoventral patterning despite increased Gli3 protein.
Species
Mouse
Genotype
Spop-null (constitutive and conditional)
Publication
PMID:27930311
Pathograph links
Impaired CUL3-SPOP Substrate Degradation perturbs fidelity: low Genetic Spop ablation removes SPOP-dependent substrate degradation in vivo, an extreme version of the reduced-function state produced by the human dominant-negative class, and identifies GLI3 as an in vivo SPOP substrate.
Limitations: Complete biallelic loss in mouse versus heterozygous dominant-negative missense in patients; the mouse phenotype is predominantly skeletal, and the human neurocognitive and craniofacial syndrome is not reproduced. The GLI3/Hedgehog axis has not been examined in patient tissue.
Readouts
Gli3 protein level in Spop-null tissue
Direction: INCREASED
Interpretation: Accumulation of an endogenous SPOP substrate when SPOP-mediated degradation is lost, grounding the degradation node in vivo.
Show evidence (1 reference)
PMID:27930311 SUPPORT Model Organism
"Strikingly, both the full-length and repressor forms of Gli3, but not Gli2, were up-regulated in Spop mutants, and Ihh target genes Patched 1 (Ptch1) and parathyroid hormone-like peptide (Pthlh) were down-regulated, indicating compromised Hh signaling."
Direct in vivo measurement of GLI3 accumulation upon loss of SPOP-mediated degradation.
Show evidence (1 reference)
PMID:28412462 SUPPORT Model Organism
"This correlates with a moderate but significant increase in the level of Gli3 protein in the Spop mutant spinal cords."
Shows the model is informative for SPOP-dependent substrate degradation in neural tissue in vivo.
{ }

