Sandestig-Stefanova Syndrome

🔗

Mappings

MONDO

MONDO:0032926 sandestig-stefanova syndrome

The entry's own disease_term, recorded explicitly so the exact-match relationship is queryable rather than implied by the binding alone. MONDO gives this term a single causal gene (RO:0004003 HGNC:17859, NUP188), no descendants, and cross-references to OMIM:618804, DOID:0081272, MEDGEN:1718072 and UMLS:C5394118. It records no Orphanet cross-reference.

👪

Inheritance

1

Autosomal recessive HP:0000007

Biallelic NUP188 variants. Consanguinity is common among reported families, sibship recurrence has been documented, and parents are heterozygous carriers without the phenotype. Heterozygous carriers of the truncating alleles are unaffected, including for the cardiac phenotype: the parents and carrier sibling of one proband with tetralogy of Fallot had no detectable cardiac abnormality.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:36158057 SUPPORT Human Clinical

"Sandestig-Stefanova syndrome is an autosomal recessive developmental syndrome characterized by microcephaly, trigonocephaly, congenital cataracts, microphthalmia, facial findings, camptodactyly, periventricular white matter loss, thin corpus callosum, delayed myelination, and poor prognosis."

States the mode of inheritance.

PMID:39911172 SUPPORT Human Clinical

"Familial segregation analysis using Sanger sequencing revealed that both the healthy brother and the parents carried this variant in a heterozygous state"

Documents heterozygous carriage in unaffected parents and a healthy sibling, which is what recessive segregation looks like.

◈

Mechanistic Hypotheses

2

Reduced Nucleocytoplasmic Protein Import Model

nuclear_import_deficiency_model CANONICAL

Evidence balance 2 support

The mainstream account: NUP188 is a scaffold subunit of the NUP93 subcomplex that builds the nuclear pore complex inner ring, and its loss degrades nucleocytoplasmic transport, starving developing tissues of the nuclear delivery of regulatory proteins. This is the only arm with a direct measurement in patient material - nuclear protein import was reduced in fibroblasts from affected individuals - and the authors of that measurement state it as a possible rather than an established mechanism.

Pathograph links

Absent or Truncated NUP188 Protein -> Nuclear Pore Complex Inner-Ring Scaffold Defect DIRECT Losing NUP188 removes a scaffold subunit of the NUP93 subcomplex that builds the inner ring of the pore.

Nuclear Pore Complex Inner-Ring Scaffold Defect -> Reduced Nucleocytoplasmic Protein Import DIRECT A defective inner-ring scaffold degrades the pore's ability to move cargo into the nucleus.

Reduced Nucleocytoplasmic Protein Import -> Impaired Neuronal Dendrite Development INDIRECT UNKNOWN INTERMEDIATES Loss of NUP188 disrupts dendritic development. The connection to the transport deficit is inferential: the dendrite result comes from Drosophila knockout, not from a transport-rescue experiment.

Reduced Nucleocytoplasmic Protein Import -> Deficient Cerebral White Matter Development and Myelination INDIRECT UNKNOWN INTERMEDIATES White-matter loss, corpus callosum hypoplasia and delayed myelination are present in essentially every reported patient. No intermediate between the transport deficit and the oligodendroglial failure has been identified.

Reduced Nucleocytoplasmic Protein Import -> Impaired Lens and Anterior Eye Development INDIRECT UNKNOWN INTERMEDIATES Congenital bilateral cataract with microphthalmia is a cardinal feature. Nothing has been measured in lens tissue from these patients; the edge records that the ocular malformation follows from the NUP188 lesion, not how.

Reduced Nucleocytoplasmic Protein Import -> Disrupted Cardiac Morphogenesis INDIRECT UNKNOWN INTERMEDIATES Congenital heart defects occur in most patients. Under the canonical model this is a consequence of the transport deficit during cardiac development; the ciliary model offers a competing route to the same node.

Reduced Nucleocytoplasmic Protein Import -> Impaired Craniofacial and Distal Limb Morphogenesis INDIRECT UNKNOWN INTERMEDIATES The facial gestalt, trigonocephaly, palatal clefting and the digital anomalies are reproducible enough across unrelated families to be described as recognizable, which is what makes them a consequence of the gene lesion rather than incidental.

Reduced Nucleocytoplasmic Protein Import -> Prenatal Growth Restriction INDIRECT UNKNOWN INTERMEDIATES Growth restriction begins before birth and affects head circumference as well as body size, so it is a prenatal consequence of the gene lesion rather than a postnatal feeding effect.

Show evidence (2 references)

PMID:32275884 SUPPORT In Vitro

"Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism."

The direct patient-cell measurement on which this model rests, stated by its authors with the hedge they used.

PMID:39911172 SUPPORT BACKGROUND Other

"NUP188 is part of the NUP93 subcomplex, the second major structural unit of the NPC, which controls the passage of membrane or transmembrane proteins through NPC"

States the structural position of NUP188 in the pore that makes a transport deficit the expected consequence of losing it.

Ciliary and Moonlighting-Function Model

ciliary_nup188_model EMERGING

Evidence balance 2 support

An alternative or additional route in which the disease-relevant lesion is not at the nuclear pore at all. NUP188 localises to the cilium base, and morpholino depletion in Xenopus abolishes cilia while leaving nuclear pore function largely intact - so a ciliary deficit can be produced by loss of NUP188 without a transport deficit. The clinical features that motivate this arm are the congenital heart disease, the hydrocephalus, and the heterotaxy-like findings reported in some patients. It is EMERGING rather than CANONICAL because no patient cell or tissue has been assayed for ciliation: the supporting work is amphibian and cell-line depletion, and a NUP188 duplication rather than the biallelic loss-of-function alleles that cause this disease.

Pathograph links

Absent or Truncated NUP188 Protein -> Loss of Cilia and Ciliary-Base NUP188 Function DIRECT Under the ciliary model the same protein loss acts at the cilium base instead. This edge is supported by amphibian and cell-line depletion rather than by patient tissue, and it is asserted as a model arm, not as an established step in this disease.

Loss of Cilia and Ciliary-Base NUP188 Function -> Disrupted Cardiac Morphogenesis INDIRECT UNKNOWN INTERMEDIATES The ciliary route to the cardiac phenotype. Nup188 was first implicated in heart disease through a patient with congenital heart disease and heterotaxy - a left-right patterning disorder generated at the ciliated left-right organizer.

Loss of Cilia and Ciliary-Base NUP188 Function -> Prenatal-Onset Ventriculomegaly and Hydrocephalus INDIRECT UNKNOWN INTERMEDIATES Hydrocephalus is a recognised ciliopathy manifestation, and this is the route the report that first documented overt hydrocephalus in the syndrome proposed for it.

Show evidence (2 references)

PMID:27593162 SUPPORT Model Organism

"Here, we show that knockdown of Nup188 or its binding partner Nup93 leads to a loss of cilia during embryonic development while leaving NPC function largely intact."

Demonstrates that losing Nup188 can produce a ciliary phenotype without a nuclear-transport phenotype, which is what makes this a distinct model rather than a downstream consequence of the canonical one.

PMID:39911172 SUPPORT BACKGROUND Other

"Cilia dysfunction contributes to various ciliopathies including hydrocephalus, polycystic kidney disease, retinal dystrophy, and congenital heart disease."

States the clinical link this model proposes between a ciliary lesion and the hydrocephalus and heart disease seen in these patients.

?

Discussions and Knowledge Gaps

2

Is Sandestig-Stefanova syndrome a nucleocytoplasmic transport disorder, a ciliopathy, or both?

KNOWLEDGE GAP OPEN transport_versus_ciliary_mechanism

Attached to

pathophysiology#Reduced Nucleocytoplasmic Protein Import pathophysiology#Loss of Cilia and Ciliary-Base NUP188 Function

The only measurement in patient material is reduced nuclear protein import in fibroblasts, and its authors called it a possible mechanism rather than an established one. Meanwhile the clinical picture contains features a transport deficit does not obviously explain - structurally heterogeneous congenital heart disease, hydrocephalus, and heterotaxy-like findings in some patients - and there is direct evidence that depleting Nup188 abolishes cilia while the nuclear pore keeps working. That experiment is the crux: it means a ciliary phenotype is not a downstream consequence of a transport phenotype, so the two are genuinely competing accounts and not two descriptions of one lesion. No patient with this syndrome has had ciliation assayed, and no rescue experiment has been reported, so the question is open.

Show evidence (2 references)

PMID:27593162 SUPPORT Model Organism

"Here, we show that knockdown of Nup188 or its binding partner Nup93 leads to a loss of cilia during embryonic development while leaving NPC function largely intact."

Establishes that the two candidate lesions are dissociable, which is what makes this a real question.

PMID:32275884 SUPPORT In Vitro

"Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism."

The hedged patient-cell measurement that is the sole direct support for the transport account.

Does the Drosophila NUP188 knockout tell us anything about the brainstem respiratory failure that kills these infants?

HUMAN MODEL MISMATCH OPEN drosophila_model_translational_validity

Attached to

pathophysiology#Progressive Encephalopathy with Central Respiratory Control Failure animal_models#Drosophila melanogaster

The fly knockout is the only in vivo model of NUP188 loss with a neurological readout, and its authors describe the recapitulation as partial. What it reproduces is motor deficit and seizure susceptibility. What kills affected infants is failure of central respiratory drive, and the fly has no brainstem respiratory control to fail. It also has no counterpart of the progressive microcephaly, periventricular white-matter loss, or corpus callosum hypoplasia that dominate the human imaging. So the model supports the claim that NUP188 is required for normal neuronal function, and supports no claim about the specific lesion that is lethal. A vertebrate model with a brainstem, or human neural tissue, would be needed to close this.

Show evidence (2 references)

PMID:32275884 SUPPORT Model Organism

"CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals."

The authors' own statement that the recapitulation is partial, which is the mismatch this discussion records.

PMID:36158057 SUPPORT Human Clinical

"Patients die in the early period due to respiratory failure secondary to CNS anomalies. No signs of congenital pulmonary or tracheal disease were detected in the identified patients."

Establishes that the lethal lesion is central respiratory control, the element the fly model cannot address.