Source YAML

click to show 
name: SPOP-Related Neurodevelopmental Disorder
creation_date: "2026-09-02T13:30:00Z"
category: Mendelian
description: >-
  SPOP-related neurodevelopmental disorder (Nabais Sa-de Vries syndrome, NSDVS)
  is an autosomal dominant condition caused by de novo missense variants in
  SPOP, which encodes the MATH-domain substrate-recognition adaptor of the
  CUL3-RING E3 ubiquitin ligase. Affected individuals show developmental delay
  and/or intellectual disability, congenital anomalies, and a recognizable
  facial gestalt. Functional studies distinguish two variant classes with
  opposite effects on SPOP-mediated substrate ubiquitination: gain-of-function
  variants that increase substrate (including BET protein) degradation cause
  NSDVS type 1 with congenital microcephaly (OMIM:618828, this MONDO term),
  whereas dominant-negative variants that impair substrate degradation cause
  NSDVS type 2 with relative macrocephaly and hypertelorism (OMIM:618829,
  MONDO:0032943). Somatic SPOP mutation is separately a well-known driver of
  prostate and endometrial cancer; that is a distinct, non-heritable disease
  process and is contextual background only for this germline disorder.
synonyms:
- Nabais Sa-de Vries syndrome
- NSDVS
- NEDMIDF
disease_term:
  preferred_term: neurodevelopmental disorder with microcephaly and dysmorphic facies
  term:
    id: MONDO:0032942
    label: neurodevelopmental disorder with microcephaly and dysmorphic facies
parents:
- Mendelian neurodevelopmental disorder
inheritance:
- name: Autosomal dominant (de novo)
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    All molecularly confirmed individuals reported to date carry heterozygous
    de novo SPOP variants; no familial transmission has been described.
  evidence:
  - reference: PMID:36063898
    reference_title: "C-terminal truncated SPOP, a Janus-faced variant, causing a mixed type 1 and type 2 Nabais Sa-de Vries syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nabais Sa-de Vries syndrome (NSDVS) is an autosomal dominant
      neurodevelopmental disorder first described in 2020 and is classified
      into type 1 (NSDVS1) and type 2 (NSDVS2) which encompassed of spectrum
      of distinct clinical features due to gain-of-function (GOF) and
      loss-of-function (LOF) variants respectively.
    explanation: >-
      States the autosomal dominant inheritance pattern and the two-type
      classification of the syndrome.
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By using clinical exome sequencing, we identified six de novo pathogenic
      missense variants in SPOP in seven individuals with developmental delay
      and/or intellectual disability, facial dysmorphisms, and congenital
      anomalies.
    explanation: >-
      The defining cohort: every pathogenic SPOP variant was de novo,
      supporting dominant disease from new heterozygous mutations.
has_subtypes:
- name: Type 1
  display_name: NSDVS type 1 (microcephaly; gain-of-function)
  subtype_term:
    preferred_term: neurodevelopmental disorder with microcephaly and dysmorphic facies
    term:
      id: MONDO:0032942
      label: neurodevelopmental disorder with microcephaly and dysmorphic facies
  description: >-
    NSDVS type 1 (OMIM:618828) is caused by gain-of-function SPOP variants
    (e.g. p.Arg121Gln, p.Asp144Asn) that increase SPOP-mediated substrate
    degradation. The craniofacial phenotype includes congenital microcephaly,
    narrow forehead, highly arched eyebrows, and blepharophimosis; hearing
    loss and ocular abnormalities are recurrent.
  genes:
  - preferred_term: SPOP
    term:
      id: hgnc:11254
      label: SPOP
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two individuals shared craniofacial dysmorphisms, including congenital
      microcephaly, that were strikingly different from those of the other
      five individuals, who had (relative) macrocephaly and hypertelorism.
    explanation: >-
      Defines the microcephalic subgroup that became NSDVS type 1, contrasted
      with the macrocephalic type 2 subgroup.
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn),
      identified in the first two individuals, resulted in a gain of function
    explanation: >-
      Assigns the microcephalic individuals' variants to the gain-of-function
      class in cell-based assays.
- name: Type 2
  display_name: NSDVS type 2 (relative macrocephaly; dominant-negative)
  subtype_term:
    preferred_term: neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies
    term:
      id: MONDO:0032943
      label: neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies
  description: >-
    NSDVS type 2 (OMIM:618829) is caused by dominant-negative SPOP variants
    (p.Thr25Ala, p.Tyr83Cys, p.Gly132Val, p.Arg138Cys) that impair
    SPOP-mediated substrate degradation. The phenotype includes relative
    macrocephaly, hypertelorism, and broad forehead, with or without cardiac
    or endocrine anomalies (per the MONDO term for this subtype).
  genes:
  - preferred_term: SPOP
    term:
      id: hgnc:11254
      label: SPOP
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val),
      and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative
      effect
    explanation: >-
      Assigns the macrocephalic individuals' variants to the dominant-negative
      class in cell-based assays.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Approximately 10-13 molecularly confirmed cases had been published as of
    2025-2026; the syndrome was first described in 2020.
  evidence:
  - reference: PMID:39918173
    reference_title: "Clinical Insights Into Nabais Sá-De Vries Syndrome due to a Novel SPOP Mutation: Neuromotor, Cognitive, Adaptive, Behavioral, and Neurovisual Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only 10 cases have been described presenting with intellectual
      disability, neurological signs and symptoms, and a variable association
      of dysmorphic features.
    explanation: >-
      Documents the extreme rarity of the syndrome as a literature case count.
mechanistic_hypotheses:
- hypothesis_group_id: bet_bidirectional_dysregulation
  hypothesis_label: Bidirectional BET protein dysregulation drives the contrasting phenotypes
  status: EMERGING
  description: >-
    The two clinical types track with opposite functional effects of SPOP
    variants on substrate ubiquitination, measured on BET proteins
    (BRD2/BRD3/BRD4) in endometrial cancer cell models: gain-of-function
    variants deplete BET proteins (type 1, microcephaly) while
    dominant-negative variants stabilize them (type 2, macrocephaly). Whether
    BET dysregulation itself, or dysregulation of other SPOP substrates, is
    the proximate driver of abnormal human brain development has not been
    established in neural cells or in vivo.
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings suggest that these opposite functional effects caused by
      the variants in SPOP result in two distinct and clinically recognizable
      syndromic forms of intellectual disability with contrasting craniofacial
      dysmorphisms.
    explanation: >-
      The genotype-phenotype correlation at the core of the hypothesis:
      opposite biochemical effects segregate with opposite craniofacial
      phenotypes.
  - reference: PMID:28805821
    reference_title: "Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we analyzed changes in the ubiquitin landscape induced by
      endometrial cancer-associated SPOP mutations and identified BRD2, BRD3
      and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially
      degraded by endometrial cancer-associated SPOP mutants.
    explanation: >-
      Establishes BET proteins as SPOP-CUL3 substrates whose degradation is
      bidirectionally modulated by SPOP mutation class, the biochemical basis
      borrowed by the germline model.
pathophysiology:
- name: De Novo SPOP Missense Variation
  biological_scale: MOLECULAR
  description: >-
    Heterozygous de novo missense variants alter SPOP, the MATH-domain
    substrate-recognition adaptor that docks substrates onto the CUL3-RING E3
    ubiquitin ligase. NSDVS variants cluster in and around the MATH
    substrate-binding domain and split into two functional classes with
    opposite consequences for substrate turnover.
  genes:
  - preferred_term: SPOP
    term:
      id: hgnc:11254
      label: SPOP
  molecular_functions:
  - preferred_term: ubiquitin ligase-substrate adaptor activity
    term:
      id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
  cellular_components:
  - preferred_term: CUL3-RING ubiquitin ligase complex
    term:
      id: GO:0031463
      label: Cul3-RING ubiquitin ligase complex
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By using clinical exome sequencing, we identified six de novo pathogenic
      missense variants in SPOP in seven individuals with developmental delay
      and/or intellectual disability, facial dysmorphisms, and congenital
      anomalies.
    explanation: >-
      Identifies de novo SPOP missense variation as the initiating lesion of
      the disorder.
  - reference: PMID:19818708
    reference_title: "Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In the largest E3 ligase subfamily, Cul3 binds a BTB domain, and an
      associated protein-interaction domain such as MATH recruits substrates
      for ubiquitination.
    explanation: >-
      Structural basis for SPOP's role: the MATH domain recruits substrates to
      the CUL3 ligase, so missense change there alters substrate handling.
  downstream:
  - target: Increased CUL3-SPOP Substrate Degradation
    causal_link_type: DIRECT
    description: Gain-of-function variant class (NSDVS type 1).
    evidence:
    - reference: PMID:32109420
      reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A
        (p.Asp144Asn), identified in the first two individuals, resulted in a
        gain of function
      explanation: >-
        Cell-based assays show these de novo variants enhance SPOP function,
        the causal step from variant to increased substrate degradation.
  - target: Impaired CUL3-SPOP Substrate Degradation
    causal_link_type: DIRECT
    description: Dominant-negative variant class (NSDVS type 2).
    evidence:
    - reference: PMID:32109420
      reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T
        (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a
        dominant-negative effect
      explanation: >-
        Cell-based assays show these de novo variants act dominant-negatively,
        the causal step from variant to impaired substrate degradation.
- name: Increased CUL3-SPOP Substrate Degradation
  biological_scale: MOLECULAR
  description: >-
    Gain-of-function variants (NSDVS type 1) enhance SPOP-mediated
    ubiquitination, accelerating proteasomal degradation of SPOP substrates.
  genetic_context:
    functional_impact_category: GAIN_OF_FUNCTION
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    description: >-
      Type 1 variants p.Arg121Gln and p.Asp144Asn (and, per later case
      reports, p.Arg121Trp and p.Met117Ile).
  biological_processes:
  - preferred_term: proteasome-mediated degradation of SPOP substrates
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn),
      identified in the first two individuals, resulted in a gain of function
    explanation: >-
      Direct functional classification of the type 1 variants as
      gain-of-function toward SPOP substrate handling.
  downstream:
  - target: Reduced BET Protein Abundance
    causal_link_type: DIRECT
    hypothesis_groups:
    - bet_bidirectional_dysregulation
    evidence:
    - reference: PMID:28805821
      reference_title: "Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Here we analyzed changes in the ubiquitin landscape induced by
        endometrial cancer-associated SPOP mutations and identified BRD2, BRD3
        and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are
        preferentially degraded by endometrial cancer-associated SPOP mutants.
      explanation: >-
        Shows that gain-type SPOP mutants preferentially degrade BET proteins;
        the NSDVS type 1 variant p.Arg121Gln is one of the endometrial
        cancer-type mutants studied, so the edge is inferred from the shared
        mutation class rather than from neural tissue.
- name: Impaired CUL3-SPOP Substrate Degradation
  biological_scale: MOLECULAR
  description: >-
    Dominant-negative variants (NSDVS type 2) interfere with residual
    wild-type SPOP, repressing ubiquitination and proteasomal degradation of
    SPOP substrates.
  genetic_context:
    functional_impact_category: DOMINANT_NEGATIVE
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    description: >-
      Type 2 variants p.Thr25Ala, p.Tyr83Cys, p.Gly132Val, and p.Arg138Cys.
  biological_processes:
  - preferred_term: proteasome-mediated degradation of SPOP substrates
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val),
      and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative
      effect
    explanation: >-
      Direct functional classification of the type 2 variants as
      dominant-negative toward SPOP substrate handling.
  downstream:
  - target: BET Protein Accumulation
    causal_link_type: DIRECT
    hypothesis_groups:
    - bet_bidirectional_dysregulation
    evidence:
    - reference: PMID:28805821
      reference_title: "Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Conversely, prostate cancer-specific SPOP mutations resulted in
        impaired degradation of BETs, promoting their resistance to
        pharmacologic inhibition.
      explanation: >-
        Shows that dominant-negative SPOP mutants stabilize BET proteins; the
        NSDVS type 2 class shares this dominant-negative mechanism, so the
        edge is inferred from the mutation class rather than from neural
        tissue.
- name: Reduced BET Protein Abundance
  biological_scale: CELLULAR
  description: >-
    Enhanced SPOP activity depletes BET family proteins (BRD2, BRD3, BRD4),
    chromatin readers broadly required for transcriptional regulation. In the
    defining study, type 1 patient variants reduced BET protein amounts in
    endometrial cancer cells and patient-derived cell lines.
  genes:
  - preferred_term: BRD2
    term:
      id: hgnc:1103
      label: BRD2
  - preferred_term: BRD3
    term:
      id: hgnc:1104
      label: BRD3
  - preferred_term: BRD4
    term:
      id: hgnc:13575
      label: BRD4
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We measured the effect of SPOP variants on BET protein amounts in human
      Ishikawa endometrial cancer cells and patient-derived cell lines because
      we hypothesized that variants would lead to functional divergent effects
      on BET proteins.
    explanation: >-
      BET protein abundance was the functional readout used to classify the
      NSDVS variants, including in patient-derived cells.
  downstream:
  - target: Aberrant Neurodevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - bet_bidirectional_dysregulation
    description: >-
      Inferred step: how reduced BET protein levels (or depletion of other
      SPOP substrates) perturbs human brain growth has not been demonstrated
      directly; the association rests on the genotype-phenotype correlation.
  - target: Congenital Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - bet_bidirectional_dysregulation
    description: >-
      Head-size correlation for the gain-of-function class: the individuals
      whose variants deplete BET proteins are the individuals with congenital
      microcephaly. The intermediate steps are unknown.
    evidence:
    - reference: PMID:32109420
      reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Two individuals shared craniofacial dysmorphisms, including congenital
        microcephaly, that were strikingly different from those of the other
        five individuals, who had (relative) macrocephaly and hypertelorism.
      explanation: >-
        The congenital-microcephaly individuals are exactly the
        gain-of-function (BET-depleting) variant carriers, supporting the
        class-to-head-size edge by correlation.
- name: BET Protein Accumulation
  biological_scale: CELLULAR
  description: >-
    Dominant-negative SPOP variants stabilize BET family proteins (BRD2,
    BRD3, BRD4) by repressing their ubiquitin-dependent degradation, the
    opposite cellular state to the type 1 class.
  genes:
  - preferred_term: BRD2
    term:
      id: hgnc:1103
      label: BRD2
  - preferred_term: BRD3
    term:
      id: hgnc:1104
      label: BRD3
  - preferred_term: BRD4
    term:
      id: hgnc:13575
      label: BRD4
  evidence:
  - reference: PMID:28805821
    reference_title: "Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Conversely, prostate cancer-specific SPOP mutations resulted in impaired
      degradation of BETs, promoting their resistance to pharmacologic
      inhibition.
    explanation: >-
      Demonstrates BET protein stabilization by dominant-negative SPOP
      mutants, the mechanism shared by the NSDVS type 2 variant class.
  downstream:
  - target: Aberrant Neurodevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - bet_bidirectional_dysregulation
    description: >-
      Inferred step: how BET protein accumulation (or stabilization of other
      SPOP substrates) perturbs human brain growth has not been demonstrated
      directly; the association rests on the genotype-phenotype correlation.
  - target: Relative Macrocephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - bet_bidirectional_dysregulation
    description: >-
      Head-size correlation for the dominant-negative class: the individuals
      whose variants stabilize BET proteins are the individuals with
      (relative) macrocephaly. The intermediate steps are unknown.
    evidence:
    - reference: PMID:32109420
      reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Two individuals shared craniofacial dysmorphisms, including congenital
        microcephaly, that were strikingly different from those of the other
        five individuals, who had (relative) macrocephaly and hypertelorism.
      explanation: >-
        The macrocephaly individuals are exactly the dominant-negative
        (BET-stabilizing) variant carriers, supporting the class-to-head-size
        edge by correlation.
- name: Aberrant Neurodevelopment
  biological_scale: ORGANISM
  description: >-
    Disturbed brain growth and development producing global developmental
    delay, intellectual disability, and abnormal head size, with the direction
    of head-size change tracking the variant class: congenital microcephaly in
    the gain-of-function type 1 and relative macrocephaly in the
    dominant-negative type 2.
  downstream:
  - target: Global Developmental Delay
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32109420
      reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        By using clinical exome sequencing, we identified six de novo pathogenic
        missense variants in SPOP in seven individuals with developmental delay
        and/or intellectual disability, facial dysmorphisms, and congenital
        anomalies.
      explanation: >-
        Developmental delay is the clinical expression of the disturbed
        neurodevelopment in every reported individual.
  - target: Intellectual Disability
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32109420
      reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our findings suggest that these opposite functional effects caused by
        the variants in SPOP result in two distinct and clinically recognizable
        syndromic forms of intellectual disability with contrasting craniofacial
        dysmorphisms.
      explanation: >-
        Both syndromic forms are described as forms of intellectual
        disability, the cognitive expression of the aberrant
        neurodevelopment.
  - target: Language Disorder
    causal_link_type: DIRECT
    description: >-
      Delayed language acquisition is part of the developmental expression of
      the disturbed neurodevelopment.
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings suggest that these opposite functional effects caused by
      the variants in SPOP result in two distinct and clinically recognizable
      syndromic forms of intellectual disability with contrasting craniofacial
      dysmorphisms.
    explanation: >-