⚙

Pathophysiology

13

Biallelic NUP188 Loss of Function

Germline biallelic truncating variants in NUP188 - homozygous nonsense in consanguineous kindreds, compound heterozygous elsewhere. Every reported disease allele is predicted to truncate: nonsense, frameshift, and a canonical splice-acceptor variant. No missense allele has been shown to cause the syndrome, so this is a loss-of-function mechanism rather than a dominant-negative or gain-of-function one.

NUP188 hgnc:17859

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Biallelic germline truncating NUP188 variants. A premature termination codon early in the 44-exon transcript is expected to trigger nonsense-mediated decay, and a splice-acceptor allele produced no detectable RT-PCR amplification in the proband.

Downstream

Absent or Truncated NUP188 Protein Premature termination codons either trigger nonsense-mediated decay of the transcript or yield a truncated product, so the cell has no functional NUP188.

Show evidence (2 references)

PMID:32021605 SUPPORT Human Clinical

"For the first time, we report 2 unrelated patients with 2 different homozygous nonsense gene variants of NUP188, p.Tyr96* and p.Gln113*, respectively."

The first report of biallelic NUP188 nonsense variants in this phenotype.

PMID:32275884 SUPPORT Human Clinical

"We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families."

The independent series establishing biallelic truncating NUP188 variants as the cause of a recognizable syndrome.

Absent or Truncated NUP188 Protein

Protein-level consequence of the truncating alleles, established directly rather than inferred: immunoblot and immunofluorescence of fibroblasts from two of the reported individuals showed either complete loss of NUP188 or a non-functional stump. This is the node from which the two competing mechanistic models diverge - one through the nuclear pore, one through the cilium base.

Ciliary and Moonlighting-Function Model Reduced Nucleocytoplasmic Protein Import Model

patient-derived skin fibroblast CL:0002620

NUP188 hgnc:17859

Downstream

Nuclear Pore Complex Inner-Ring Scaffold Defect Losing NUP188 removes a scaffold subunit of the NUP93 subcomplex that builds the inner ring of the pore.

Loss of Cilia and Ciliary-Base NUP188 Function Under the ciliary model the same protein loss acts at the cilium base instead. This edge is supported by amphibian and cell-line depletion rather than by patient tissue, and it is asserted as a model arm, not as an established step in this disease.

Show evidence (2 references)

PMID:39911172 SUPPORT BACKGROUND In Vitro

"Immunoblot and immunofluorescence analyses of fibroblasts from individuals carrying p.Ile302Valfs*7 and p.Tyr1048Ter variants showed that these variants resulted in either complete loss of NUP188 or a non-functional stump protein product."

Reports the protein-level result obtained in patient fibroblasts. The quote is this case report restating the finding of the earlier Muir series rather than its own experiment, hence BACKGROUND; the evidence it describes is in vitro work on human patient cells.

PMID:40859750 SUPPORT Human Clinical

"RT-PCR analysis showed no detectable amplification in the proband, while parental samples displayed two bands, indicating carrier status."

Independent transcript-level demonstration that a disease allele abolishes the normal NUP188 message.

Nuclear Pore Complex Inner-Ring Scaffold Defect

The nuclear pore complex is built from roughly thirty nucleoporins; the NUP93 subcomplex to which NUP188 belongs forms the inner ring of its scaffold. Complete loss of pore function is incompatible with cell viability, so a viable disease allele produces a partial structural defect rather than an absent pore.

Reduced Nucleocytoplasmic Protein Import Model

NUP188 hgnc:17859

nuclear pore inner ring GO:0044611 nuclear pore GO:0005643

Downstream

Reduced Nucleocytoplasmic Protein Import A defective inner-ring scaffold degrades the pore's ability to move cargo into the nucleus.

Show evidence (2 references)

PMID:39911172 SUPPORT BACKGROUND Other

"NUP188 is part of the NUP93 subcomplex, the second major structural unit of the NPC, which controls the passage of membrane or transmembrane proteins through NPC"

Locates NUP188 within the pore's inner-ring scaffold.

PMID:32275884 SUPPORT BACKGROUND Other

"Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules."

States the function of the structure this node describes as defective.

Reduced Nucleocytoplasmic Protein Import

The one cellular lesion measured directly in patient material. Fibroblasts from affected individuals import protein into the nucleus less efficiently than control cells. The authors present it as a possible disease mechanism, and the step from a fibroblast transport deficit to the developmental malformations below is not itself demonstrated - the edges out of this node are therefore marked as having unknown intermediates.

Reduced Nucleocytoplasmic Protein Import Model

patient-derived skin fibroblast CL:0002620

protein import into nucleus GO:0006606 ↓ DECREASED nucleocytoplasmic transport GO:0006913 ↓ DECREASED

Experimental models

Patient-derived skin fibroblasts PRIMARY CELL CULTURE Nuclear protein import was measured in patient fibroblasts and found to be reduced.

Downstream

Impaired Neuronal Dendrite Development Loss of NUP188 disrupts dendritic development. The connection to the transport deficit is inferential: the dendrite result comes from Drosophila knockout, not from a transport-rescue experiment.

Deficient Cerebral White Matter Development and Myelination White-matter loss, corpus callosum hypoplasia and delayed myelination are present in essentially every reported patient. No intermediate between the transport deficit and the oligodendroglial failure has been identified.

Impaired Lens and Anterior Eye Development Congenital bilateral cataract with microphthalmia is a cardinal feature. Nothing has been measured in lens tissue from these patients; the edge records that the ocular malformation follows from the NUP188 lesion, not how.

Disrupted Cardiac Morphogenesis Congenital heart defects occur in most patients. Under the canonical model this is a consequence of the transport deficit during cardiac development; the ciliary model offers a competing route to the same node.

Impaired Craniofacial and Distal Limb Morphogenesis The facial gestalt, trigonocephaly, palatal clefting and the digital anomalies are reproducible enough across unrelated families to be described as recognizable, which is what makes them a consequence of the gene lesion rather than incidental.

Prenatal Growth Restriction Growth restriction begins before birth and affects head circumference as well as body size, so it is a prenatal consequence of the gene lesion rather than a postnatal feeding effect.

Show evidence (2 references)

PMID:32275884 SUPPORT In Vitro

"Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism."

The primary measurement of the deficit this node names.

PMID:36158057 SUPPORT BACKGROUND In Vitro

"Functional analysis showed that disruption of NUP188 was associated with low active protein transport to the nucleus."

A later report restating the same in vitro functional result.

Loss of Cilia and Ciliary-Base NUP188 Function

The alternative arm. NUP188 is found at the base of cilia as well as at the nuclear envelope, and depleting it costs cells their cilia while the nuclear pore keeps working. This node exists because it explains parts of the clinical picture the transport model handles poorly - the heart defects, the hydrocephalus, and the heterotaxy-like findings - but it has never been demonstrated in a patient with this syndrome.

Ciliary and Moonlighting-Function Model

NUP188 hgnc:17859

cilium assembly GO:0060271 ↓ DECREASED

Animal models

Xenopus Nup188 morpholino knockdown Xenopus recapitulates The model is the source of this node: it shows that depleting Nup188 costs cells their cilia.

Downstream

Disrupted Cardiac Morphogenesis The ciliary route to the cardiac phenotype. Nup188 was first implicated in heart disease through a patient with congenital heart disease and heterotaxy - a left-right patterning disorder generated at the ciliated left-right organizer.

Prenatal-Onset Ventriculomegaly and Hydrocephalus Hydrocephalus is a recognised ciliopathy manifestation, and this is the route the report that first documented overt hydrocephalus in the syndrome proposed for it.

Show evidence (2 references)

PMID:27593162 SUPPORT Model Organism

"Here, we show that knockdown of Nup188 or its binding partner Nup93 leads to a loss of cilia during embryonic development while leaving NPC function largely intact."

The primary demonstration that Nup188 depletion produces a ciliary rather than a transport phenotype.

PMID:36158057 SUPPORT BACKGROUND Other

"Apart from its role in nuclear transport, NUP188 also plays a role in various cellular functions, including ciliogenesis"

States the non-transport role of NUP188 that this node is built on.

Impaired Neuronal Dendrite Development

Removing NUP188 in Drosophila produces aberrant dendrite tiling alongside motor deficits and seizure susceptibility. This is the only cellular account of the neurological phenotype offered so far, and it is an invertebrate one.

neuron CL:0000540

dendrite morphogenesis GO:0048813 ↓ DECREASED

Animal models

NUP188 CRISPR knockout Drosophila Drosophila melanogaster recapitulates Dendrite tiling is disrupted by NUP188 removal, which is the observation the node records.

Downstream

Progressive Encephalopathy with Central Respiratory Control Failure A route from disordered neuronal development to the progressive encephalopathy. The supporting knockout reproduces motor deficits and seizure susceptibility but only partially recapitulates the human neurological phenotype, and the fly has no counterpart of the brainstem respiratory control that kills these infants.

Seizure Seizure susceptibility follows NUP188 removal in the fly, and seizures appear in affected infants during the first months.

Show evidence (1 reference)

PMID:32275884 SUPPORT Model Organism

"Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development."

The dendritic observation this node records.

Deficient Cerebral White Matter Development and Myelination

Loss of periventricular white matter, a thin or hypoplastic corpus callosum and delayed myelination together form the imaging signature of the syndrome and are present in essentially every reported patient. Whether the primary failure is oligodendroglial or axonal has not been established in these patients, so this node is stated at tissue level.

oligodendrocyte CL:0000128

myelination GO:0042552 ↓ DECREASED

Downstream

Delayed myelination Deficient myelination presents radiologically as delayed myelination.

Abnormal periventricular white matter morphology Loss of periventricular white matter is the specific white-matter finding reported.

Thin corpus callosum The callosal commissure is thin or hypoplastic on imaging and at postmortem.

Cerebral atrophy Cerebral atrophy develops over the course of the illness and is listed among the most important central nervous system findings.

Progressive Encephalopathy with Central Respiratory Control Failure The white-matter and callosal deficit is the structural correlate of the encephalopathy that dominates the clinical course.

Show evidence (2 references)

PMID:32021605 SUPPORT Human Clinical

"the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as..."

Establishes the white-matter loss, thin corpus callosum and delayed myelination in the index patients.