      Connects the two molecular classes to the two clinically distinct
      neurodevelopmental syndromes.
  - reference: PMID:39918173
    reference_title: "Clinical Insights Into Nabais Sá-De Vries Syndrome due to a Novel SPOP Mutation: Neuromotor, Cognitive, Adaptive, Behavioral, and Neurovisual Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings suggest a predominant involvement of the central nervous
      system in NSDVS and expand the phenotypic spectrum of this syndrome.
    explanation: >-
      Longitudinal phenotyping supports the central nervous system as the
      primary organ system affected.
phenotypes:
- name: Global Developmental Delay
  category: Neurological
  description: >-
    Motor and language milestones are delayed from infancy in both types.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By using clinical exome sequencing, we identified six de novo pathogenic
      missense variants in SPOP in seven individuals with developmental delay
      and/or intellectual disability, facial dysmorphisms, and congenital
      anomalies.
    explanation: >-
      Developmental delay was a defining feature in all seven individuals of
      the original cohort, supporting the VERY_FREQUENT band.
  - reference: PMID:42147571
    reference_title: "Nabais Sá-de Vries Syndrome Type 1 in a Mexican Girl: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She currently has delayed neurodevelopment and language acquisition, as
      well as microcephaly, low weight and height, and normal hearing.
    explanation: >-
      Case-level documentation of delayed neurodevelopment in a type 1
      patient.
- name: Intellectual Disability
  category: Neurological
  description: >-
    Intellectual disability, commonly of moderate degree, is a core feature.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39918173
    reference_title: "Clinical Insights Into Nabais Sá-De Vries Syndrome due to a Novel SPOP Mutation: Neuromotor, Cognitive, Adaptive, Behavioral, and Neurovisual Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only 10 cases have been described presenting with intellectual
      disability, neurological signs and symptoms, and a variable association
      of dysmorphic features.
    explanation: >-
      Intellectual disability is reported across the described cases,
      supporting the VERY_FREQUENT band.
- name: Congenital Microcephaly
  category: Craniofacial
  subtype: Type 1
  description: >-
    Congenital microcephaly characterizes the gain-of-function type 1
    phenotype.
  phenotype_term:
    preferred_term: Congenital microcephaly
    term:
      id: HP:0011451
      label: Primary microcephaly
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two individuals shared craniofacial dysmorphisms, including congenital
      microcephaly, that were strikingly different from those of the other
      five individuals, who had (relative) macrocephaly and hypertelorism.
    explanation: >-
      Congenital microcephaly defined the type 1 subgroup in the original
      cohort.
  - reference: PMID:35892095
    reference_title: "Ocular manifestations of Nabais Sa-de Vries Syndrome type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similar to other individuals with NSDVS1, he had features of congenital
      microcephaly, developmental delay, behavioral abnormalities, hearing
      loss, and facial dysmorphisms.
    explanation: >-
      Independent case confirming congenital microcephaly as a recurrent
      type 1 feature.
- name: Relative Macrocephaly
  category: Craniofacial
  subtype: Type 2
  description: >-
    Relative or absolute macrocephaly characterizes the dominant-negative
    type 2 phenotype.
  phenotype_term:
    preferred_term: Relative macrocephaly
    term:
      id: HP:0004482
      label: Relative macrocephaly
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two individuals shared craniofacial dysmorphisms, including congenital
      microcephaly, that were strikingly different from those of the other
      five individuals, who had (relative) macrocephaly and hypertelorism.
    explanation: >-
      (Relative) macrocephaly defined the type 2 subgroup in the original
      cohort.
  - reference: PMID:36259278
    reference_title: "Nabais Sa-de Vries syndrome in a Chinese infant associated with a novel SPOP mutation: A clinical study and genetic report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 7-month-old boy presented with an enlarged head circumference,
      widened eye distance, and a protruding nose.
    explanation: >-
      Case with a novel SPOP variant showing enlarged head circumference, the
      type 2-like head-size phenotype.
- name: Hypertelorism
  category: Craniofacial
  subtype: Type 2
  description: Widely spaced eyes are recurrent in the type 2 phenotype.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two individuals shared craniofacial dysmorphisms, including congenital
      microcephaly, that were strikingly different from those of the other
      five individuals, who had (relative) macrocephaly and hypertelorism.
    explanation: >-
      Hypertelorism co-defined the type 2 subgroup in the original cohort.
- name: Facial Dysmorphism
  category: Craniofacial
  description: >-
    A shared facial gestalt distinguishes each type: narrow forehead, highly
    arched eyebrows, and blepharophimosis in type 1; broad forehead and
    hypertelorism in type 2.
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By using clinical exome sequencing, we identified six de novo pathogenic
      missense variants in SPOP in seven individuals with developmental delay
      and/or intellectual disability, facial dysmorphisms, and congenital
      anomalies.
    explanation: >-
      Facial dysmorphism was present across the defining cohort, supporting
      the VERY_FREQUENT band.
- name: Blepharophimosis
  category: Ophthalmological
  subtype: Type 1
  description: Narrowed palpebral fissures are part of the type 1 gestalt.
  phenotype_term:
    preferred_term: Blepharophimosis
    term:
      id: HP:0000581
      label: Blepharophimosis
  evidence:
  - reference: PMID:39918173
    reference_title: "Clinical Insights Into Nabais Sá-De Vries Syndrome due to a Novel SPOP Mutation: Neuromotor, Cognitive, Adaptive, Behavioral, and Neurovisual Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Along with a global developmental delay, she showed microcephaly,
      dysmorphic features (such as narrow forehead, highly arched eyebrows,
      and blepharophimosis), moderate intellectual disability, adaptive
      difficulties, language disorder, and several neurovisual signs and
      symptoms (such as refractive errors, strabismus, nystagmus, altered
      oculomotor functions and deficits of visual acuity, and contrast
      sensitivity).
    explanation: >-
      Documents blepharophimosis within the type 1 facial gestalt.
- name: Ptosis
  category: Ophthalmological
  subtype: Type 1
  description: Eyelid ptosis is among the recurrent periorbital features.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:35892095
    reference_title: "Ocular manifestations of Nabais Sa-de Vries Syndrome type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ocular and periorbital manifestations in this patient included thick
      high-arched eyebrows, mild synophrys, long eyelashes, ptosis, and
      downslanting palpebral fissures; comparable to features described in
      other individuals with NSDVS1.
    explanation: >-
      Ptosis is listed among the recurrent periorbital manifestations of
      type 1.
- name: Downslanted Palpebral Fissures
  category: Ophthalmological
  description: Downslanting palpebral fissures recur across reported cases.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:35892095
    reference_title: "Ocular manifestations of Nabais Sa-de Vries Syndrome type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ocular and periorbital manifestations in this patient included thick
      high-arched eyebrows, mild synophrys, long eyelashes, ptosis, and
      downslanting palpebral fissures; comparable to features described in
      other individuals with NSDVS1.
    explanation: >-
      Downslanting palpebral fissures are among the recurrent periorbital
      features.
- name: Strabismus
  category: Ophthalmological
  description: >-
    Strabismus (including surgically managed esotropia) and refractive errors
    are recurrent ocular features.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:35892095
    reference_title: "Ocular manifestations of Nabais Sa-de Vries Syndrome type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, this patient had esotropia that required multiple
      strabismus surgeries and a refractive error that required the use of
      corrective lenses.
    explanation: >-
      Documents esotropia requiring surgery in a type 1 patient.
  - reference: PMID:39918173
    reference_title: "Clinical Insights Into Nabais Sá-De Vries Syndrome due to a Novel SPOP Mutation: Neuromotor, Cognitive, Adaptive, Behavioral, and Neurovisual Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Along with a global developmental delay, she showed microcephaly,
      dysmorphic features (such as narrow forehead, highly arched eyebrows,
      and blepharophimosis), moderate intellectual disability, adaptive
      difficulties, language disorder, and several neurovisual signs and
      symptoms (such as refractive errors, strabismus, nystagmus, altered
      oculomotor functions and deficits of visual acuity, and contrast
      sensitivity).
    explanation: >-
      Independent case documenting strabismus among the neurovisual features.
- name: Nystagmus
  category: Ophthalmological
  description: Nystagmus is among the reported neurovisual abnormalities.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:39918173
    reference_title: "Clinical Insights Into Nabais Sá-De Vries Syndrome due to a Novel SPOP Mutation: Neuromotor, Cognitive, Adaptive, Behavioral, and Neurovisual Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Along with a global developmental delay, she showed microcephaly,
      dysmorphic features (such as narrow forehead, highly arched eyebrows,
      and blepharophimosis), moderate intellectual disability, adaptive
      difficulties, language disorder, and several neurovisual signs and
      symptoms (such as refractive errors, strabismus, nystagmus, altered
      oculomotor functions and deficits of visual acuity, and contrast
      sensitivity).
    explanation: >-
      Documents nystagmus among the neurovisual signs in a type 1 patient.
- name: Hearing Impairment
  category: Otolaryngological
  subtype: Type 1
  description: >-
    Hearing loss is recurrent in type 1; reported as hearing loss or
    hypoacusia and as abnormal newborn hearing screening, without the
    mechanism (sensorineural vs conductive) being established across cases.
  phenotype_term:
    preferred_term: Hearing loss
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:35892095
    reference_title: "Ocular manifestations of Nabais Sa-de Vries Syndrome type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similar to other individuals with NSDVS1, he had features of congenital
      microcephaly, developmental delay, behavioral abnormalities, hearing
      loss, and facial dysmorphisms.
    explanation: >-
      Hearing loss is listed among the recurrent type 1 features.
- name: Behavioral Abnormalities
  category: Behavioral
  description: >-
    Behavioral abnormalities and adaptive difficulties are reported in
    several individuals.
  phenotype_term:
    preferred_term: Behavioral abnormalities
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:35892095
    reference_title: "Ocular manifestations of Nabais Sa-de Vries Syndrome type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similar to other individuals with NSDVS1, he had features of congenital
      microcephaly, developmental delay, behavioral abnormalities, hearing
      loss, and facial dysmorphisms.
    explanation: >-
      Behavioral abnormalities are listed among the recurrent type 1
      features.
- name: Language Disorder
  category: Neurological
  description: >-
    Delayed language acquisition and language disorder are consistently
    reported.
  phenotype_term:
    preferred_term: Language disorder
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:42147571
    reference_title: "Nabais Sá-de Vries Syndrome Type 1 in a Mexican Girl: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She currently has delayed neurodevelopment and language acquisition, as
      well as microcephaly, low weight and height, and normal hearing.
    explanation: >-
      Documents delayed language acquisition in a type 1 patient.
- name: Congenital Heart Disease
  category: Cardiovascular
  description: >-
    Congenital heart defects are among the reported congenital anomalies in
    both types. The general term is kept deliberately: the reported cardiac
    findings are heterogeneous (patent ductus arteriosus, patent foramen
    ovale, and pulmonary hypertension in a type 1 girl; patent foramen ovale
    and tricuspid regurgitation in another infant; unspecified cardiovascular
    anomalies in the type 2 founding-cohort group), and no single specific
    lesion characterizes the syndrome. Deliberately not subtype-keyed because
    cardiac disease is documented in type 1 cases as well as the type 2
    group; the type 2-specific claim is carried by the Cardiovascular
    Anomalies phenotype.
  phenotype_term:
    preferred_term: Congenital heart disease
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:42147571
    reference_title: "Nabais Sá-de Vries Syndrome Type 1 in a Mexican Girl: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A medical genetic evaluation was initiated at one week of age due to
      congenital heart disease.
    explanation: >-
      Documents congenital heart disease as the presenting anomaly in a
      type 1 patient.
- name: Patent Ductus Arteriosus
  category: Cardiovascular
  description: >-
    Reported in a type 1 neonate together with patent foramen ovale and
    pulmonary hypertension.
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:42147571
    reference_title: "Nabais Sá-de Vries Syndrome Type 1 in a Mexican Girl: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Findings included a patent ductus arteriosus, a patent foramen ovale,
      and pulmonary hypertension, which added to minor dysmorphic features
      and warranted a medical genetic evaluation.
    explanation: >-
      Names the specific neonatal cardiac lesions in a type 1 patient.
- name: Patent Foramen Ovale
  category: Cardiovascular
  description: >-
    Patent foramen ovale has been reported in two unrelated infants (one
    type 1, one with a type 2-like presentation).
  phenotype_term:
    preferred_term: Patent foramen ovale
    term:
      id: HP:0001655
      label: Patent foramen ovale
  evidence:
  - reference: PMID:42147571
    reference_title: "Nabais Sá-de Vries Syndrome Type 1 in a Mexican Girl: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Findings included a patent ductus arteriosus, a patent foramen ovale,
      and pulmonary hypertension, which added to minor dysmorphic features
      and warranted a medical genetic evaluation.
    explanation: >-
      Documents patent foramen ovale in the type 1 proband.
  - reference: PMID:36259278
    reference_title: "Nabais Sa-de Vries syndrome in a Chinese infant associated with a novel SPOP mutation: A clinical study and genetic report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An echocardiography revealed a patent foramen ovale and tricuspid
      regurgitation
    explanation: >-
      Independent infant case with patent foramen ovale.
- name: Cardiovascular Anomalies
  category: Cardiovascular
  subtype: Type 2
  description: >-
    Cardiovascular anomalies are a systemic manifestation associated with the
    type 2 phenotype (4/4 of the type 2 individuals in the founding cohort);
    the MONDO concept for type 2 names cardiac anomalies in its label.
  phenotype_term:
    preferred_term: Cardiovascular anomalies
    term:
      id: HP:0001626
      label: Abnormality of the cardiovascular system
  evidence:
  - reference: PMID:42147571
    reference_title: "Nabais Sá-de Vries Syndrome Type 1 in a Mexican Girl: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The second phenotype is also associated with systemic manifestations
      such as short stature and failure to thrive, as well as cardiovascular
      and endocrinological anomalies, epilepsy, and sleep disorders,
      demonstrating pleiotropy
    explanation: >-
      Literature synthesis (summarizing the founding cohort) attributing
      cardiovascular anomalies to the type 2 phenotype.
- name: Epilepsy
  category: Neurological
  subtype: Type 2
  description: Epilepsy is reported among the type 2 systemic manifestations.
  phenotype_term:
    preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:42147571
    reference_title: "Nabais Sá-de Vries Syndrome Type 1 in a Mexican Girl: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The second phenotype is also associated with systemic manifestations
      such as short stature and failure to thrive, as well as cardiovascular
      and endocrinological anomalies, epilepsy, and sleep disorders,
      demonstrating pleiotropy
    explanation: >-
      Literature synthesis (summarizing the founding cohort) attributing
      epilepsy to the type 2 phenotype.
- name: Sleep Disturbance
  category: Neurological
  subtype: Type 2
  description: >-
    Sleep disorders are reported among the type 2 systemic manifestations.
  phenotype_term:
    preferred_term: Sleep disorders
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:42147571
    reference_title: "Nabais Sá-de Vries Syndrome Type 1 in a Mexican Girl: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The second phenotype is also associated with systemic manifestations
      such as short stature and failure to thrive, as well as cardiovascular
      and endocrinological anomalies, epilepsy, and sleep disorders,
      demonstrating pleiotropy
    explanation: >-
      Literature synthesis (summarizing the founding cohort) attributing
      sleep disorders to the type 2 phenotype.
- name: Endocrine Anomalies
  category: Endocrine
  subtype: Type 2
  description: >-
    Endocrine anomalies are reported among the type 2 systemic
    manifestations; the MONDO concept for type 2 names endocrine anomalies
    in its label.
  phenotype_term:
    preferred_term: Endocrinological anomalies
    term:
      id: HP:0000818
      label: Abnormality of the endocrine system
  evidence:
  - reference: PMID:42147571
    reference_title: "Nabais Sá-de Vries Syndrome Type 1 in a Mexican Girl: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The second phenotype is also associated with systemic manifestations
      such as short stature and failure to thrive, as well as cardiovascular
      and endocrinological anomalies, epilepsy, and sleep disorders,
      demonstrating pleiotropy
    explanation: >-
      Literature synthesis (summarizing the founding cohort) attributing
      endocrinological anomalies to the type 2 phenotype.
- name: Short Stature
  category: Growth
  subtype: Type 2
  description: >-
    Short stature is reported among the type 2 systemic manifestations.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:42147571
    reference_title: "Nabais Sá-de Vries Syndrome Type 1 in a Mexican Girl: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The second phenotype is also associated with systemic manifestations
      such as short stature and failure to thrive, as well as cardiovascular
      and endocrinological anomalies, epilepsy, and sleep disorders,
      demonstrating pleiotropy
    explanation: >-
      Literature synthesis (summarizing the founding cohort) attributing
      short stature to the type 2 phenotype.
- name: Failure to Thrive
  category: Growth
  subtype: Type 2
  description: >-
    Failure to thrive is reported among the type 2 systemic manifestations.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:42147571
    reference_title: "Nabais Sá-de Vries Syndrome Type 1 in a Mexican Girl: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The second phenotype is also associated with systemic manifestations
      such as short stature and failure to thrive, as well as cardiovascular
      and endocrinological anomalies, epilepsy, and sleep disorders,
      demonstrating pleiotropy
    explanation: >-
      Literature synthesis (summarizing the founding cohort) attributing
      failure to thrive to the type 2 phenotype.
- name: Ventriculomegaly
  category: Neurological
  description: >-
    Enlargement of the lateral and third ventricles with a thin corpus
    callosum was documented on MRI in one reported infant.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:36259278
    reference_title: "Nabais Sa-de Vries syndrome in a Chinese infant associated with a novel SPOP mutation: A clinical study and genetic report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging showed enlargement of the bilateral
      lateral ventricles and the third ventricle, with the frontal horn of
      the bilateral lateral ventricles and the anterior part of the body
      obviously deformed.
    explanation: >-
      MRI documentation of ventriculomegaly in a reported infant.
genetic:
- name: SPOP
  gene_term:
    preferred_term: SPOP
    term:
      id: hgnc:11254
      label: SPOP
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  association: >-
    Heterozygous de novo missense (and rare truncating) variants in SPOP
    cause both types of Nabais Sa-de Vries syndrome; the functional class of
    the variant determines the type.
  notes: >-
    Somatic SPOP mutation is separately one of the most recurrent driver
    events in prostate cancer (dominant-negative class) and endometrial
    cancer (gain-of-function class). The germline NSDVS variants overlap
    these functional classes (e.g. p.Arg121Gln is an endometrial-type
    gain-of-function change), but the cancers are somatic, non-heritable
    processes and are not part of this disorder's phenotype; no tumor
    predisposition has been established in NSDVS.
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By using clinical exome sequencing, we identified six de novo pathogenic
      missense variants in SPOP in seven individuals with developmental delay
      and/or intellectual disability, facial dysmorphisms, and congenital
      anomalies.
    explanation: >-
      Establishes de novo SPOP variants as the cause of the disorder.
  variants:
  - name: SPOP p.Arg121Gln (c.362G>A)
    description: >-
      Gain-of-function variant; NSDVS type 1 (congenital microcephaly). Also
      a recurrent endometrial cancer somatic mutation.
    evidence:
    - reference: PMID:32109420
      reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A
        (p.Asp144Asn), identified in the first two individuals, resulted in a
        gain of function
      explanation: >-
        Functional classification of this variant as gain-of-function.
  - name: SPOP p.Asp144Asn (c.430G>A)
    description: Gain-of-function variant; NSDVS type 1.
    evidence:
    - reference: PMID:32109420
      reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A
        (p.Asp144Asn), identified in the first two individuals, resulted in a
        gain of function
      explanation: >-
        Functional classification of this variant as gain-of-function.
  - name: SPOP p.Thr25Ala (c.73A>G)
    description: Dominant-negative variant; NSDVS type 2.
    evidence:
    - reference: PMID:32109420
      reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T
        (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a
        dominant-negative effect
      explanation: >-
        Functional classification of this variant as dominant-negative.
  - name: SPOP p.Tyr83Cys (c.248A>G)
    description: Dominant-negative variant; NSDVS type 2.
    evidence:
    - reference: PMID:32109420
      reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T
        (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a
        dominant-negative effect
      explanation: >-
        Functional classification of this variant as dominant-negative.
  - name: SPOP p.Gly132Val (c.395G>T)
    description: Dominant-negative variant; NSDVS type 2.
    evidence:
    - reference: PMID:32109420
      reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T
        (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a
        dominant-negative effect
      explanation: >-
        Functional classification of this variant as dominant-negative.
  - name: SPOP p.Arg138Cys (c.412C>T)
    description: Dominant-negative variant; NSDVS type 2.
    evidence:
    - reference: PMID:32109420
      reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T
        (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a
        dominant-negative effect
      explanation: >-
        Functional classification of this variant as dominant-negative.
  - name: SPOP p.Arg121Trp (c.361C>T)
    description: >-
      Later-reported missense at the Arg121 hotspot; classified as NSDVS
      type 1.
    evidence:
    - reference: PMID:39918173
      reference_title: "Clinical Insights Into Nabais Sá-De Vries Syndrome due to a Novel SPOP Mutation: Neuromotor, Cognitive, Adaptive, Behavioral, and Neurovisual Features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The girl, followed-up from the first months of life to 11 years of
        age, presented with a de novo heterozygous missense in Exon 5 of the
        SPOP gene (NM_001007228.2:c.361C>T, p.Arg121Trp) and, thus,
        classified as NSDVS Type 1.
      explanation: >-
        Reports this novel variant and its type 1 classification.
  - name: SPOP p.Met117Ile (c.351G>T)
    description: >-
      Later-reported missense classified in silico as gain-of-function
      (NSDVS type 1).
    evidence:
    - reference: PMID:42147571
      reference_title: "Nabais Sá-de Vries Syndrome Type 1 in a Mexican Girl: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Exome sequencing revealed a heterozygous missense variant:
        NM_001007228.2(SPOP):c.351G>T(p.Met117Ile).
      explanation: >-
        Reports this novel variant in a patient diagnosed with NSDVS type 1.
    - reference: PMID:42147571
      reference_title: "Nabais Sá-de Vries Syndrome Type 1 in a Mexican Girl: A Case Report."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        In silicotesting classifies this variant as likely pathogenic with
        protein gain of function, which confirms the diagnosis of NSDVS
        type 1.
      explanation: >-
        In silico (not experimental) classification of the variant as
        gain-of-function.
  - name: SPOP p.Tyr353Ter (BACK-domain truncation)
    description: >-
      De novo nonsense variant truncating the BACK domain, reported with
      mixed type 1 and type 2 features; proposed to act by attenuating SPOP
      higher-order oligomerization.
    evidence:
    - reference: PMID:36063898
      reference_title: "C-terminal truncated SPOP, a Janus-faced variant, causing a mixed type 1 and type 2 Nabais Sa-de Vries syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we report a novel and de novo heterozygous nonsense pathogenic
        variant, p.Tyr353Term at the BACK domain in a patient with
        neurodevelopmental delay plus mixed phenotypes of NSDVS type 1 and 2
        using trio exome analysis.
      explanation: >-
        Reports the truncating variant and its mixed-type presentation.
  - name: SPOP p.Cys23Arg (c.67T>C)
    description: >-
      De novo missense near the MATH domain in an infant with an enlarged
      head circumference (type 2-like presentation); showed decreased mutant
      mRNA and protein expression in transfected cells.
    evidence:
    - reference: PMID:36259278
      reference_title: "Nabais Sa-de Vries syndrome in a Chinese infant associated with a novel SPOP mutation: A clinical study and genetic report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Trio-whole exome sequencing was used to identify the SPOP mutation
        c.67 T > C (p.Cys23Arg).
      explanation: >-
        Reports the novel variant in an infant with a neurodevelopmental
        disorder.
    - reference: PMID:36259278
      reference_title: "Nabais Sa-de Vries syndrome in a Chinese infant associated with a novel SPOP mutation: A clinical study and genetic report."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Analysis via qPCR and WB experiments indicated decreased mutant mRNA
        and protein expression levels.
      explanation: >-
        Cell-based expression data for the variant, consistent with reduced
        SPOP function.
diagnosis:
- name: Trio Exome Sequencing
  description: >-
    Diagnosis is molecular. There are no consensus clinical diagnostic
    criteria, and the facial gestalt has low specificity in infancy, so the
    diagnosis rests on identifying a de novo pathogenic SPOP variant -
    typically by trio (proband plus parents) exome sequencing with Sanger
    confirmation, which also establishes the de novo origin needed for
    counseling.
  diagnosis_term:
    preferred_term: trio whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:36259278
    reference_title: "Nabais Sa-de Vries syndrome in a Chinese infant associated with a novel SPOP mutation: A clinical study and genetic report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Trio-whole exome sequencing of the patient's family was performed, and
      a variant was identified by bioinformatics analysis and further
      verified by Sanger sequencing.
    explanation: >-
      The diagnostic route actually used: trio exome sequencing with Sanger
      confirmation.
  - reference: PMID:36259278
    reference_title: "Nabais Sa-de Vries syndrome in a Chinese infant associated with a novel SPOP mutation: A clinical study and genetic report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings suggest that genetic testing should be performed as soon
      as possible for children with NDD showing low phenotypic specificity.
    explanation: >-
      States the diagnostic strategy for this low-specificity presentation:
      early genetic testing rather than clinical criteria.
treatments:
- name: Rehabilitation and Developmental Therapy
  description: >-
    Management is supportive; early rehabilitation training addresses motor,
    language, and adaptive delays. No disease-specific therapy exists.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: PMID:36259278
    reference_title: "Nabais Sa-de Vries syndrome in a Chinese infant associated with a novel SPOP mutation: A clinical study and genetic report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prompt testing will provide more accurate diagnoses, which in turn
      offers evidence to assist in the formulation of rehabilitation training
      plans, and genetic counseling for patients' families.
    explanation: >-
      Rehabilitation training is the management step enabled by molecular
      diagnosis in this ultrarare disorder.
- name: Genetic Counseling
  description: >-
    Genetic counseling for families follows molecular confirmation; because
    all reported variants are de novo, recurrence risk for parents is low.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:36259278
    reference_title: "Nabais Sa-de Vries syndrome in a Chinese infant associated with a novel SPOP mutation: A clinical study and genetic report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prompt testing will provide more accurate diagnoses, which in turn
      offers evidence to assist in the formulation of rehabilitation training
      plans, and genetic counseling for patients' families.
    explanation: >-
      Genetic counseling is a core management component after diagnosis.
- name: Multidisciplinary Supportive Care
  description: >-
    Multidisciplinary follow-up (developmental, ophthalmological, audiological,
    cardiological) matches the multi-system phenotype.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:42147571
    reference_title: "Nabais Sá-de Vries Syndrome Type 1 in a Mexican Girl: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case report of a Mexican girl contributes to the expansion of the
      phenotypic spectrum of NSDVS and supports the implementation of improved
      multidisciplinary follow-up for affected patients.
    explanation: >-
      Supports multidisciplinary follow-up as the recommended model of care.
animal_models:
- name: Spop-null mouse
  species: Mouse
  genotype: Spop-null (constitutive and conditional)
  publication: PMID:27930311
  description: >-
    Spop-null mice model complete loss of Spop function rather than the
    heterozygous missense classes seen in patients. They show skeletal defects
    (brachydactyly, osteopenia, impaired chondrocyte/osteoblast
    differentiation) driven by GLI3-repressor accumulation, and grossly normal
    spinal cord dorsoventral patterning despite increased Gli3 protein.
  modeled_mechanisms:
  - target: Impaired CUL3-SPOP Substrate Degradation
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      Genetic Spop ablation removes SPOP-dependent substrate degradation in
      vivo, an extreme version of the reduced-function state produced by the
      human dominant-negative class, and identifies GLI3 as an in vivo SPOP
      substrate.
    limitations: >-
      Complete biallelic loss in mouse versus heterozygous dominant-negative
      missense in patients; the mouse phenotype is predominantly skeletal, and
      the human neurocognitive and craniofacial syndrome is not reproduced.
      The GLI3/Hedgehog axis has not been examined in patient tissue.
    readouts:
    - name: Gli3 protein level in Spop-null tissue
      target: Impaired CUL3-SPOP Substrate Degradation
      direction: INCREASED
      interpretation: >-
        Accumulation of an endogenous SPOP substrate when SPOP-mediated
        degradation is lost, grounding the degradation node in vivo.
      evidence:
      - reference: PMID:27930311
        reference_title: "Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Strikingly, both the full-length and repressor forms of Gli3, but
          not Gli2, were up-regulated in Spop mutants, and Ihh target genes
          Patched 1 (Ptch1) and parathyroid hormone-like peptide (Pthlh) were
          down-regulated, indicating compromised Hh signaling.
        explanation: >-
          Direct in vivo measurement of GLI3 accumulation upon loss of
          SPOP-mediated degradation.
    evidence:
    - reference: PMID:28412462
      reference_title: "Spop regulates Gli3 activity and Shh signaling in dorsoventral patterning of the mouse spinal cord."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This correlates with a moderate but significant increase in the level
        of Gli3 protein in the Spop mutant spinal cords.
      explanation: >-
        Shows the model is informative for SPOP-dependent substrate
        degradation in neural tissue in vivo.
discussions:
- discussion_id: neural_substrate_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which SPOP substrates mediate the neurodevelopmental phenotype in vivo,
    and do the BET protein changes measured in endometrial cancer cell models
    occur in human neural cells?
  rationale: >-
    The functional classification of NSDVS variants rests on BET protein
    abundance measured in Ishikawa endometrial cancer cells and
    patient-derived (non-neural) cell lines. SPOP has many other substrates,
    and no neural cell model, brain organoid, or in vivo study has yet linked
    a specific substrate to the abnormal brain growth, so the middle of the
    causal chain (substrate dysregulation to aberrant neurodevelopment) is
    inferred from genotype-phenotype correlation.
  attaches_to:
  - pathophysiology#Reduced BET Protein Abundance
  - pathophysiology#BET Protein Accumulation
  evidence:
  - reference: PMID:32109420
    reference_title: "De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We measured the effect of SPOP variants on BET protein amounts in human
      Ishikawa endometrial cancer cells and patient-derived cell lines because
      we hypothesized that variants would lead to functional divergent effects
      on BET proteins.
    explanation: >-
      Shows the functional evidence base is cancer cell lines and
      patient-derived non-neural cells, not neural systems, which is the gap
      this discussion records.
- discussion_id: oligomerization_mixed_phenotype
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    How do BACK-domain truncations that attenuate SPOP higher-order
    oligomerization produce mixed type 1/type 2 phenotypes, and should
    oligomerization state be modeled as a third functional class?
  rationale: >-
    A de novo p.Tyr353Ter BACK-domain truncation was reported with combined
    type 1 and type 2 features. Because the BACK domain drives higher-order
    oligomerization that enhances substrate avidity and ubiquitylation
    efficiency, a truncation could simultaneously reduce degradation of some
    substrates and dysregulate others, blurring the binary gain/loss model
    used in this entry's pathophysiology.
  attaches_to:
  - genetic#SPOP
  - pathophysiology#De Novo SPOP Missense Variation
  evidence:
  - reference: PMID:36063898
    reference_title: "C-terminal truncated SPOP, a Janus-faced variant, causing a mixed type 1 and type 2 Nabais Sa-de Vries syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude the p.Tyr353Term is a Janus-faced variant which explains
      the dual NSDVS type 1 and 2 phenotypes in this case.
    explanation: >-
      The mixed-phenotype case motivating the question.
  - reference: PMID:36063898
    reference_title: "C-terminal truncated SPOP, a Janus-faced variant, causing a mixed type 1 and type 2 Nabais Sa-de Vries syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The BACK domain is functionally critical for the SPOP higher-order
      oligomerization and is shown to increase substrate binding avidity with
      enhanced ubiquitylation efficiency in vitro.
    explanation: >-
      In vitro basis for expecting BACK-domain truncation to perturb
      oligomerization-dependent substrate handling.
- discussion_id: gli3_hedgehog_axis_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does SPOP-dependent GLI3/Hedgehog dysregulation, firmly established in
    mouse genetics, contribute to the human SPOP neurodevelopmental syndrome?
  rationale: >-
    Mouse studies show that Spop targets the Gli3 repressor for degradation in
    vivo and that reducing Gli3 dosage rescues the Spop-null skeletal
    phenotype - unusually strong genetic evidence for a SPOP-GLI3 axis. But
    the mouse phenotype is predominantly skeletal, Spop-null spinal cord
    patterning is grossly normal, and no study has examined GLI3 or Hedgehog
    signaling in patient-derived neural tissue, so the translational validity
    of this axis for the human microcephaly/macrocephaly and cognitive
    phenotype is the open question. The BET-protein model (this entry's
    pathograph) and the GLI3 axis are not mutually exclusive.
  attaches_to:
  - pathophysiology#Impaired CUL3-SPOP Substrate Degradation
  - animal_models#Spop-null mouse
  evidence:
  - reference: PMID:27930311
    reference_title: "Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with this finding, reducing Gli3 dosage greatly rescued the
      Spop mutant skeletal defects.
    explanation: >-
      The genetic rescue that establishes GLI3 as the mediator of the mouse
      Spop-null phenotype, motivating the question of its role in the human
      syndrome.
  - reference: PMID:28412462
    reference_title: "Spop regulates Gli3 activity and Shh signaling in dorsoventral patterning of the mouse spinal cord."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we show that loss of Spop does not alter spinal cord patterning,
      but it suppresses the loss of floor plate and V3 interneuron phenotype
      of Gli2 mutants, suggesting a negative role of Spop in Gli3 activator
      activity, Shh signaling and the specification of ventral cell fates in
      the spinal cord.
    explanation: >-
      Shows the context dependence of the neural Hedgehog effect in the
      model, part of why fidelity to the human syndrome is uncertain.
notes: >-
  MONDO models the two OMIM types as separate diseases: this entry is keyed to
  MONDO:0032942 (NSDVS type 1, OMIM:618828) and carries NSDVS type 2
  (MONDO:0032943, OMIM:618829) as a subtype, since both are SPOP allelic
  disorders distinguished only by variant functional class and are described
  together in the defining literature.
📚