PMID:32275884 SUPPORT Human Clinical

"Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."

Independent confirmation of the same white-matter and corpus callosum findings.

Progressive Encephalopathy with Central Respiratory Control Failure

The clinical convergence point and the cause of death. Generalised hypotonia is present from birth, microcephaly is progressive, seizures appear, swallowing is lost, and central hypoventilation develops. The respiratory failure is central: no congenital pulmonary or tracheal disease has been found in any reported patient, so the lung is not the lesion.

Animal models

NUP188 CRISPR knockout Drosophila Drosophila melanogaster partially recapitulates Motor deficits and seizure susceptibility reproduce part of the human neurological picture, and the authors describe the recapitulation as partial.

Downstream

Hypotonia Generalised hypotonia is present congenitally and persists.

Central hypoventilation Loss of central respiratory drive, listed among the cardinal CNS findings and the proximate cause of the terminal respiratory failure.

Respiratory failure Central hypoventilation progresses to respiratory failure, which has killed every reported patient.

Feeding difficulties Swallowing is lost over time, so infants who fed orally at birth become dependent on nasogastric or orogastric tubes.

Microcephaly Microcephaly is present at birth and progresses postnatally, which is what makes it a consequence of the encephalopathy as well as of prenatal growth restriction.

Show evidence (2 references)

PMID:36158057 SUPPORT Human Clinical

"Patients die in the early period due to respiratory failure secondary to CNS anomalies. No signs of congenital pulmonary or tracheal disease were detected in the identified patients."

Establishes that the fatal respiratory failure is of central nervous system origin.

PMID:32275884 SUPPORT Human Clinical

"All affected individuals died as a result of respiratory failure, and five of them died within the first year of life."

Establishes the uniform terminal event.

Impaired Lens and Anterior Eye Development

Congenital bilateral cataract with microphthalmia. Cataract is one of the two or three features that make the syndrome recognizable, and it was present in four of the six individuals in the defining series. No lens tissue from an affected individual has been examined, so the node asserts the developmental failure without specifying its cellular route - in particular, no crystallin aggregation has been demonstrated here.

Downstream

Developmental cataract Bilateral lens opacity present at birth.

Microphthalmia Reduced globe size accompanies the cataract.

Show evidence (1 reference)

PMID:32021605 SUPPORT Human Clinical

"the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as..."

Establishes congenital bilateral cataract and microphthalmia together in the index patients.

Disrupted Cardiac Morphogenesis

Congenital heart disease occurred in five of the six individuals of the defining series and in most patients reported since. The lesions are structurally heterogeneous - ventricular septal defect, bicuspid aortic valve, patent ductus arteriosus, partial anomalous pulmonary venous return, and in one patient tetralogy of Fallot - which is what a morphogenetic rather than a single-structure defect looks like.

Downstream

Ventricular septal defect A septal defect among the cardiac lesions reported in biallelic cases.

Bicuspid aortic valve One of the valvar lesions reported in the defining series.

Patent ductus arteriosus Persistence of the ductus is among the reported cardiac lesions.

Partial anomalous pulmonary venous return An anomalous venous connection reported in the defining series.

Tetralogy of Fallot A conotruncal lesion documented prenatally in one patient and her affected sibling.

Show evidence (3 references)

PMID:36158057 SUPPORT BACKGROUND Human Clinical

"Congenital cataracts in 4 patients and congenital heart anomalies including bicuspid aortic valve, partial abnormal pulmonary venous return, and patent ductus arteriosus were seen in 5 patients."

Gives the cardiac lesion spectrum and its frequency in the defining series. The quote is this case report summarising that earlier series rather than its own patient.

PMID:39911172 SUPPORT Human Clinical

"Our patients presented with ToF, expanding the cardiac spectrum of NUP188."

Adds tetralogy of Fallot to the cardiac spectrum.

PMID:39911172 SUPPORT REVIEW SYNTHESIS Human Clinical

"Congenital heart defects | + | + | + | + | + | Not tested | + | + | + | +"

The report's per-patient comparison table across all ten published cases: a congenital heart defect is recorded in nine, with the tenth not tested. This is the denominator behind the claim that most patients have one.

Prenatal-Onset Ventriculomegaly and Hydrocephalus

Ventricular enlargement begins before birth and is one of the key features of the syndrome. In most patients it stays as ventriculomegaly; in one it progressed to overt tetraventricular hydrocephalus requiring a shunt, and that report was careful to note that concurrent neonatal sepsis may have contributed, so whether progression to frank hydrocephalus belongs to the syndrome is not settled.

Downstream

Ventriculomegaly Ventricular enlargement detectable from the second trimester.

Hydrocephalus Progression from ventriculomegaly to shunt-requiring hydrocephalus, documented once. The reporting authors explicitly left open whether the progression is part of the syndrome or was driven by the neonatal sepsis their patient also had.

Show evidence (2 references)

PMID:32275884 SUPPORT Human Clinical

"Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."

Establishes the prenatal onset of the ventriculomegaly.

PMID:39911172 SUPPORT Human Clinical

"Similar to previous reports, prenatal-onset mild ventriculomegaly was identified in our case during the 2nd trimester."

Independent confirmation of second-trimester ventriculomegaly.

Impaired Craniofacial and Distal Limb Morphogenesis

A reproducible dysmorphic gestalt across unrelated families with different alleles: trigonocephaly from metopic ridging, small palpebral fissures, a wide nasal bridge and nose, micrognathia, palatal clefting or a high arched palate, and distal limb anomalies including camptodactyly, clinodactyly and rocker-bottom feet. That two unrelated index patients with different nonsense alleles looked alike is what made this a recognizable syndrome rather than a collection of malformations.

Downstream

Trigonocephaly Triangular forehead from metopic ridging.

Short palpebral fissure Small palpebral fissures are part of the characteristic gestalt.

Wide nasal bridge A wide, prominent nasal bridge with a wide convex nose.

Micrognathia A small mandible, part of the characteristic gestalt.

Low-set ears Low-set ears with hypoplastic tragus and a prominent angulated antihelix.

Hypertelorism Increased interocular distance, recorded on examination.

Orofacial cleft Cleft lip and palate in one index patient.

High palate A high arched palate, the milder end of the same palatal spectrum.

Bifid uvula Incomplete midline fusion of the uvula, at the mildest end of the palatal clefting spectrum this node already covers. Reported once, and the reporting authors flagged it as a new finding in this syndrome.

Camptodactyly Fixed flexion of the digits, present in essentially all reported patients.

Clinodactyly Curvature of a digit in the coronal plane, reported alongside camptodactyly.

Rocker bottom foot Convex plantar surface with a prominent heel.

Show evidence (2 references)

PMID:32021605 SUPPORT Human Clinical

"Both patients showed very similar facial features such as laterally extended arched eyebrows, wide convex nose with a wide prominent nasal bridge, and prominent angulated antihelix."

Documents the reproducible facial gestalt across two unrelated patients.

PMID:32275884 SUPPORT Human Clinical

"Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies."

Independent statement of the same dysmorphic set.

Prenatal Growth Restriction

Growth is restricted before birth. Affected infants are born small for gestational age, and intrauterine growth restriction has been seen on second-trimester ultrasound.

Downstream

Small for gestational age Birth weight and length below expectation for gestation.

Intrauterine growth retardation Growth restriction detectable on prenatal ultrasound.

Microcephaly Head growth is restricted prenatally as well as postnatally, which is why the literature describes the microcephaly as both pre- and postnatal.

Show evidence (1 reference)

PMID:32021605 SUPPORT Human Clinical

"They were both born small for gestational age and died shortly after birth at the age of 67 and 140 days, respectively, as a result of central respiratory failure."

Establishes small-for-gestational-age birth in the index patients.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

40

Cardiovascular 5

Ventricular septal defect FREQUENT HP:0001629

Show evidence (2 references)

PMID:39911172 SUPPORT REVIEW SYNTHESIS Human Clinical

"Heterozygous truncating variants have been linked to mitral valve prolapse, while patients with bi-allelic variants were reported to have a ventricular septal defect, bicuspid aortic valve, patent ductus arteriosus, partial anomalous pulmonary venous return, and left ventricular hypertrophy"

The report's synthesis of the cardiac spectrum across published biallelic cases, where the ventricular septal defect is itemised.

PMID:39911172 SUPPORT REVIEW SYNTHESIS Human Clinical

"presented two unrelated individuals with bi-allelic truncating variants of NUP188, who exhibited overlapping features including premature birth, pre- and postnatal microcephaly, trigonocephaly, bilateral congenital cataracts, microphthalmia, ventricular septal defect, camptodactyly,..."

Names ventricular septal defect in both index patients, so the frequency band here is supported by a stated count rather than only by the lesion appearing in a spectrum list.

Bicuspid aortic valve OCCASIONAL HP:0001647

Show evidence (1 reference)

PMID:36158057 SUPPORT BACKGROUND Human Clinical

"Congenital cataracts in 4 patients and congenital heart anomalies including bicuspid aortic valve, partial abnormal pulmonary venous return, and patent ductus arteriosus were seen in 5 patients."

Itemises the cardiac lesions of the defining series. The quote is the later Turkish report summarising that series rather than its own patient.

Patent ductus arteriosus OCCASIONAL HP:0001643

Show evidence (1 reference)

PMID:36158057 SUPPORT BACKGROUND Human Clinical

"Congenital cataracts in 4 patients and congenital heart anomalies including bicuspid aortic valve, partial abnormal pulmonary venous return, and patent ductus arteriosus were seen in 5 patients."

Itemises patent ductus arteriosus among the cardiac lesions of the defining series.

Partial anomalous pulmonary venous return OCCASIONAL HP:0010773

Show evidence (1 reference)

PMID:36158057 SUPPORT BACKGROUND Human Clinical

"Congenital cataracts in 4 patients and congenital heart anomalies including bicuspid aortic valve, partial abnormal pulmonary venous return, and patent ductus arteriosus were seen in 5 patients."

Itemises partial anomalous pulmonary venous return among the cardiac lesions of the defining series.

Tetralogy of Fallot OCCASIONAL HP:0001636

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Our patients presented with ToF, expanding the cardiac spectrum of NUP188."

Records tetralogy of Fallot as a new addition to the cardiac spectrum of this syndrome.

Digestive 2

Feeding difficulties VERY_FREQUENT HP:0011968

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"As in our patient, patients who are fed orally after birth lose their swallowing function over time and become dependent on nasogastric/orogastric tubes."

Documents the progressive loss of swallowing in this syndrome.

Hepatomegaly OCCASIONAL HP:0002240

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Additional novel clinical findings include hepatomegaly and a pelvic ectopic kidney; however, further reports are required to confirm these associations within the disease spectrum."

Records the hepatomegaly together with the authors' own caveat about its status.

Ear 1

Low-set ears FREQUENT HP:0000369

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"In his physical examination, hypotonia, bilateral congenital cataracts, ambiguous genitalia, hypospadias, undescended testis, bifid scrotum, and facial dysmorphic findings (hypertelorism, high palate, micrognathia, microphthalmia, low ear) were recorded"

Documents the low-set ears on physical examination.

Endocrine 1

Congenital hypothyroidism OCCASIONAL HP:0000851

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"With the diagnosis of congenital hypothyroidism, levothyroxine treatment was started."

Documents the diagnosis and its treatment in a molecularly confirmed patient.

Eye 3

Developmental cataract VERY_FREQUENT HP:0000519

Show evidence (1 reference)

PMID:32275884 SUPPORT Human Clinical

"Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."

Names congenital cataract first among the key clinical features.

Microphthalmia FREQUENT HP:0000568

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"Sandestig-Stefanova syndrome is an autosomal recessive developmental syndrome characterized by microcephaly, trigonocephaly, congenital cataracts, microphthalmia, facial findings, camptodactyly, periventricular white matter loss, thin corpus callosum, delayed myelination, and poor prognosis."

Names microphthalmia among the defining features.

Hypertelorism OCCASIONAL HP:0000316

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"In his physical examination, hypotonia, bilateral congenital cataracts, ambiguous genitalia, hypospadias, undescended testis, bifid scrotum, and facial dysmorphic findings (hypertelorism, high palate, micrognathia, microphthalmia, low ear) were recorded"

Documents hypertelorism on physical examination.

Genitourinary 4

Ambiguous genitalia OCCASIONAL HP:0000062

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"In addition, immunodeficiency, congenital hypothyroidism, biotinidase deficiency, undescended testis, hypospadias, and ambiguous genitalia are defined for the first time in this syndrome."

Records ambiguous genitalia as a first-time finding in this syndrome.

Hypospadias OCCASIONAL HP:0000047

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"In addition, immunodeficiency, congenital hypothyroidism, biotinidase deficiency, undescended testis, hypospadias, and ambiguous genitalia are defined for the first time in this syndrome."

Records hypospadias as a first-time finding in this syndrome.

Cryptorchidism OCCASIONAL HP:0000028

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"In addition, immunodeficiency, congenital hypothyroidism, biotinidase deficiency, undescended testis, hypospadias, and ambiguous genitalia are defined for the first time in this syndrome."

Records undescended testis as a first-time finding in this syndrome.

Ectopic kidney OCCASIONAL HP:0000086

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Additional novel clinical findings include hepatomegaly and a pelvic ectopic kidney; however, further reports are required to confirm these associations within the disease spectrum."

Records the pelvic ectopic kidney together with the authors' own caveat about its status.

Head and Neck 8

Microcephaly VERY_FREQUENT HP:0000252

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Bi-allelic loss-of-function variants of NUP188 are associated with Sandestig-Stefanova syndrome, which is characterized by pre- and postnatal microcephaly, trigonocephaly, congenital cataracts, periventricular white matter loss, thin corpus callosum, delayed myelination, microphthalmia,..."

States that microcephaly is both prenatal and postnatal in this syndrome.

Trigonocephaly VERY_FREQUENT HP:0000243

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Bi-allelic loss-of-function variants of NUP188 are associated with Sandestig-Stefanova syndrome, which is characterized by pre- and postnatal microcephaly, trigonocephaly, congenital cataracts, periventricular white matter loss, thin corpus callosum, delayed myelination, microphthalmia,..."

Names trigonocephaly among the characterizing features.

Short palpebral fissure VERY_FREQUENT HP:0012745

Show evidence (1 reference)

PMID:32275884 SUPPORT Human Clinical

"Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies."

Names small palpebral fissures as a characteristic dysmorphic feature.

Wide nasal bridge VERY_FREQUENT HP:0000431

Show evidence (1 reference)

PMID:32275884 SUPPORT Human Clinical

"Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies."

Names the wide nasal bridge as a characteristic dysmorphic feature.

Micrognathia VERY_FREQUENT HP:0000347

Show evidence (1 reference)

PMID:32275884 SUPPORT Human Clinical

"Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies."

Names micrognathia as a characteristic dysmorphic feature.

Orofacial cleft OCCASIONAL HP:0000202

Show evidence (1 reference)

PMID:32021605 SUPPORT Human Clinical

"the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as..."

States that the index patients had cleft lip and palate or a high-arched palate.

High palate FREQUENT HP:0000218

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"phenotypic features such as microcephaly, trigonocephaly, microphthalmia, high-arched palate, retrognathia, clinodactyly, camptodactyly, rocker-bottom feet"

Lists the high-arched palate among the features shared with previously reported patients.

Bifid uvula OCCASIONAL HP:0000193

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Our patient, born to consanguineous parents, presented with tetralogy of Fallot, bilateral congenital cataracts, hydrocephalus, a bifid uvula, a right pelvic kidney, hepatomegaly, facial feature findings, and a history of a similarly affected ex-sibling."

Documents the bifid uvula in a molecularly confirmed patient.

Immune 1

Combined immunodeficiency OCCASIONAL HP:0005387

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"In the cluster of differentiation (CD) panel, CD8 was low (9.9%), and the patient had lymphopenia. The patient was followed up with the diagnosis of combined immunodeficiency."

Documents the immunological findings and the diagnosis made from them.

Limbs 2

Clinodactyly OCCASIONAL HP:0030084

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"phenotypic features such as microcephaly, trigonocephaly, microphthalmia, high-arched palate, retrognathia, clinodactyly, camptodactyly, rocker-bottom feet"

Lists clinodactyly among the features shared with previously reported patients.

Rocker bottom foot FREQUENT HP:0001838

Show evidence (1 reference)

PMID:32021605 SUPPORT Human Clinical

"the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as..."

Names rocker-bottom feet among the shared features of the index patients.

Musculoskeletal 2

Hypotonia VERY_FREQUENT HP:0001252

Temporal: CHRONIC

Show evidence (1 reference)

PMID:32275884 SUPPORT Human Clinical

"Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."

Names hypotonia among the key clinical features.

Camptodactyly VERY_FREQUENT HP:0012385

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Bi-allelic loss-of-function variants of NUP188 are associated with Sandestig-Stefanova syndrome, which is characterized by pre- and postnatal microcephaly, trigonocephaly, congenital cataracts, periventricular white matter loss, thin corpus callosum, delayed myelination, microphthalmia,..."

Names camptodactyly among the characterizing features.

Nervous System 7

Delayed myelination VERY_FREQUENT HP:0012448

Show evidence (1 reference)

PMID:36158057 SUPPORT BACKGROUND Human Clinical

"All 6 patients presented with congenital hypotonia, delayed myelination, and white matter abnormalities."

Documents delayed myelination in all six individuals of the defining series. The quote is the later Turkish case report summarising that series rather than reporting its own patient.

Abnormal periventricular white matter morphology VERY_FREQUENT HP:0002518

Show evidence (1 reference)

PMID:32021605 SUPPORT Human Clinical

"the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as..."

Names loss of periventricular white matter among the brain changes shared by the index patients.

Thin corpus callosum VERY_FREQUENT HP:0033725

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Postnatal MRI showed progression of ventriculomegaly, along with a thin corpus callosum."

Documents the thin corpus callosum on postnatal MRI.

Ventriculomegaly VERY_FREQUENT HP:0002119

Show evidence (1 reference)

PMID:32275884 SUPPORT Human Clinical

"Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."

Names prenatal-onset ventriculomegaly among the key features.

Hydrocephalus OCCASIONAL HP:0000238

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"This study defines Sandestig-Stefanova syndrome with hydrocephalus, liver and kidney malformations, and tetralogy of Fallot for the first time."

Records the first and so far only documentation of hydrocephalus in this syndrome.

Cerebral atrophy FREQUENT HP:0002059

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"Generalized hypotonia, progressive microcephaly, seizures, cerebral atrophy, thin corpus callosum, and central hypoventilation are the most important CNS findings."

Names cerebral atrophy among the cardinal CNS findings.

Seizure FREQUENT HP:0001250

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"When he had a seizure in the form of a spasm in the upper extremities, levetiracetam was started at the age of 2.5 months."

Documents seizure onset in infancy in a molecularly confirmed patient.

Respiratory 2

Central hypoventilation VERY_FREQUENT HP:0007110

Show evidence (1 reference)

PMID:32275884 SUPPORT Human Clinical

"Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."

Names central hypoventilation among the key clinical features.

Respiratory failure OBLIGATE HP:0002878

Show evidence (1 reference)

PMID:32275884 SUPPORT Human Clinical

"All affected individuals died as a result of respiratory failure, and five of them died within the first year of life."

Establishes respiratory failure in every affected individual of the defining series.

Growth 2

Small for gestational age VERY_FREQUENT HP:0001518

Show evidence (1 reference)

PMID:32021605 SUPPORT Human Clinical

"They were both born small for gestational age and died shortly after birth at the age of 67 and 140 days, respectively, as a result of central respiratory failure."

Documents small-for-gestational-age birth in the index patients.

Intrauterine growth retardation FREQUENT HP:0001511

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Fetal ultrasound at 23 weeks of gestation revealed intrauterine growth restriction, tetralogy of Fallot (ToF), mild ventriculomegaly, a right pelvic kidney, hyperechogenic bowel (grade III), and an echogenic intracardiac focus in the left ventricle."

Documents intrauterine growth restriction on prenatal ultrasound.

🧬

Genetic Associations

1

NUP188

Gene: NUP188 hgnc:17859 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:32275884 SUPPORT Human Clinical

"Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype."