References & Deep Research

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 23 citations 2026-09-02T13:37:56.273909

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: SPOP-Related Neurodevelopmental Disorder
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on SPOP-Related Neurodevelopmental Disorder covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

SPOP-Related Neurodevelopmental Disorder

Executive summary

SPOP-related neurodevelopmental disorder is an ultra-rare, autosomal-dominant developmental disorder caused principally by heterozygous de novo missense variants in SPOP, encoding the substrate-recognition adaptor of the CUL3–RBX1 E3 ubiquitin-ligase complex. It is also called Nabais Sá–de Vries syndrome (NSDVS). Two molecularly and clinically distinguishable forms have been proposed: a microcephaly/hearing-loss form associated with SPOP variants that increase degradation of BET-family proteins, and a macrocephaly/multisystem form associated with dominant-negative variants that increase BET-protein abundance. The foundational evidence remains a 2020 series of only seven individuals; therefore, frequencies, penetrance, prognosis, and genotype–phenotype relationships are provisional. (sa2020denovovariants pages 2-4, sa2020denovovariants pages 1-2)

The strongest disease-specific mechanism is altered stability of BRD2, BRD3, and BRD4. SPOP–GLI3/Hedgehog dysregulation is strongly supported by mouse genetic and rescue studies but has not been demonstrated in affected human neural tissue. No disease-modifying treatment, clinical-management guideline, validated biomarker, epidemiologic estimate, or relevant interventional trial was identified. Current care is multidisciplinary and symptom directed. (sa2020denovovariants pages 5-6, cai2016spoppromotesskeletal pages 4-5, olivareshuerta2026nabaissádevries pages 7-8, olivareshuerta2026nabaissádevries pages 8-9)

Domain Key finding Quantitative detail Evidence type Source/date/DOI
Disease definition Foundational description of SPOP-related neurodevelopmental disorder identified two clinically distinct syndromic presentations caused by de novo SPOP missense variants 7 affected individuals; 6 unique de novo missense variants; ascertainment from large exome cohorts including 4,749 unexplained ID cases, 1,133 developmental disorder cases, and 14,183 NDD cases Human clinical + human functional Sá et al., Am J Hum Genet, Mar 2020, doi:10.1016/j.ajhg.2020.02.001 (sa2020denovovariants pages 2-4, sa2020denovovariants pages 1-2)
Core phenotype Shared phenotype across reported individuals includes intellectual disability, motor delay, speech delay, facial dysmorphism, and congenital anomalies ID 7/7; motor delay 7/7; speech delay 7/7; facial dysmorphism 7/7; congenital anomalies 7/7 Human clinical Sá et al., Mar 2020, doi:10.1016/j.ajhg.2020.02.001 (sa2020denovovariants pages 2-4)
Variant group 1 p.Arg121Gln and p.Asp144Asn define a microcephaly/hearing-loss group with gain-of-function behavior toward BET protein reduction 2/7 individuals; congenital microcephaly 2/2; hearing loss 2/2 Human clinical + human cell functional Sá et al., Mar 2020, doi:10.1016/j.ajhg.2020.02.001 (sa2020denovovariants pages 2-4)
Variant group 2 p.Thr25Ala, p.Tyr83Cys, p.Gly132Val, and recurrent p.Arg138Cys define a macrocephaly/multisystem group with dominant-negative behavior and BET protein increase 5/7 individuals; macrocephaly/relative macrocephaly 5/5; cardiovascular abnormalities 4/4 reported; endocrine abnormalities 3/4; epilepsy 2/5; sleep disturbance 4/5; short stature/failure to thrive 2/5 Human clinical + human cell functional Sá et al., Mar 2020, doi:10.1016/j.ajhg.2020.02.001 (sa2020denovovariants pages 2-4)
Molecular mechanism in patients Opposite functional classes converge on dysregulation of BET proteins BRD2/3/4 Group 1 variants reduced BET protein amounts; group 2 variants increased BET protein amounts Human cell functional Sá et al., Mar 2020, doi:10.1016/j.ajhg.2020.02.001 (sa2020denovovariants pages 2-4, sa2020denovovariants pages 5-6)
Structural interpretation Disease variants cluster in or near the substrate-recognition region of SPOP, consistent with altered substrate handling 6 pathogenic missense alleles reported in MATH/BTB-related functional regions; recurrent p.Arg138Cys in 2 individuals Human genetics + structural inference Sá et al., Mar 2020, doi:10.1016/j.ajhg.2020.02.001 (sa2020denovovariants pages 4-5, sa2020denovovariants pages 5-6)
General SPOP biology SPOP is the substrate adaptor of the CUL3/RBX1 E3 ligase complex; substrate binding uses MATH domain, dimerization/oligomerization uses BTB/BACK, and LLPS-like condensates can enhance ubiquitination 374-aa protein; >33 substrates reported in review literature; BET proteins included among substrates Authoritative review; non-disease-specific Zhang et al., Cancer Research, Dec 2023, doi:10.1158/0008-5472.CAN-22-2801 (zhang2023deregulationofspop pages 1-1, zhang2023deregulationofspop pages 2-3); Ovalle et al., Sep 2021, doi:10.35509/01239015.717 (ovalle2021speckletypepozadaptor pages 2-5, ovalle2021speckletypepozadaptor pages 1-2)
Upstream/downstream interpretation Inferred: altered substrate recognition by mutant SPOP leads to abnormal BRD2/3/4 turnover, which likely perturbs cell-cycle progression and neuronal differentiation, contributing to head-size and neurodevelopmental phenotypes No patient neural tissue transcriptomic/proteomic readout available Inference from human functional data + literature Sá et al., Mar 2020 (sa2020denovovariants pages 5-6); Zhang et al., Dec 2023 (zhang2023deregulationofspop pages 1-1)
Brain imaging/anatomy Available neuroimaging evidence is limited but includes ventriculomegaly in part of the macrocephaly group Postnatal ventriculomegaly reported in 2 individuals (individuals 3-4) Human clinical Sá et al., Mar 2020, doi:10.1016/j.ajhg.2020.02.001 (sa2020denovovariants pages 5-6)
Mouse developmental mechanism Spop regulates Gli3 abundance and modulates Shh/Hedgehog signaling during spinal cord development; nervous-system defects occur in some loss-of-function embryos Subset with exencephaly/spina bifida; normal D/V patterning in simple Spop mutants but severe ventralization in sensitized double/triple mutant contexts Mouse genetics/mechanistic Cai & Liu, Dev Biol, Dec 2017, doi:10.1016/j.ydbio.2017.04.002 (cai2017spopregulatesgli3 pages 9-9, cai2017spopregulatesgli3 pages 2-3, cai2017spopregulatesgli3 pages 3-7)
Mouse skeletal rescue Spop promotes skeletal development by restraining Gli3 repressor; lowering Gli3 dosage rescues Spop skeletal phenotypes Spop-null/conditional mice show brachydactyly, osteopenia, delayed ossification; rescue demonstrated in Spop;Gli3+/− backgrounds Mouse genetics + rescue Cai & Liu, PNAS, Dec 2016, doi:10.1073/pnas.1612520114 (cai2016spoppromotesskeletal pages 4-5, cai2016spoppromotesskeletal pages 5-5, cai2016spoppromotesskeletal pages 1-1, cai2016spoppromotesskeletal pages 1-2, cai2016spoppromotesskeletal pages 2-4)
Relevance of animal models to human NDD Inferred/plausible branch: GLI3/Hedgehog dysregulation may contribute to human SPOP syndrome, but this has not been directly demonstrated in patient-derived neural tissue or patient cohorts 0 direct patient GLI3/Hedgehog biomarker studies identified Cross-species inference/data gap Human study + mouse studies (sa2020denovovariants pages 5-6, cai2017spopregulatesgli3 pages 9-9, cai2016spoppromotesskeletal pages 1-2)
Recent developments (2023-2024) Recent literature places SPOP-related disease within the broader chromatinopathy/epigene-disorder landscape and emphasizes epigenetic-state imbalance as a diagnostic concept Review notes 154 epigenes linked to chromatinopathies overall; no SPOP-specific episignature demonstrated in retrieved evidence 2024 review; contextual Bukowska-Olech et al., J Appl Genet, Jan 2024, doi:10.1007/s13353-023-00824-1 (context available from paper search results; no disease-specific context ID extracted)
Diagnostics Real-world identification is via exome/genome-based rare-disease diagnostics, typically trio analysis with de novo confirmation All foundational SPOP variants were de novo; Sanger confirmation reported Human clinical genomics Sá et al., Mar 2020, doi:10.1016/j.ajhg.2020.02.001 (sa2020denovovariants pages 2-4)
Epidemiology Ultra-rare Mendelian disorder; no prevalence or incidence estimates were found in retrieved authoritative sources Prevalence: not available; incidence: not available Data gap No retrievable disease-specific epidemiology in available evidence (sa2020denovovariants pages 2-4, olivareshuerta2026nabaissádevries pages 8-9)
Treatment/guidelines No disease-specific pharmacologic therapy, gene therapy, or formal management guideline identified 0 relevant clinical trials found; 0 disease-specific treatment studies found Negative evidence / data gap Clinical-trial searches negative; case-report literature states no follow-up guidelines established (olivareshuerta2026nabaissádevries pages 7-8, olivareshuerta2026nabaissádevries pages 8-9)
Current care implementation Management is phenotype-driven multidisciplinary care rather than syndrome-specific therapy Specialists explicitly suggested include neurology, cardiology, ophthalmology, and otorhinolaryngology Case report / extrapolated standard care Olivares-Huerta et al., Cureus, Apr 2026, doi:10.7759/cureus.107064 (olivareshuerta2026nabaissádevries pages 7-8, olivareshuerta2026nabaissádevries pages 8-9)
Evidence gaps No disease-specific natural history, survival statistics, QoL studies, penetrance estimates, protective factors, environmental triggers, gene-environment interactions, single-cell/spatial omics, or episignature validation were found 0 direct studies identified for each listed category in retrieved evidence Data gap Synthesized from all retrieved evidence (sa2020denovovariants pages 2-4, olivareshuerta2026nabaissádevries pages 8-9)

Table: This compact table summarizes the strongest available evidence for SPOP-related neurodevelopmental disorder, spanning the founding human cohort, mechanistic variant groups, relevant SPOP biology, and model-organism studies. It also highlights major evidence gaps, including the lack of disease-specific trials or guidelines.