The gene-disease claim in the authors' own summary.

PMID:32021605 SUPPORT Human Clinical

"Our findings strongly suggest a correlation between the homozygous nonsense gene variants of NUP188 and a severe phenotype of a new developmental syndrome with poor prognosis resulting from nucleoporin 188 homolog protein insufficiency."

The independent gene-disease claim from the first report.

Variants (5)

Homozygous c.287dupA p.(Tyr96Ter) and homozygous c.337C>T p.(Gln113Ter)

The two alleles of the index patients: different homozygous nonsense variants in two unrelated girls whose phenotypes were nonetheless strikingly alike, which is what made the syndrome recognizable.

Show evidence (1 reference)

PMID:32021605 SUPPORT Human Clinical

"For the first time, we report 2 unrelated patients with 2 different homozygous nonsense gene variants of NUP188, p.Tyr96* and p.Gln113*, respectively."

Names the two index alleles.

Compound heterozygous c.904_907delATTT p.(Ile302Valfs*7) and c.3144C>G p.(Tyr1048Ter)

The Ashkenazi Jewish founder pair, shared by three individuals from two families. Both alleles are enriched in gnomAD's Ashkenazi Jewish population, and a targeted screen of 3,225 healthy Ashkenazi Jewish individuals confirmed the enrichment.

Show evidence (2 references)

PMID:39911172 SUPPORT REVIEW SYNTHESIS Human Clinical

"Three individuals from two different families were of Ashkenazi Jewish descent, and all three individuals shared the same two variants in compound heterozygous state, c.904_907delATTT; p.(Ile302Valfs*7) and c.3144C>G; p.(Tyr1048Ter), in NUP188."

Names the two founder alleles and the families carrying them, as itemised by the later report's review of the literature.

PMID:32275884 SUPPORT Human Clinical

"Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals."

Establishes the population enrichment of these two alleles and the screen that confirmed it.

Homozygous c.1087C>T p.(Gln363Ter)

The allele of the first reported male patient, from a consanguineous Turkish family; novel at the time of report, absent from gnomAD, ClinVar and dbSNP, and classified pathogenic on PVS1, PM2, PP3 and PP4.

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"In our patient, a homozygous c.1087C>T (p.Gln363Ter) variant was detected in exon 11 of the NUP188 (NM_015354.3) gene."

Names the allele and its exon.

Homozygous c.124C>T p.(Arg42Ter)

An early nonsense allele in exon 3 of 44, expected to trigger nonsense-mediated decay, in a consanguineous Turkish family with a second similarly affected child.

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Whole exome sequence analysis in the index case revealed a novel homozygous variant NM_015354.2: c.124C>T/p.(Arg42Ter) in the NUP188 gene."

Names the allele and how it was found.

Homozygous c.1962-2A>C splice acceptor variant

A canonical splice-acceptor allele in a Saudi patient. RT-PCR gave no detectable product in the proband while both parents showed two bands, which is direct transcript evidence that the allele abolishes the normal message.

Show evidence (1 reference)

PMID:40859750 SUPPORT Human Clinical

"RT-PCR analysis showed no detectable amplification in the proband, while parental samples displayed two bands, indicating carrier status."

Gives the transcript-level consequence of this splice allele and the parental carrier status.

💊

Medical Actions

8

Genetic counseling and recurrence-risk assessment

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

There is no disease-modifying therapy. Counselling about the one-in-four recurrence risk is the intervention with the largest effect on families, several of whom have had more than one affected child - one reported proband had a similarly affected older brother who died at 42 days without a molecular diagnosis.

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Familial segregation analysis using Sanger sequencing revealed that both the healthy brother and the parents carried this variant in a heterozygous state"

Documents the carrier testing on which recurrence-risk counselling in these families is based. The recurrence risk itself follows from the recessive inheritance recorded in the inheritance block.

Cataract surgery

Action: Cataract Surgery NCIT:C157809

Platform: Surgery

Extraction of the congenital cataract, performed in at least one reported patient.

Mechanism Target:

MODULATES Developmental cataract — Symptomatic surgery addressing the lens opacity itself, not its cause.

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"He underwent surgery on his left eye due to a congenital cataract."

Documents cataract surgery in a molecularly confirmed patient.

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"He underwent surgery on his left eye due to a congenital cataract."

Documents that cataract surgery is used in this syndrome.

Anticonvulsant therapy

Action: Anticonvulsant Therapy NCIT:C64172

Agent: levetiracetam CHEBI:6437

Platform: Small molecule

Levetiracetam was started for infantile spasm-like seizures in one reported patient. No published series reports seizure outcome, so no efficacy claim is made here.

Mechanism Target:

INHIBITS Seizure — Symptomatic anticonvulsant treatment of the seizures.

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"When he had a seizure in the form of a spasm in the upper extremities, levetiracetam was started at the age of 2.5 months."

Documents the drug and the indication in a molecularly confirmed patient.

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"When he had a seizure in the form of a spasm in the upper extremities, levetiracetam was started at the age of 2.5 months."

Documents anticonvulsant use in this syndrome.

Levothyroxine replacement

Action: Pharmacotherapy NCIT:C15986

Agent: levothyroxine CHEBI:18332

Platform: Small molecule

Started in the one patient found to have congenital hypothyroidism. Whether the hypothyroidism belongs to the syndrome is unresolved, so this is recorded as management of a reported comorbidity rather than of a syndrome feature.

Mechanism Target:

MODULATES Congenital hypothyroidism — Hormone replacement for the hypothyroidism found in that patient.

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"With the diagnosis of congenital hypothyroidism, levothyroxine treatment was started."

Documents the treatment and its indication.

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"With the diagnosis of congenital hypothyroidism, levothyroxine treatment was started."

Documents levothyroxine use in a patient with this syndrome.

Ventriculoperitoneal shunt placement

Action: Ventriculoperitoneal Shunt Placement NCIT:C168483

Platform: Surgery

A shunt was placed on day 38 in the one patient whose ventriculomegaly progressed to tetraventricular hydrocephalus. It did not alter the outcome; she died at 72 days.

Mechanism Target:

MODULATES Hydrocephalus — Cerebrospinal fluid diversion for the hydrocephalus.

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"On the 38th day of life, a shunt was placed due to tetraventricular hydrocephalus."

Documents the shunt and its indication.

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"On the 38th day of life, a shunt was placed due to tetraventricular hydrocephalus."

Documents shunt placement in a patient with this syndrome.

Respiratory support

Action: Mechanical Ventilation NCIT:C70909

Platform: Device

Escalating support for the central hypoventilation - high-flow nasal cannula, then intubation and mechanical ventilation. It is life-prolonging, not life-saving: every published patient has died of respiratory failure regardless.

Mechanism Target:

MODULATES Central hypoventilation — Mechanical support substituting for absent central respiratory drive.

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"He was followed up in the PICU for a total of 2 months, 3 weeks with a high-flow nasal cannula and 5 weeks as intubated."

Documents the escalating respiratory support given.

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"He was followed up in the PICU for a total of 2 months, 3 weeks with a high-flow nasal cannula and 5 weeks as intubated."

Documents the respiratory support used in this syndrome.

Enteral tube feeding

Action: Nasogastric Intubation NCIT:C91836

Platform: Device

Patients lose swallowing function and become dependent on nasogastric or orogastric tube feeding.

Mechanism Target:

MODULATES Feeding difficulties — Tube feeding substituting for lost swallowing function.

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"As in our patient, patients who are fed orally after birth lose their swallowing function over time and become dependent on nasogastric/orogastric tubes."

Documents the tube dependence and what it substitutes for.

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"As in our patient, patients who are fed orally after birth lose their swallowing function over time and become dependent on nasogastric/orogastric tubes."

Documents enteral tube feeding as standard management in this syndrome.

Intravenous immunoglobulin

Action: Intravenous Immunoglobulin Therapy NCIT:C121331

Platform: Protein replacement

Given twice for hypogammaglobulinemia in the one patient with documented combined immunodeficiency. A single case, not established management.

Mechanism Target:

MODULATES Combined immunodeficiency — Immunoglobulin replacement for the hypogammaglobulinemia in that patient.

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"Intravenous immunoglobulin was given twice due to hypogammaglobulinemia."

Documents the treatment and its indication.

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"Intravenous immunoglobulin was given twice due to hypogammaglobulinemia."

Documents immunoglobulin use in a patient with this syndrome.

🔬

Diagnosis

7

Exome sequencing

Every published diagnosis has been made by exome sequencing, typically after normal karyotype and chromosomal microarray. NUP188 is not on targeted panels for any of the presenting features, so the diagnosis is a sequencing rather than a clinical one.

whole exome sequencing NCIT:C101295

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"Metabolic screening tests and chromosome and microarray analyses of the patient were found to be normal. Thereupon whole-exome sequencing (WES) analysis was performed."

Documents the diagnostic sequence - normal karyotype and microarray first, then exome sequencing.

Chromosomal microarray

Performed before sequencing in reported cases and normal in each, which is part of why the diagnosis requires sequencing.

chromosomal microarray analysis NCIT:C18477

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"Metabolic screening tests and chromosome and microarray analyses of the patient were found to be normal. Thereupon whole-exome sequencing (WES) analysis was performed."

Documents that the microarray was normal before sequencing was undertaken.

Sanger sequencing for variant confirmation and family segregation

Candidate variants are confirmed by Sanger sequencing and segregation is checked in the parents, who are heterozygous carriers.

Sanger sequencing NCIT:C19641

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Familial segregation analysis using Sanger sequencing revealed that both the healthy brother and the parents carried this variant in a heterozygous state"

Documents the confirmatory and segregation role of Sanger sequencing.

Brain magnetic resonance imaging

MRI establishes the imaging signature - ventriculomegaly, thin corpus callosum, loss of periventricular white matter, delayed myelination, and later cerebral atrophy.

brain magnetic resonance imaging NCIT:C16809

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Postnatal MRI showed progression of ventriculomegaly, along with a thin corpus callosum."

Documents the role of MRI in establishing the intracranial findings.

Ophthalmologic examination

Eye examination detects the bilateral congenital cataract and microphthalmia.

eye examination NCIT:C38060

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Bilateral cataracts were detected on eye examination, and hepatomegaly was observed on abdominal ultrasound."

Documents cataract detection by eye examination.

Fetal ultrasound

Second-trimester ultrasound can show growth restriction, ventriculomegaly and the cardiac and renal malformations before birth, which is the earliest point at which the syndrome can be suspected.

fetal ultrasound imaging NCIT:C222238

Show evidence (1 reference)

PMID:39911172 SUPPORT Human Clinical

"Fetal ultrasound at 23 weeks of gestation revealed intrauterine growth restriction, tetralogy of Fallot (ToF), mild ventriculomegaly, a right pelvic kidney, hyperechogenic bowel (grade III), and an echogenic intracardiac focus in the left ventricle."

Documents what second-trimester ultrasound detected in a molecularly confirmed case.

When to consider the diagnosis

The clinical trigger stated in the literature: an infant with neurological deficits, congenital cataract, congenital heart defect and unexplained respiratory failure should have NUP188 evaluated.

Show evidence (1 reference)

PMID:36158057 SUPPORT Human Clinical

"Evaluation of NUP188 should be considered in infants with neurologic deficits, congenital cataracts, congenital heart defects, and unexplained respiratory failure."

States the diagnostic trigger for considering this gene.

📈

Progression

4

Prenatal

Abnormalities are detectable before birth. Ventriculomegaly is prenatal in onset, and second-trimester ultrasound has shown growth restriction together with the cardiac and renal malformations. Affected pregnancies deliver small for gestational age.

Show evidence (2 references)

PMID:32275884 SUPPORT Human Clinical

"Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."

States that the ventriculomegaly is prenatal in onset.

PMID:39911172 SUPPORT Human Clinical

"Fetal ultrasound at 23 weeks of gestation revealed intrauterine growth restriction, tetralogy of Fallot (ToF), mild ventriculomegaly, a right pelvic kidney, hyperechogenic bowel (grade III), and an echogenic intracardiac focus in the left ventricle."

Documents what second-trimester ultrasound showed in a molecularly confirmed case.

Neonatal

Infants are born small for gestational age and present at once with hypotonia, respiratory distress and the dysmorphic gestalt. Congenital cataract and the cardiac lesion are usually identified in this window.

Show evidence (1 reference)

PMID:32021605 SUPPORT Human Clinical

"They were both born small for gestational age and died shortly after birth at the age of 67 and 140 days, respectively, as a result of central respiratory failure."

Establishes small-for-gestational-age birth and the neonatal-to-early-infantile course.

Progressive infantile encephalopathy

Development does not progress. Microcephaly is progressive, seizures appear, cerebral atrophy develops, and oral feeding is lost so that tube feeding becomes necessary. Patients do not achieve sitting or walking.

Show evidence (2 references)

PMID:36158057 SUPPORT Human Clinical

"Generalized hypotonia, progressive microcephaly, seizures, cerebral atrophy, thin corpus callosum, and central hypoventilation are the most important CNS findings."

Names the progressive central nervous system course of the disorder.

PMID:36158057 SUPPORT Human Clinical

"Neurologic functions are progressive neurodegenerative and patients cannot gain functions such as sitting and walking."

States that motor milestones are never acquired.

Death from central respiratory failure

Every published patient has died of respiratory failure. Reported ages at death run from one month to two years and seven months, with most deaths in the first year. The respiratory failure is central rather than pulmonary: no congenital lung or tracheal disease has been found in these patients.

Show evidence (2 references)

PMID:32275884 SUPPORT Human Clinical

"All affected individuals died as a result of respiratory failure, and five of them died within the first year of life."

Establishes the uniform cause of death and the age distribution in the largest series.

PMID:36158057 SUPPORT Human Clinical

"Patients die in the early period due to respiratory failure secondary to CNS anomalies. No signs of congenital pulmonary or tracheal disease were detected in the identified patients."

States that the terminal respiratory failure is of central rather than pulmonary origin.

📊

Prevalence

1

Worldwide

Cases In Literature <1 in 1,000,000

Ultra-rare. Two independent counts a year apart agree: the 2025 Turkish report put the cumulative total at ten patients, and the 2026 Saudi report independently states that only ten cases had been published before its own. No population-based estimate exists and none is asserted here, so the published case count is the meaningful figure and no numeric rate is given. Ancestry is scattered rather than clustered - non-Finnish European, Syrian, Indian, Turkish, Ashkenazi Jewish and Saudi patients have been reported - although two of the alleles in the Muir series are enriched in the Ashkenazi Jewish population.

Show evidence (3 references)

PMID:39911172 SUPPORT Human Clinical

"This study identified a novel truncating variant in the NUP188 gene, bringing the total number of patients with Sandestig-Stefanova syndrome up to ten."

Gives the cumulative published patient count on which the ultra-rare class asserted here rests.

PMID:40859750 SUPPORT Human Clinical

"To date, only 10 cases have been reported in the literature."

An independent count published a year later, corroborating the order of magnitude.

PMID:32275884 SUPPORT Human Clinical

"Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD"

Supports the founder-allele observation recorded in the notes above.

⚖️

Clinical Burden

High

Uniformly fatal in infancy or early childhood, with no disease-modifying therapy. Every published patient has died of central respiratory failure; developmental progress does not occur, and management is entirely supportive - ventilatory support, tube feeding, anticonvulsants, cataract surgery, shunting - directed at individual manifestations rather than at the disease.

Show evidence (2 references)

PMID:32275884 SUPPORT Human Clinical

"All affected individuals died as a result of respiratory failure, and five of them died within the first year of life."

Establishes the mortality that drives the HIGH burden assignment.

PMID:36158057 SUPPORT Human Clinical

"Neurologic functions are progressive neurodegenerative and patients cannot gain functions such as sitting and walking."

Establishes the functional impact component of the burden assessment.

🧫

Experimental Models

1

Patient-derived skin fibroblasts PRIMARY_CELL_CULTURE

Primary fibroblasts from affected individuals, used both to establish the protein-level consequence of the truncating alleles and to measure nuclear protein import. These are the only patient-derived cells in which the mechanism has been assayed.

Organism

human NCBITaxon:9606

Publication

PMID:32275884

Pathograph links

Reduced Nucleocytoplasmic Protein Import measures fidelity: moderate observes: cellular Nuclear protein import was measured in patient fibroblasts and found to be reduced.

Limitations: A dermal fibroblast is not a lens, cardiomyocyte, or neuron. The measurement establishes that the transport deficit exists in a patient cell, not that it is the deficit that produces the malformations in the tissues that are actually affected.

Show evidence (1 reference)

PMID:32275884 SUPPORT In Vitro

"Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism."

The measurement this link records.

🐁

Animal Models

2

NUP188 CRISPR knockout Drosophila

A fly knockout generated alongside the human genetics, used to ask whether removing NUP188 produces a neurological phenotype at all. It does - motor deficits and seizure susceptibility - and it also revealed aberrant dendrite tiling, which is the origin of the dendritic-development hypothesis for this syndrome.

Species

Drosophila melanogaster

Genotype

CRISPR-mediated NUP188 knockout

Publication

PMID:32275884

Pathograph links

Impaired Neuronal Dendrite Development recapitulates fidelity: moderate observes: cellular Dendrite tiling is disrupted by NUP188 removal, which is the observation the node records.

Limitations: Drosophila dendritic arborisation neurons are not a model of human cortical or brainstem circuitry, and no dendritic abnormality has been demonstrated in tissue from an affected individual.

Show evidence (1 reference)

PMID:32275884 SUPPORT Model Organism

"Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development."

The dendritic result that grounds this link.

Progressive Encephalopathy with Central Respiratory Control Failure partially recapitulates fidelity: low observes: organism Motor deficits and seizure susceptibility reproduce part of the human neurological picture, and the authors describe the recapitulation as partial.

Limitations: The fly has no counterpart of the brainstem respiratory control whose failure kills these infants, and no counterpart of the progressive microcephaly, white-matter loss, or corpus callosum hypoplasia. The model speaks to neuronal excitability and motor output, not to the fatal element of the syndrome.

Show evidence (1 reference)

PMID:32275884 SUPPORT Model Organism

"CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals."

States both the recapitulation and its partiality, in the authors' own words.

Xenopus Nup188 morpholino knockdown

Morpholino depletion of Nup188 in Xenopus, used to test whether a nucleoporin can cause congenital heart disease through cilia rather than through nuclear transport. Cilia are lost at the left-right organizer and in mammalian cell lines while nuclear pore function stays largely intact - which is what makes the ciliary model a distinct proposal rather than a downstream consequence of a transport deficit.

Species

Xenopus

Genotype

Nup188 morpholino knockdown

Publication

PMID:27593162

Pathograph links

Loss of Cilia and Ciliary-Base NUP188 Function recapitulates fidelity: moderate observes: cellular The model is the source of this node: it shows that depleting Nup188 costs cells their cilia.

Limitations: Morpholino knockdown is a partial, transient depletion rather than the biallelic germline truncation that causes the human syndrome, and the human genetic observation that motivated the work was a NUP188 duplication in a heterotaxy patient, not a loss-of-function allele. No patient with this syndrome has had ciliation assayed.

Show evidence (1 reference)

PMID:27593162 SUPPORT Model Organism

"Here, we show that knockdown of Nup188 or its binding partner Nup93 leads to a loss of cilia during embryonic development while leaving NPC function largely intact."

The primary result grounding this link.