1. Disease information

Definition and scope

The disorder was delineated by Sá and colleagues in The American Journal of Human Genetics in 2020. Clinical exome sequencing identified seven affected individuals carrying six unique de novo SPOP missense variants. Every individual had intellectual disability, motor delay, speech delay, facial dysmorphism, and congenital anomalies. Opposite effects on BET-protein abundance separated the cohort into two clinical groups. (sa2020denovovariants pages 2-4)

The source is therefore primarily an aggregated disease-level case series, although it is assembled from individual clinical records and sequencing results. The seven cases arose from large diagnostic cohorts, including 4,749 individuals with unexplained intellectual disability, 1,133 with developmental disorders, and 14,183 with neurodevelopmental disorders; these denominators are ascertainment cohorts, not prevalence studies. (sa2020denovovariants pages 2-4)

Names and identifiers

  • Preferred descriptive name: SPOP-related neurodevelopmental disorder.
  • Eponym: Nabais Sá–de Vries syndrome.
  • Subtype terminology: Nabais Sá–de Vries syndrome type 1/type 2; published usage is not yet fully standardized, so knowledge-base records should retain the functional and phenotypic description alongside any subtype number.
  • Gene: SPOP, speckle-type POZ protein; chromosomal locus 17q21.33. (ovalle2021speckletypepozadaptor pages 2-5)
  • MONDO, OMIM, Orphanet, ICD-10/11, and MeSH identifiers: not independently verified in the retrieved evidence. A dedicated syndrome-specific ICD or MeSH code was not demonstrated; clinically, coding will generally use manifestations such as developmental delay, intellectual disability, epilepsy, hearing loss, and congenital anomalies.

Key primary source

Sá MJN et al. “De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders.” Am J Hum Genet. Published February 27/March 5, 2020. DOI: 10.1016/j.ajhg.2020.02.001. The retrieved record did not expose a PMID, so one is not supplied here rather than risk an erroneous identifier. (sa2020denovovariants pages 2-4, sa2020denovovariants pages 5-6)

A source-supported summary quotation is: “all had intellectual disability, motor and speech delay, facial dysmorphisms”; the paper further separated them into two phenotypic groups according to opposite functional effects on BET proteins. (sa2020denovovariants pages 2-4)

2. Etiology

Causal factors and genetic risk

The established cause is a heterozygous germline SPOP variant affecting protein function. In the foundational series, all variants were missense, de novo, and confirmed by Sanger sequencing:

  • NM-reference transcript as reported: c.73A>G, p.Thr25Ala
  • c.248A>G, p.Tyr83Cys
  • c.362G>A, p.Arg121Gln
  • c.395G>T, p.Gly132Val
  • c.412C>T, p.Arg138Cys, recurrent in two unrelated individuals
  • c.430G>A, p.Asp144Asn. (sa2020denovovariants pages 2-4)

These variants cluster in or near the SPOP MATH substrate-binding region, supporting altered substrate recognition rather than simple haploinsufficiency. Tyr83, Arg138, and Asp144 lie on a protein surface relevant to substrate interaction, whereas replacement of Gly132 by the larger valine was predicted to disturb local conformation. (sa2020denovovariants pages 4-5)

Environmental, infectious, and lifestyle risk

No environmental toxin, infection, maternal exposure, diet, smoking, alcohol use, occupation, or lifestyle factor has been shown to cause or modify this Mendelian disorder. No gene–environment interaction has been reported. Likewise, no protective genetic allele, modifier gene, diet, exposure, or behavioral factor is established.

Family history is usually absent because reported variants were de novo. A negative family history therefore does not reduce suspicion. Conversely, family history could become relevant if an affected person reproduces or if parental germline mosaicism is present, although neither was quantified in the available series. (sa2020denovovariants pages 2-4)

3. Phenotypes

All frequency estimates below are based on the original seven-person series and are vulnerable to missing data and ascertainment bias.

Core neurodevelopmental phenotype

  • Intellectual disability: 7/7; suggested HPO: Intellectual disability (HP:0001249).
  • Global/motor developmental delay: 7/7; suggested HPO: Global developmental delay (HP:0001263), Delayed gross motor development.
  • Speech/language delay: 7/7; suggested HPO: Delayed speech and language development (HP:0000750).
  • Facial dysmorphism and congenital anomalies: 7/7; use feature-specific HPO terms rather than a nonspecific dysmorphism term where possible. (sa2020denovovariants pages 2-4)

Developmental manifestations begin in infancy or early childhood and are chronic. Severity was variable, but sufficiently marked for all seven individuals to undergo clinical exome evaluation. The foundational cohort included children and adults aged approximately 4–20 years, demonstrating persistence rather than a transient delay. Available evidence does not establish neurodegeneration or regression. (sa2020denovovariants pages 4-4)

Microcephaly/BET-reduction group

The p.Arg121Gln and p.Asp144Asn group comprised two individuals:

  • Congenital microcephaly: 2/2; HPO HP:0000252.
  • Hearing loss: 2/2; HPO Hearing impairment (HP:0000365), with a more specific conductive/sensorineural term if audiology permits.
  • Craniofacial pattern: small forehead, highly arched eyebrows, blepharophimosis/narrow palpebral fissures, round face, prominent glabella, depressed nasal bridge, and micrognathia. Suggested HPO terms include Blepharophimosis (HP:0000581), Highly arched eyebrow, Depressed nasal bridge (HP:0005280), and Micrognathia (HP:0000347). (sa2020denovovariants pages 1-2, sa2020denovovariants pages 2-4)

Macrocephaly/BET-increase group

The other five individuals showed:

  • Macrocephaly or relative macrocephaly: 5/5; HPO Macrocephaly (HP:0000256) or Relative macrocephaly.
  • High/broad forehead, hypertelorism, long face, and widely spaced eyes; suggested HPO: High forehead (HP:0000348), Broad forehead (HP:0000337), Hypertelorism (HP:0000316), Long face (HP:0000276).
  • Cardiovascular abnormalities: 4/4 evaluated; HPO should be assigned at lesion level after echocardiography.
  • Endocrine abnormalities: 3/4 evaluated; assign the specific endocrine HPO term rather than a generic category.
  • Sleep disturbance: 4/5; HPO Sleep disturbance (HP:0002360).
  • Epilepsy/seizures: approximately 2/4–2/5, depending on the available-data denominator; HPO Seizure (HP:0001250) or epilepsy subtype after EEG classification.
  • Failure to thrive and/or short stature: approximately 2/5; HPO Failure to thrive (HP:0001508), Short stature (HP:0004322).
  • Postnatal ventriculomegaly was reported in individuals 3 and 4; HPO Ventriculomegaly (HP:0002119). (sa2020denovovariants pages 2-4, sa2020denovovariants pages 5-6)

Function and quality of life

Formal EQ-5D, SF-36, PROMIS, adaptive-function, or caregiver-burden data have not been published in the retrieved literature. Nonetheless, intellectual, motor, and speech impairment plausibly affect education, communication, independence, and daily living; hearing loss, epilepsy, sleep disturbance, and cardiac/endocrine disease add morbidity. These impacts are clinical inferences, not quantified syndrome-specific outcomes.

4. Genetic and molecular information

Gene and protein

SPOP encodes a 374-amino-acid predominantly nuclear protein. It contains an N-terminal MATH domain that recognizes SPOP-binding-consensus motifs in substrates, a BTB domain that binds CUL3 and supports dimerization, a BACK domain supporting higher-order oligomerization, and a C-terminal nuclear-localization sequence. SPOP acts as the substrate adaptor in a CUL3–RBX1 E3 ubiquitin-ligase complex and can mediate degradative or nondegradative polyubiquitination. (zhang2023deregulationofspop pages 1-1, zhang2023deregulationofspop pages 2-3, ovalle2021speckletypepozadaptor pages 1-2)

The 2023 authoritative review states that SPOP is a “substrate-binding adaptor of the CULLIN3/RING-box1 E3 ubiquitin ligase complex.” Oligomerization permits multivalent substrate binding and formation of phase-separated SPOP/substrate condensates that increase ubiquitination efficiency. Documented substrates include BRD4, androgen receptor, SRC-3, TRIM24, PD-L1, 53BP1, GLP/G9a, c-MYC, and SENP7. These general substrate relationships are largely derived from cancer/cell biology, not neural tissue from affected patients. (zhang2023deregulationofspop pages 1-1)

Suggested annotations include GO ubiquitin-protein transferase regulator activity, protein ubiquitination, proteasome-mediated ubiquitin-dependent protein catabolic process, regulation of transcription, and cellular components nucleus, nuclear speck, and biomolecular condensate. Exact GO accessions should be validated against the current GO release before database ingestion.

Variant consequences

  • p.Arg121Gln and p.Asp144Asn: disease study classified these as gain-of-function toward substrate degradation; they reduced BRD2/3/4 abundance and were associated with microcephaly and hearing loss.
  • p.Thr25Ala, p.Tyr83Cys, p.Gly132Val, and p.Arg138Cys: dominant-negative effects increased BET-protein abundance and were associated with macrocephaly and multisystem disease. (sa2020denovovariants pages 2-4)

Some retrieved secondary summaries reversed generic “loss-of-function/gain-of-function” labels while agreeing on the measured direction of BET abundance. For a knowledge base, the least ambiguous representation is therefore “BET-reducing SPOP functional class” versus “dominant-negative, BET-increasing class,” with the assay result stored separately from categorical labels. (sa2020denovovariants pages 2-4, sa2020denovovariants pages 5-6)

All six variants were germline in affected individuals, although de novo in origin. Somatic SPOP variants are well known in cancer, but somatic cancer mechanisms must not be conflated with this congenital disorder. No cancers had been reported in NSDVS in the later case-report literature. (sa2020denovovariants pages 5-6, olivareshuerta2026nabaissádevries pages 7-8)

Classification and population frequency

The founding report regarded these de novo variants as disease causing based on recurrence, absence/rarity in reference populations, phenotype concordance, structural location, and functional assays. However, variant-by-variant current ClinVar assertions, review status, and gnomAD frequencies were not independently retrieved. The knowledge base should query the current ClinVar and gnomAD releases and should not assume that every missense change in SPOP is pathogenic.

No disease modifier, protective allele, founder variant, epigenetic signature, chromosomal rearrangement, or recurrent pathogenic copy-number alteration is established. A later C-terminal truncating variant reportedly produced a mixed phenotype, but the full report was unavailable and cannot be characterized reliably here.

5. Environmental information

No non-genetic etiologic factor is established. Toxins, radiation, pollution, occupation, nutrition, exercise, alcohol, tobacco, and pathogens are not implicated as causes or validated modifiers. The disorder is not infectious or transmissible. Routine healthy-lifestyle and immunization advice remains appropriate for general health but is not syndrome-specific prevention.

6. Mechanism and pathophysiology

Ordered causal chain

  1. A heterozygous germline SPOP missense variant leads to altered structure or substrate recognition in/near the MATH substrate-binding region. (sa2020denovovariants pages 4-5)
  2. Altered substrate recognition leads to abnormal CUL3–RBX1-mediated ubiquitination and turnover of selected SPOP substrates. (zhang2023deregulationofspop pages 1-1, zhang2023deregulationofspop pages 2-3)
  3. Branch A: p.Arg121Gln/p.Asp144Asn lead to lower BRD2/BRD3/BRD4 abundance; Branch B: dominant-negative p.Thr25Ala/p.Tyr83Cys/p.Gly132Val/p.Arg138Cys lead to higher BRD2/BRD3/BRD4 abundance. This step was demonstrated in cellular assays. (sa2020denovovariants pages 2-4)
  4. Abnormal BET abundance is inferred to lead to altered chromatin-dependent transcription, cell-cycle timing, and neuronal differentiation; reduced BET levels were linked to accelerated cell-cycle progression and impaired neuronal differentiation, whereas increased levels were linked to increased differentiation. Direct confirmation in patient neural cells is lacking. (sa2020denovovariants pages 5-6)
  5. Altered progenitor proliferation/differentiation is inferred to result in opposite effects on brain growth—microcephaly versus macrocephaly—and disrupted circuit development results in intellectual, motor, and speech disability. (sa2020denovovariants pages 5-6, sa2020denovovariants pages 2-4)
  6. Additional model-supported branch: altered SPOP activity may lead to abnormal GLI3 turnover and Hedgehog-signal amplitude; this can result in neural-patterning and skeletal defects in mice, but this branch remains unproven in affected humans. (cai2016spoppromotesskeletal pages 4-5, cai2017spopregulatesgli3 pages 2-3, cai2017spopregulatesgli3 pages 3-7)
  7. Multisystem developmental disturbance results in craniofacial, auditory, cardiac, endocrine, growth, sleep, seizure, and other congenital manifestations. (sa2020denovovariants pages 2-4)

Molecular and cellular detail

SPOP oligomerization through BTB/BACK domains creates multivalent complexes and can promote liquid–liquid phase separation with substrates. This provides a biophysical mechanism by which relatively subtle substrate-binding changes could alter ubiquitination efficiency. Whether condensate properties are altered by NSDVS alleles has not been tested directly. (zhang2023deregulationofspop pages 1-1, ovalle2021speckletypepozadaptor pages 2-5)

BET proteins are chromatin readers involved in transcription and cell-cycle regulation. The human study’s BET-protein measurements provide the most direct disease-specific molecular readout. No patient-brain transcriptomics, neural proteomics, metabolomics, lipidomics, single-cell sequencing, spatial transcriptomics, or multi-omics dataset was identified. (sa2020denovovariants pages 5-6)

In mice, Spop directly regulates GLI3 abundance. Spop loss increases full-length and repressor GLI3 in spinal cord; uncomplicated mutants can retain normal dorsoventral patterning, whereas sensitized Gli/Sufu backgrounds show marked changes in Shh response and ventral cell fates. This context dependence cautions against a simplistic “SPOP activates” or “SPOP inhibits” Hedgehog model. (cai2017spopregulatesgli3 pages 9-9, cai2017spopregulatesgli3 pages 2-3, cai2017spopregulatesgli3 pages 3-7)

Suggested biological-process GO labels include neural precursor-cell proliferation, neuron differentiation, chromatin organization, regulation of cell cycle, protein polyubiquitination, Hedgehog signaling, spinal-cord patterning, chondrocyte differentiation, and osteoblast differentiation. Candidate Cell Ontology labels, based mainly on inferred targets and mouse evidence, include neural stem/progenitor cell, neuron, oligodendrocyte precursor cell, floor-plate cell, V3 interneuron, chondrocyte, hypertrophic chondrocyte, osteoblast, and limb mesenchymal cell. These are mechanistic annotations, not proven patient-cell lesions.