{ }

Source YAML

click to show

name: Sandestig-Stefanova Syndrome
category: Mendelian
creation_date: '2026-09-18T00:00:00Z'
synonyms:
- SANDSTEF
- Nucleoporin 188 insufficiency syndrome
- NUP188-related syndrome
- Bi-allelic NUP188 loss-of-function syndrome
description: >-
  Sandestig-Stefanova syndrome is an autosomal recessive, prenatal-onset multisystem
  developmental disorder caused by biallelic loss-of-function variants in NUP188, which
  encodes a scaffold component of the nuclear pore complex inner ring. The recognizable
  picture is pre- and postnatal microcephaly with trigonocephaly, congenital bilateral
  cataract and microphthalmia, congenital heart disease, camptodactyly and rocker-bottom
  feet, and a distinctive facial gestalt, on a background of prenatal-onset
  ventriculomegaly, loss of periventricular white matter, a thin corpus callosum and
  delayed myelination. Infants are hypotonic from birth, do not acquire motor milestones,
  develop central hypoventilation, and die of central respiratory failure, almost always
  within the first year. The condition was delineated independently and near-simultaneously
  by Sandestig et al. (two unrelated girls with homozygous nonsense variants) and by Muir
  et al. (six individuals from four families with biallelic truncating variants); the two
  descriptions are of the same entity, and the name honours the first report. Roughly ten
  patients had been published as of 2025-2026. The best-supported cellular lesion is
  reduced nuclear protein import, measured directly in patient fibroblasts, but NUP188 also
  acts at the cilium base and at spindle poles, and how much of the phenotype those
  non-transport roles account for is unsettled.
disease_term:
  preferred_term: Sandestig-Stefanova syndrome
  term:
    id: MONDO:0032926
    label: sandestig-stefanova syndrome
parents:
- Nucleoporinopathy
- Congenital Multiple Anomaly Syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0032926
      label: sandestig-stefanova syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The entry's own disease_term, recorded explicitly so the exact-match relationship is
      queryable rather than implied by the binding alone. MONDO gives this term a single
      causal gene (RO:0004003 HGNC:17859, NUP188), no descendants, and cross-references to
      OMIM:618804, DOID:0081272, MEDGEN:1718072 and UMLS:C5394118. It records no Orphanet
      cross-reference.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Ultra-rare. Two independent counts a year apart agree: the 2025 Turkish report put the
    cumulative total at ten patients, and the 2026 Saudi report independently states that
    only ten cases had been published before its own. No population-based estimate exists
    and none is asserted here, so the published case count is the meaningful figure and no
    numeric rate is given. Ancestry is scattered rather than clustered - non-Finnish
    European, Syrian, Indian, Turkish, Ashkenazi Jewish and Saudi patients have been
    reported - although two of the alleles in the Muir series are enriched in the
    Ashkenazi Jewish population.
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study identified a novel truncating variant in the NUP188 gene, bringing the total number of patients with Sandestig-Stefanova syndrome up to ten."
    explanation: Gives the cumulative published patient count on which the ultra-rare class asserted here rests.
  - reference: PMID:40859750
    reference_title: A Novel Homozygous Splice Variant in the NUP188 Gene Causing Sandestig-Stefanova Syndrome in a Saudi Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, only 10 cases have been reported in the literature."
    explanation: An independent count published a year later, corroborating the order of magnitude.
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD"
    explanation: Supports the founder-allele observation recorded in the notes above.
progression:
- phase: Prenatal
  notes: >-
    Abnormalities are detectable before birth. Ventriculomegaly is prenatal in onset, and
    second-trimester ultrasound has shown growth restriction together with the cardiac and
    renal malformations. Affected pregnancies deliver small for gestational age.
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."
    explanation: States that the ventriculomegaly is prenatal in onset.
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fetal ultrasound at 23 weeks of gestation revealed intrauterine growth restriction, tetralogy of Fallot (ToF), mild ventriculomegaly, a right pelvic kidney, hyperechogenic bowel (grade III), and an echogenic intracardiac focus in the left ventricle."
    explanation: Documents what second-trimester ultrasound showed in a molecularly confirmed case.
- phase: Neonatal
  notes: >-
    Infants are born small for gestational age and present at once with hypotonia,
    respiratory distress and the dysmorphic gestalt. Congenital cataract and the cardiac
    lesion are usually identified in this window.
  evidence:
  - reference: PMID:32021605
    reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They were both born small for gestational age and died shortly after birth at the age of 67 and 140 days, respectively, as a result of central respiratory failure."
    explanation: Establishes small-for-gestational-age birth and the neonatal-to-early-infantile course.
- phase: Progressive infantile encephalopathy
  notes: >-
    Development does not progress. Microcephaly is progressive, seizures appear, cerebral
    atrophy develops, and oral feeding is lost so that tube feeding becomes necessary.
    Patients do not achieve sitting or walking.
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generalized hypotonia, progressive microcephaly, seizures, cerebral atrophy, thin corpus callosum, and central hypoventilation are the most important CNS findings."
    explanation: Names the progressive central nervous system course of the disorder.
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurologic functions are progressive neurodegenerative and patients cannot gain functions such as sitting and walking."
    explanation: States that motor milestones are never acquired.
- phase: Death from central respiratory failure
  notes: >-
    Every published patient has died of respiratory failure. Reported ages at death run
    from one month to two years and seven months, with most deaths in the first year. The
    respiratory failure is central rather than pulmonary: no congenital lung or tracheal
    disease has been found in these patients.
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals died as a result of respiratory failure, and five of them died within the first year of life."
    explanation: Establishes the uniform cause of death and the age distribution in the largest series.
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients die in the early period due to respiratory failure secondary to CNS anomalies. No signs of congenital pulmonary or tracheal disease were detected in the identified patients."
    explanation: States that the terminal respiratory failure is of central rather than pulmonary origin.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Uniformly fatal in infancy or early childhood, with no disease-modifying therapy. Every
    published patient has died of central respiratory failure; developmental progress does
    not occur, and management is entirely supportive - ventilatory support, tube feeding,
    anticonvulsants, cataract surgery, shunting - directed at individual manifestations
    rather than at the disease.
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals died as a result of respiratory failure, and five of them died within the first year of life."
    explanation: Establishes the mortality that drives the HIGH burden assignment.
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurologic functions are progressive neurodegenerative and patients cannot gain functions such as sitting and walking."
    explanation: Establishes the functional impact component of the burden assessment.
mechanistic_hypotheses:
- hypothesis_group_id: nuclear_import_deficiency_model
  hypothesis_label: Reduced Nucleocytoplasmic Protein Import Model
  status: CANONICAL
  description: >-
    The mainstream account: NUP188 is a scaffold subunit of the NUP93 subcomplex that builds
    the nuclear pore complex inner ring, and its loss degrades nucleocytoplasmic transport,
    starving developing tissues of the nuclear delivery of regulatory proteins. This is the
    only arm with a direct measurement in patient material - nuclear protein import was
    reduced in fibroblasts from affected individuals - and the authors of that measurement
    state it as a possible rather than an established mechanism.
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism."
    explanation: The direct patient-cell measurement on which this model rests, stated by its authors with the hedge they used.
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "NUP188 is part of the NUP93 subcomplex, the second major structural unit of the NPC, which controls the passage of membrane or transmembrane proteins through NPC"
    explanation: States the structural position of NUP188 in the pore that makes a transport deficit the expected consequence of losing it.
- hypothesis_group_id: ciliary_nup188_model
  hypothesis_label: Ciliary and Moonlighting-Function Model
  status: EMERGING
  description: >-
    An alternative or additional route in which the disease-relevant lesion is not at the
    nuclear pore at all. NUP188 localises to the cilium base, and morpholino depletion in
    Xenopus abolishes cilia while leaving nuclear pore function largely intact - so a
    ciliary deficit can be produced by loss of NUP188 without a transport deficit. The
    clinical features that motivate this arm are the congenital heart disease, the
    hydrocephalus, and the heterotaxy-like findings reported in some patients. It is
    EMERGING rather than CANONICAL because no patient cell or tissue has been assayed for
    ciliation: the supporting work is amphibian and cell-line depletion, and a NUP188
    duplication rather than the biallelic loss-of-function alleles that cause this disease.
  evidence:
  - reference: PMID:27593162
    reference_title: Congenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we show that knockdown of Nup188 or its binding partner Nup93 leads to a loss of cilia during embryonic development while leaving NPC function largely intact."
    explanation: Demonstrates that losing Nup188 can produce a ciliary phenotype without a nuclear-transport phenotype, which is what makes this a distinct model rather than a downstream consequence of the canonical one.
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Cilia dysfunction contributes to various ciliopathies including hydrocephalus, polycystic kidney disease, retinal dystrophy, and congenital heart disease."
    explanation: States the clinical link this model proposes between a ciliary lesion and the hydrocephalus and heart disease seen in these patients.
pathophysiology:
- name: Biallelic NUP188 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Germline biallelic truncating variants in NUP188 - homozygous nonsense in consanguineous
    kindreds, compound heterozygous elsewhere. Every reported disease allele is predicted to
    truncate: nonsense, frameshift, and a canonical splice-acceptor variant. No missense
    allele has been shown to cause the syndrome, so this is a loss-of-function mechanism
    rather than a dominant-negative or gain-of-function one.
  genes:
  - preferred_term: NUP188
    term:
      id: hgnc:17859
      label: NUP188
  genetic_context:
    description: >-
      Biallelic germline truncating NUP188 variants. A premature termination codon early in
      the 44-exon transcript is expected to trigger nonsense-mediated decay, and a
      splice-acceptor allele produced no detectable RT-PCR amplification in the proband.
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
  evidence:
  - reference: PMID:32021605
    reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For the first time, we report 2 unrelated patients with 2 different homozygous nonsense gene variants of NUP188, p.Tyr96* and p.Gln113*, respectively."
    explanation: The first report of biallelic NUP188 nonsense variants in this phenotype.
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families."
    explanation: The independent series establishing biallelic truncating NUP188 variants as the cause of a recognizable syndrome.
  downstream:
  - target: Absent or Truncated NUP188 Protein
    causal_link_type: DIRECT
    description: >-
      Premature termination codons either trigger nonsense-mediated decay of the transcript
      or yield a truncated product, so the cell has no functional NUP188.
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This variant introduces a premature termination codon in exon 3 of 44 of NUP188, likely resulting in nonsense-mediated decay of the mRNA product."
      explanation: States the expected consequence of an early premature termination codon in this gene.
- name: Absent or Truncated NUP188 Protein
  biological_scale: MOLECULAR
  description: >-
    Protein-level consequence of the truncating alleles, established directly rather than