7. Anatomical structures affected

Organ and system level

  • Primary: central nervous system/brain, with abnormal brain growth and neurodevelopment.
  • Sensory: auditory system; vision abnormalities have appeared in case-report tables but were not quantified in the founding cohort.
  • Craniofacial structures.
  • Cardiovascular and endocrine systems, especially in the macrocephaly group.
  • Growth and skeletal system; direct skeletal mechanisms are strongest in mouse models.
  • Sleep and seizure networks as functional CNS manifestations. (sa2020denovovariants pages 2-4, cai2016spoppromotesskeletal pages 1-2)

Suggested UBERON labels include brain (UBERON:0000955), cerebral cortex (UBERON:0000956), spinal cord (UBERON:0002240), inner ear (UBERON:0001846), heart (UBERON:0000948), endocrine system, craniofacial skeleton, cartilage, and bone tissue. Ventriculomegaly implies ventricular-system involvement; no consistent lateralization has been reported. (sa2020denovovariants pages 5-6)

Subcellular level

The principal compartment is the nucleus, including nuclear speckles and SPOP/substrate condensates. The ubiquitin–proteasome system is the key biochemical machinery. SPOP’s nuclear localization sequence supports this localization. (zhang2023deregulationofspop pages 1-1, ovalle2021speckletypepozadaptor pages 1-2)

8. Temporal development

The disorder is congenital/developmental. Head-size abnormality and congenital anomalies may be evident prenatally or at birth, whereas developmental, speech, motor, seizure, sleep, and behavioral manifestations become apparent through infancy and childhood. Individuals aged up to 20 years were reported, supporting a chronic lifelong course. (sa2020denovovariants pages 4-4)

No validated clinical stages, progression rate, remission pattern, or critical therapeutic window has been defined. Available evidence is more consistent with a static developmental encephalopathy than demonstrated progressive neurodegeneration, but longitudinal data are inadequate. Early childhood is nevertheless a practical intervention window for hearing correction, developmental therapy, communication support, seizure treatment, nutrition, and cardiac/endocrine surveillance.

9. Inheritance and population

The expected inheritance pattern is autosomal dominant. All foundational cases were de novo; thus, most parents have a low recurrence risk, but recurrence is not zero because parental germline mosaicism cannot be excluded. An affected individual would theoretically have a 50% chance of transmitting the variant in each pregnancy, subject to reproductive fitness and uncertain penetrance. (sa2020denovovariants pages 2-4)

Penetrance appears high for the functionally established alleles, because every identified carrier was affected, but the sample is too small to estimate penetrance. Expressivity is variable and strongly related to functional class. Anticipation, founder effects, consanguinity, carrier frequency, and population-specific enrichment have not been demonstrated.

No incidence or prevalence per 100,000 is available. The original cohort’s sex distribution was approximately four females and three males, but seven cases cannot establish a sex ratio. Cases from different diagnostic settings suggest no demonstrated ethnic or geographic restriction. (sa2020denovovariants pages 4-4)

10. Diagnostics

Clinical recognition

Consider SPOP testing in a child with global developmental delay/intellectual disability, marked speech and motor delay, dysmorphic features, and congenital anomalies, especially when either of the following patterns is present:

  1. Congenital microcephaly plus hearing impairment and blepharophimosis-like craniofacial features.
  2. Macrocephaly/relative macrocephaly plus hypertelorism/high forehead, cardiac or endocrine anomalies, sleep disturbance, epilepsy, or abnormal growth. (sa2020denovovariants pages 2-4)

No consensus clinical diagnostic criteria exist. Phenotype alone is insufficient because many chromatinopathies and monogenic NDDs overlap.

Genetic testing strategy

  1. First choice: trio whole-exome or whole-genome sequencing with SNV/indel and copy-number analysis. All foundational diagnoses were made through clinical exome approaches and de novo status was confirmed by Sanger sequencing. (sa2020denovovariants pages 2-4)
  2. A comprehensive NDD/intellectual-disability panel that includes SPOP is reasonable where exome/genome sequencing is unavailable.
  3. Single-gene SPOP sequencing is appropriate when the phenotype is highly suggestive or for familial confirmation.
  4. Confirm candidate variants by an orthogonal method and test both parents to establish de novo status.
  5. Interpret missense variants using ACMG/AMP criteria, phenotype concordance, population frequency, domain location, computational/structural evidence, and—where available—functional evidence. Do not classify a novel SPOP missense variant solely from gene-level association.

WGS may detect noncoding and structural variants missed by WES, but no syndrome-specific incremental yield is known. CMA is useful in unexplained syndromic NDD but will generally miss the pathogenic single-nucleotide substitutions reported here. Karyotyping and FISH are not targeted tests for this disorder. Mitochondrial and repeat-expansion testing are not indicated specifically unless the differential diagnosis suggests them.

Phenotype-directed assessment

Recommended baseline characterization, based on reported manifestations rather than formal guidelines, includes developmental and neuropsychological assessment; speech/language and augmentative-communication evaluation; audiology; ophthalmology; neurologic examination and EEG if seizures are suspected; brain MRI when macrocephaly, microcephaly, seizures, focal findings, or regression warrant it; echocardiography/ECG; growth and nutrition evaluation; endocrine testing guided by symptoms; and skeletal assessment where clinically indicated. A 2026 case report explicitly noted that follow-up guidelines had not been established. (olivareshuerta2026nabaissádevries pages 7-8, olivareshuerta2026nabaissádevries pages 8-9)

Differential diagnosis

The differential includes other monogenic chromatinopathies and syndromic NDDs with abnormal head size, including disorders involving CUL3 ubiquitin-ligase adaptors or BET/chromatin regulation; PTEN-related macrocephaly, DNMT3A-related Tatton-Brown–Rahman syndrome, SETD2/Luscan–Lumish syndrome, KBG syndrome, Cornelia de Lange spectrum, and microcephaly-hearing-loss syndromes. Distinction depends on molecular testing and the direction of head-size change, hearing phenotype, characteristic face, and multisystem findings.

No validated biochemical, circulating, proteomic, metabolomic, methylation, or imaging biomarker exists. BET abundance was a research functional readout, not a clinical assay. No SPOP-specific episignature was demonstrated in the retrieved evidence.

11. Outcome and prognosis

No survival curve, mortality rate, life-expectancy estimate, five- or ten-year outcome, or disease-specific cause-of-death data exist. Survival into young adulthood was observed in the initial cohort. There is no evidence that germline NSDVS itself causes malignancy, despite the important role of somatic SPOP variants in cancer. (sa2020denovovariants pages 4-4, olivareshuerta2026nabaissádevries pages 7-8)

Expected morbidity is driven by lifelong intellectual, speech, and motor impairment and by variable hearing loss, epilepsy, sleep disorder, growth difficulty, cardiac disease, and endocrine disease. Recovery to typical neurodevelopment has not been documented. Functional gains from supportive therapy are plausible but have not been quantified. No prognostic molecular biomarker is validated; functional variant class and head-size phenotype are the leading candidate predictors, based on seven individuals only. (sa2020denovovariants pages 2-4)

12. Treatment

Current management

There is no approved or investigational syndrome-specific pharmacotherapy and no evidence-based treatment algorithm. Management is individualized:

  • early developmental intervention;
  • physical therapy—NCIt concept: Physical Therapy;
  • occupational therapy—NCIt: Occupational Therapy;
  • speech/language and augmentative-communication therapy—NCIt: Speech Therapy;
  • hearing aids, cochlear evaluation, or ENT treatment according to audiology;
  • standard antiseizure medication selected by seizure type;
  • sleep-hygiene and behavioral sleep treatment, with medication only when clinically indicated;
  • nutrition and feeding support;
  • standard cardiology and endocrine treatment for identified lesions;
  • educational, behavioral, psychosocial, and family support.

These interventions are extrapolated from standard management of the component manifestations; syndrome-specific response rates and adverse-event data do not exist. A later case report recommends coordinated neurology, cardiology, ophthalmology, and otorhinolaryngology care while explicitly acknowledging the absence of guidelines. (olivareshuerta2026nabaissádevries pages 7-8, olivareshuerta2026nabaissádevries pages 8-9)

Advanced and experimental therapy

No SPOP-directed gene replacement, editing, ASO, siRNA, mRNA, cell therapy, immunotherapy, or BET-modulating treatment has reached clinical testing for NSDVS. Although opposite BET abnormalities suggest a future genotype-specific therapeutic strategy, systemic BET inhibition or enhancement would have broad transcriptional and developmental effects and cannot presently be recommended. Cancer-directed SPOP or BET agents are not interchangeable with treatment for a germline developmental disorder. (sa2020denovovariants pages 5-6, zhang2023deregulationofspop pages 10-11)

ClinicalTrials.gov searches using SPOP-related NDD and Nabais Sá–de Vries terminology yielded no relevant interventional studies or NCT identifiers.

13. Prevention

Primary prevention through environmental or lifestyle modification is not available. Vaccination does not prevent this genetic disorder.

The actionable prevention framework is reproductive:

  • genetic counseling after molecular diagnosis;
  • parental testing and discussion of residual germline-mosaicism risk;
  • prenatal diagnosis through chorionic-villus sampling or amniocentesis for a known familial variant;
  • preimplantation genetic testing for monogenic disease where desired and legally available;
  • cascade testing if a parent or other relative is found to carry the variant.

Population carrier screening and newborn screening are not justified because the disorder is exceptionally rare, primarily de novo, and lacks a validated population assay or presymptomatic disease-modifying treatment. Secondary/tertiary prevention consists of early recognition and treatment of hearing loss, seizures, feeding/growth problems, cardiac abnormalities, endocrine disease, sleep problems, and developmental needs.

14. Other species and natural disease

No naturally occurring SPOP-related neurodevelopmental syndrome was found in companion animals, livestock, or wildlife. There is no zoonotic potential or cross-species transmission.

Orthologous systems include mouse Spop, Drosophila hib/roadkill, and corresponding vertebrate SPOP proteins. Conservation of CUL3-adaptor control of GLI/Cubitus interruptus supports comparative relevance, but species and tissue context alter pathway output. (cai2017spopregulatesgli3 pages 9-9, cai2017spopregulatesgli3 pages 2-3)

Suggested taxonomy identifiers are Homo sapiens NCBI Taxon 9606, Mus musculus 10090, Drosophila melanogaster 7227, and Xenopus laevis 8355. Ortholog-specific NCBI Gene identifiers should be validated directly in the current NCBI Gene record.

15. Model organisms

Mouse models

Spop-null and tissue-conditional mouse models are available as experimental rather than natural-disease models. Spop loss can cause neonatal lethality, delayed ossification, enlarged fontanelles, brachydactyly, osteopenia, impaired hypertrophic-chondrocyte and osteoblast differentiation, and occasional exencephaly or spina bifida. (cai2017spopregulatesgli3 pages 2-3, cai2016spoppromotesskeletal pages 1-2, cai2016spoppromotesskeletal pages 2-4)

In skeletal tissue, Spop loss increased GLI3 repressor, reduced Ihh targets such as Ptch1, and compromised chondrocyte hypertrophy. Reducing Gli3 dosage rescued ossification, brachydactyly, and osteopenia, providing unusually strong genetic evidence that GLI3 mediates this model phenotype. (cai2016spoppromotesskeletal pages 4-5, cai2016spoppromotesskeletal pages 5-5, cai2016spoppromotesskeletal pages 1-1)

In spinal cord, Spop loss increased GLI3 but did not by itself consistently disturb dorsoventral patterning. Severe ventralization emerged in sensitized Sufu/Gli genetic backgrounds, demonstrating that SPOP’s effect depends on the broader Hedgehog regulatory state. (cai2017spopregulatesgli3 pages 9-9, cai2017spopregulatesgli3 pages 2-3, cai2017spopregulatesgli3 pages 3-7)

Drosophila and Xenopus

Drosophila HIB/Roadkill targets Cubitus interruptus for Cul3-directed proteolysis. Xenopus experiments also support conserved SPOP-mediated GLI turnover. These models are useful for pathway dissection and variant-function assays but do not reproduce the human craniofacial, cognitive, speech, or behavioral syndrome. (cai2017spopregulatesgli3 pages 9-9)

Principal limitations and priorities

Existing models mainly represent complete or conditional loss of Spop, whereas human disease is caused predominantly by heterozygous missense alleles with substrate-specific gain-of-function or dominant-negative effects. No retrieved mouse, zebrafish, fly, organoid, or iPSC model knocked in the six foundational human alleles and measured cognition, neuronal differentiation, or BET abundance in disease-relevant neural cells.

High-priority models therefore include allele-specific knock-in mice, patient-derived iPSCs differentiated into neural progenitors and cortical neurons, and cerebral organoids. Appropriate readouts include SPOP condensate dynamics; BRD2/3/4 stability; ubiquitin proteomics; cell-cycle length; neuronal differentiation; neural-network activity; GLI3 processing; Hedgehog response; and rescue with allele-specific normalization of BET abundance.

Recent-development assessment and expert interpretation

The 2023 molecular review strengthened the general mechanistic framework by emphasizing SPOP’s multivalent substrate recognition, oligomerization, phase separation, and broad control of transcriptional and genome-integrity proteins. The 2024 chromatinopathy literature places SPOP-related disease in the expanding category of developmental disorders caused by disturbed chromatin-state regulation, but no validated SPOP-specific DNA-methylation episignature was found. (zhang2023deregulationofspop pages 1-1)

The most important expert-level conclusion is that NSDVS should not be modeled as generic SPOP loss. The human alleles have directionally opposite, substrate-specific effects, and categorical “gain-of-function” versus “loss-of-function” terminology can obscure the directly measured phenotype. Database representation should preserve: variant, protein domain, substrate tested, direction of substrate-abundance change, assay system, and clinical subtype as separate fields. (sa2020denovovariants pages 2-4, sa2020denovovariants pages 5-6)

Evidence limitations

The evidence base is exceptionally small. Most clinical frequencies derive from seven individuals reported in 2020; several later case reports were unavailable in full text, and the only retrieved recent management statement was from a 2026 case report. No robust 2023–2024 disease-specific cohort, natural-history study, registry, trial, omics study, or epidemiologic analysis was identified. Consequently, absence of evidence should not be interpreted as proof that a feature never occurs. All ontology mappings beyond explicitly established HPO concepts should be validated against current ontology releases before knowledge-base import.

References

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  2. (sa2020denovovariants pages 1-2): Maria J. Nabais Sá, Geniver El Tekle, Arjan P.M. de Brouwer, Sarah L. Sawyer, Daniela del Gaudio, Michael J. Parker, Farah Kanani, Marie-José H. van den Boogaard, Koen van Gassen, Margot I. Van Allen, Klaas Wierenga, Gabriela Purcarin, Ellen Roy Elias, Amber Begtrup, Jennifer Keller-Ramey, Tiziano Bernasocchi, Laurens van de Wiel, Christian Gilissen, Hanka Venselaar, Rolph Pfundt, Lisenka E.L.M. Vissers, Jean-Philippe P. Theurillat, and Bert B.A. de Vries. De novo variants in spop cause two clinically distinct neurodevelopmental disorders. Mar 2020. URL: https://doi.org/10.1016/j.ajhg.2020.02.001, doi:10.1016/j.ajhg.2020.02.001. This article has 21 citations.

  3. (sa2020denovovariants pages 5-6): Maria J. Nabais Sá, Geniver El Tekle, Arjan P.M. de Brouwer, Sarah L. Sawyer, Daniela del Gaudio, Michael J. Parker, Farah Kanani, Marie-José H. van den Boogaard, Koen van Gassen, Margot I. Van Allen, Klaas Wierenga, Gabriela Purcarin, Ellen Roy Elias, Amber Begtrup, Jennifer Keller-Ramey, Tiziano Bernasocchi, Laurens van de Wiel, Christian Gilissen, Hanka Venselaar, Rolph Pfundt, Lisenka E.L.M. Vissers, Jean-Philippe P. Theurillat, and Bert B.A. de Vries. De novo variants in spop cause two clinically distinct neurodevelopmental disorders. Mar 2020. URL: https://doi.org/10.1016/j.ajhg.2020.02.001, doi:10.1016/j.ajhg.2020.02.001. This article has 21 citations.

  4. (cai2016spoppromotesskeletal pages 4-5): Hongchen Cai and Aimin Liu. Spop promotes skeletal development and homeostasis by positively regulating ihh signaling. Proceedings of the National Academy of Sciences, 113:14751-14756, Dec 2016. URL: https://doi.org/10.1073/pnas.1612520114, doi:10.1073/pnas.1612520114. This article has 79 citations and is from a highest quality peer-reviewed journal.

  5. (olivareshuerta2026nabaissádevries pages 7-8): Oscar Olivares-Huerta, Dulce María Castro-Coyotl, Israel Enrique Crisanto-López, Jonathan Cervantes-Larios, Renata Ochoa-Precoma, Blanca Frisia Morales-López, Itzel Alejandra Trejo-Toscano, and Daniela Juárez-Melchor. Nabais sá-de vries syndrome type 1 in a mexican girl: a case report. Cureus, Apr 2026. URL: https://doi.org/10.7759/cureus.107064, doi:10.7759/cureus.107064. This article has 0 citations.

  6. (olivareshuerta2026nabaissádevries pages 8-9): Oscar Olivares-Huerta, Dulce María Castro-Coyotl, Israel Enrique Crisanto-López, Jonathan Cervantes-Larios, Renata Ochoa-Precoma, Blanca Frisia Morales-López, Itzel Alejandra Trejo-Toscano, and Daniela Juárez-Melchor. Nabais sá-de vries syndrome type 1 in a mexican girl: a case report. Cureus, Apr 2026. URL: https://doi.org/10.7759/cureus.107064, doi:10.7759/cureus.107064. This article has 0 citations.

  7. (sa2020denovovariants pages 4-5): Maria J. Nabais Sá, Geniver El Tekle, Arjan P.M. de Brouwer, Sarah L. Sawyer, Daniela del Gaudio, Michael J. Parker, Farah Kanani, Marie-José H. van den Boogaard, Koen van Gassen, Margot I. Van Allen, Klaas Wierenga, Gabriela Purcarin, Ellen Roy Elias, Amber Begtrup, Jennifer Keller-Ramey, Tiziano Bernasocchi, Laurens van de Wiel, Christian Gilissen, Hanka Venselaar, Rolph Pfundt, Lisenka E.L.M. Vissers, Jean-Philippe P. Theurillat, and Bert B.A. de Vries. De novo variants in spop cause two clinically distinct neurodevelopmental disorders. Mar 2020. URL: https://doi.org/10.1016/j.ajhg.2020.02.001, doi:10.1016/j.ajhg.2020.02.001. This article has 21 citations.

  8. (zhang2023deregulationofspop pages 1-1): Hui Zhang, Xiaofeng Jin, and Haojie Huang. Deregulation of spop in cancer. Cancer research, 83:489-499, Dec 2023. URL: https://doi.org/10.1158/0008-5472.can-22-2801, doi:10.1158/0008-5472.can-22-2801. This article has 73 citations and is from a highest quality peer-reviewed journal.

  9. (zhang2023deregulationofspop pages 2-3): Hui Zhang, Xiaofeng Jin, and Haojie Huang. Deregulation of spop in cancer. Cancer research, 83:489-499, Dec 2023. URL: https://doi.org/10.1158/0008-5472.can-22-2801, doi:10.1158/0008-5472.can-22-2801. This article has 73 citations and is from a highest quality peer-reviewed journal.

  10. (ovalle2021speckletypepozadaptor pages 2-5): Wendy Johana Montero Ovalle, María Carolina Sanabria Salas, and Martha Lucia Serrano Lopez. Speckle-type poz adaptor protein (spop) and its role in cancer. Sep 2021. URL: https://doi.org/10.35509/01239015.717, doi:10.35509/01239015.717. This article has 1 citations.

  11. (ovalle2021speckletypepozadaptor pages 1-2): Wendy Johana Montero Ovalle, María Carolina Sanabria Salas, and Martha Lucia Serrano Lopez. Speckle-type poz adaptor protein (spop) and its role in cancer. Sep 2021. URL: https://doi.org/10.35509/01239015.717, doi:10.35509/01239015.717. This article has 1 citations.

  12. (cai2017spopregulatesgli3 pages 9-9): Hongchen Cai and Aimin Liu. Spop regulates gli3 activity and shh signaling in dorsoventral patterning of the mouse spinal cord. Developmental biology, 432 1:72-85, Dec 2017. URL: https://doi.org/10.1016/j.ydbio.2017.04.002, doi:10.1016/j.ydbio.2017.04.002. This article has 36 citations and is from a peer-reviewed journal.

  13. (cai2017spopregulatesgli3 pages 2-3): Hongchen Cai and Aimin Liu. Spop regulates gli3 activity and shh signaling in dorsoventral patterning of the mouse spinal cord. Developmental biology, 432 1:72-85, Dec 2017. URL: https://doi.org/10.1016/j.ydbio.2017.04.002, doi:10.1016/j.ydbio.2017.04.002. This article has 36 citations and is from a peer-reviewed journal.

  14. (cai2017spopregulatesgli3 pages 3-7): Hongchen Cai and Aimin Liu. Spop regulates gli3 activity and shh signaling in dorsoventral patterning of the mouse spinal cord. Developmental biology, 432 1:72-85, Dec 2017. URL: https://doi.org/10.1016/j.ydbio.2017.04.002, doi:10.1016/j.ydbio.2017.04.002. This article has 36 citations and is from a peer-reviewed journal.

  15. (cai2016spoppromotesskeletal pages 5-5): Hongchen Cai and Aimin Liu. Spop promotes skeletal development and homeostasis by positively regulating ihh signaling. Proceedings of the National Academy of Sciences, 113:14751-14756, Dec 2016. URL: https://doi.org/10.1073/pnas.1612520114, doi:10.1073/pnas.1612520114. This article has 79 citations and is from a highest quality peer-reviewed journal.

  16. (cai2016spoppromotesskeletal pages 1-1): Hongchen Cai and Aimin Liu. Spop promotes skeletal development and homeostasis by positively regulating ihh signaling. Proceedings of the National Academy of Sciences, 113:14751-14756, Dec 2016. URL: https://doi.org/10.1073/pnas.1612520114, doi:10.1073/pnas.1612520114. This article has 79 citations and is from a highest quality peer-reviewed journal.

  17. (cai2016spoppromotesskeletal pages 1-2): Hongchen Cai and Aimin Liu. Spop promotes skeletal development and homeostasis by positively regulating ihh signaling. Proceedings of the National Academy of Sciences, 113:14751-14756, Dec 2016. URL: https://doi.org/10.1073/pnas.1612520114, doi:10.1073/pnas.1612520114. This article has 79 citations and is from a highest quality peer-reviewed journal.

  18. (cai2016spoppromotesskeletal pages 2-4): Hongchen Cai and Aimin Liu. Spop promotes skeletal development and homeostasis by positively regulating ihh signaling. Proceedings of the National Academy of Sciences, 113:14751-14756, Dec 2016. URL: https://doi.org/10.1073/pnas.1612520114, doi:10.1073/pnas.1612520114. This article has 79 citations and is from a highest quality peer-reviewed journal.

  19. (sa2020denovovariants pages 4-4): Maria J. Nabais Sá, Geniver El Tekle, Arjan P.M. de Brouwer, Sarah L. Sawyer, Daniela del Gaudio, Michael J. Parker, Farah Kanani, Marie-José H. van den Boogaard, Koen van Gassen, Margot I. Van Allen, Klaas Wierenga, Gabriela Purcarin, Ellen Roy Elias, Amber Begtrup, Jennifer Keller-Ramey, Tiziano Bernasocchi, Laurens van de Wiel, Christian Gilissen, Hanka Venselaar, Rolph Pfundt, Lisenka E.L.M. Vissers, Jean-Philippe P. Theurillat, and Bert B.A. de Vries. De novo variants in spop cause two clinically distinct neurodevelopmental disorders. Mar 2020. URL: https://doi.org/10.1016/j.ajhg.2020.02.001, doi:10.1016/j.ajhg.2020.02.001. This article has 21 citations.

  20. (zhang2023deregulationofspop pages 10-11): Hui Zhang, Xiaofeng Jin, and Haojie Huang. Deregulation of spop in cancer. Cancer research, 83:489-499, Dec 2023. URL: https://doi.org/10.1158/0008-5472.can-22-2801, doi:10.1158/0008-5472.can-22-2801. This article has 73 citations and is from a highest quality peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 8
Resolved 8
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 8
On topic 1
Off topic 0

All extracted references resolved successfully.

Term Validation

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

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

Every term resolved, and every label the report gave matched.