    inferred: immunoblot and immunofluorescence of fibroblasts from two of the reported
    individuals showed either complete loss of NUP188 or a non-functional stump. This is
    the node from which the two competing mechanistic models diverge - one through the
    nuclear pore, one through the cilium base.
  genes:
  - preferred_term: NUP188
    term:
      id: hgnc:17859
      label: NUP188
  cell_types:
  - preferred_term: patient-derived skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Immunoblot and immunofluorescence analyses of fibroblasts from individuals carrying p.Ile302Valfs*7 and p.Tyr1048Ter variants showed that these variants resulted in either complete loss of NUP188 or a non-functional stump protein product."
    explanation: >-
      Reports the protein-level result obtained in patient fibroblasts. The quote is this
      case report restating the finding of the earlier Muir series rather than its own
      experiment, hence BACKGROUND; the evidence it describes is in vitro work on human
      patient cells.
  - reference: PMID:40859750
    reference_title: A Novel Homozygous Splice Variant in the NUP188 Gene Causing Sandestig-Stefanova Syndrome in a Saudi Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RT-PCR analysis showed no detectable amplification in the proband, while parental samples displayed two bands, indicating carrier status."
    explanation: Independent transcript-level demonstration that a disease allele abolishes the normal NUP188 message.
  downstream:
  - target: Nuclear Pore Complex Inner-Ring Scaffold Defect
    causal_link_type: DIRECT
    hypothesis_groups:
    - nuclear_import_deficiency_model
    description: >-
      Losing NUP188 removes a scaffold subunit of the NUP93 subcomplex that builds the
      inner ring of the pore.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "The NUP188 gene encodes a protein involved in the NPC and controlling the passage of membrane or transmembrane proteins as part of the hNup93 subcomplex"
      explanation: States the subcomplex membership that makes this edge a direct structural consequence.
  - target: Loss of Cilia and Ciliary-Base NUP188 Function
    causal_link_type: DIRECT
    hypothesis_groups:
    - ciliary_nup188_model
    description: >-
      Under the ciliary model the same protein loss acts at the cilium base instead. This
      edge is supported by amphibian and cell-line depletion rather than by patient tissue,
      and it is asserted as a model arm, not as an established step in this disease.
    evidence:
    - reference: PMID:27593162
      reference_title: Congenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In the following, we demonstrate that depletion of Nup188 and its binding partner Nup93 leads to the loss of cilia in multiple cell types including mammalian cell lines and the LRO of Xenopus."
      explanation: Demonstrates that depleting Nup188 costs the cell its cilia, in Xenopus and in mammalian cells.
- name: Nuclear Pore Complex Inner-Ring Scaffold Defect
  biological_scale: MOLECULAR
  description: >-
    The nuclear pore complex is built from roughly thirty nucleoporins; the NUP93
    subcomplex to which NUP188 belongs forms the inner ring of its scaffold. Complete loss
    of pore function is incompatible with cell viability, so a viable disease allele
    produces a partial structural defect rather than an absent pore.
  genes:
  - preferred_term: NUP188
    term:
      id: hgnc:17859
      label: NUP188
  cellular_components:
  - preferred_term: nuclear pore inner ring
    term:
      id: GO:0044611
      label: nuclear pore inner ring
  - preferred_term: nuclear pore
    term:
      id: GO:0005643
      label: nuclear pore
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "NUP188 is part of the NUP93 subcomplex, the second major structural unit of the NPC, which controls the passage of membrane or transmembrane proteins through NPC"
    explanation: Locates NUP188 within the pore's inner-ring scaffold.
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules."
    explanation: States the function of the structure this node describes as defective.
  downstream:
  - target: Reduced Nucleocytoplasmic Protein Import
    causal_link_type: DIRECT
    hypothesis_groups:
    - nuclear_import_deficiency_model
    description: >-
      A defective inner-ring scaffold degrades the pore's ability to move cargo into the
      nucleus.
    evidence:
    - reference: PMID:32275884
      reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism."
      explanation: Measures the transport deficit this edge asserts, in cells from affected individuals.
- name: Reduced Nucleocytoplasmic Protein Import
  biological_scale: CELLULAR
  description: >-
    The one cellular lesion measured directly in patient material. Fibroblasts from affected
    individuals import protein into the nucleus less efficiently than control cells. The
    authors present it as a possible disease mechanism, and the step from a fibroblast
    transport deficit to the developmental malformations below is not itself demonstrated -
    the edges out of this node are therefore marked as having unknown intermediates.
  cell_types:
  - preferred_term: patient-derived skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  biological_processes:
  - preferred_term: protein import into nucleus
    term:
      id: GO:0006606
      label: protein import into nucleus
    modifier: DECREASED
  - preferred_term: nucleocytoplasmic transport
    term:
      id: GO:0006913
      label: nucleocytoplasmic transport
    modifier: DECREASED
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism."
    explanation: The primary measurement of the deficit this node names.
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Functional analysis showed that disruption of NUP188 was associated with low active protein transport to the nucleus."
    explanation: A later report restating the same in vitro functional result.
  downstream:
  - target: Impaired Neuronal Dendrite Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - nuclear_import_deficiency_model
    description: >-
      Loss of NUP188 disrupts dendritic development. The connection to the transport deficit
      is inferential: the dendrite result comes from Drosophila knockout, not from a
      transport-rescue experiment.
    evidence:
    - reference: PMID:32275884
      reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development."
      explanation: The observation behind the dendritic node, reported with the authors' own hedge.
  - target: Deficient Cerebral White Matter Development and Myelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - nuclear_import_deficiency_model
    description: >-
      White-matter loss, corpus callosum hypoplasia and delayed myelination are present in
      essentially every reported patient. No intermediate between the transport deficit and
      the oligodendroglial failure has been identified.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "All 6 patients presented with congenital hypotonia, delayed myelination, and white matter abnormalities."
      explanation: >-
        Establishes that the white-matter and myelination phenotype is present in all
        affected individuals of the defining series. The quoted sentence is the later
        Turkish report's summary of that series.
  - target: Impaired Lens and Anterior Eye Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - nuclear_import_deficiency_model
    description: >-
      Congenital bilateral cataract with microphthalmia is a cardinal feature. Nothing has
      been measured in lens tissue from these patients; the edge records that the ocular
      malformation follows from the NUP188 lesion, not how.
    evidence:
    - reference: PMID:32021605
      reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as loss of periventricular white matter), thin corpus callosum, and delayed myelinization."
      explanation: Establishes congenital bilateral cataract and microphthalmia as part of the syndrome caused by the NUP188 lesion.
  - target: Disrupted Cardiac Morphogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - nuclear_import_deficiency_model
    description: >-
      Congenital heart defects occur in most patients. Under the canonical model this is a
      consequence of the transport deficit during cardiac development; the ciliary model
      offers a competing route to the same node.
    evidence:
    - reference: PMID:32275884
      reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."
      explanation: Establishes congenital heart defects as a key feature of the syndrome.
  - target: Impaired Craniofacial and Distal Limb Morphogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - nuclear_import_deficiency_model
    description: >-
      The facial gestalt, trigonocephaly, palatal clefting and the digital anomalies are
      reproducible enough across unrelated families to be described as recognizable, which
      is what makes them a consequence of the gene lesion rather than incidental.
    evidence:
    - reference: PMID:32021605
      reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both patients showed very similar facial features such as laterally extended arched eyebrows, wide convex nose with a wide prominent nasal bridge, and prominent angulated antihelix."
      explanation: Documents the reproducible craniofacial gestalt in two unrelated patients with different NUP188 alleles.
  - target: Prenatal Growth Restriction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - nuclear_import_deficiency_model
    description: >-
      Growth restriction begins before birth and affects head circumference as well as body
      size, so it is a prenatal consequence of the gene lesion rather than a postnatal
      feeding effect.
    evidence:
    - reference: PMID:32021605
      reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "They were both born small for gestational age and died shortly after birth at the age of 67 and 140 days, respectively, as a result of central respiratory failure."
      explanation: Establishes small-for-gestational-age birth in the two index patients.
- name: Loss of Cilia and Ciliary-Base NUP188 Function
  biological_scale: CELLULAR
  description: >-
    The alternative arm. NUP188 is found at the base of cilia as well as at the nuclear
    envelope, and depleting it costs cells their cilia while the nuclear pore keeps working.
    This node exists because it explains parts of the clinical picture the transport model
    handles poorly - the heart defects, the hydrocephalus, and the heterotaxy-like findings
    - but it has never been demonstrated in a patient with this syndrome.
  genes:
  - preferred_term: NUP188
    term:
      id: hgnc:17859
      label: NUP188
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:27593162
    reference_title: Congenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we show that knockdown of Nup188 or its binding partner Nup93 leads to a loss of cilia during embryonic development while leaving NPC function largely intact."
    explanation: The primary demonstration that Nup188 depletion produces a ciliary rather than a transport phenotype.
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Apart from its role in nuclear transport, NUP188 also plays a role in various cellular functions, including ciliogenesis"
    explanation: States the non-transport role of NUP188 that this node is built on.
  downstream:
  - target: Disrupted Cardiac Morphogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ciliary_nup188_model
    description: >-
      The ciliary route to the cardiac phenotype. Nup188 was first implicated in heart
      disease through a patient with congenital heart disease and heterotaxy - a left-right
      patterning disorder generated at the ciliated left-right organizer.
    evidence:
    - reference: PMID:27593162
      reference_title: Congenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "In a patient with CHD and heterotaxy (Htx), a disorder of left-right patterning, we previously identified a duplication in Nup188."
      explanation: >-
        The human genetic observation that motivated the ciliary work. Note it is a
        duplication, not one of the biallelic loss-of-function alleles that cause this
        syndrome, which is why the edge is a model arm rather than an established step.
    - reference: PMID:27593162
      reference_title: Congenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We suggest that the nanoscale organization and function of nucleoporins are context dependent in a way that is required for the structure of the heart."
      explanation: The authors' own statement linking the non-pore organization of Nup188 to cardiac structure.
  - target: Prenatal-Onset Ventriculomegaly and Hydrocephalus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ciliary_nup188_model
    description: >-
      Hydrocephalus is a recognised ciliopathy manifestation, and this is the route the
      report that first documented overt hydrocephalus in the syndrome proposed for it.
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "Cilia dysfunction contributes to various ciliopathies including hydrocephalus, polycystic kidney disease, retinal dystrophy, and congenital heart disease."
      explanation: States the proposed ciliary route to the hydrocephalus documented in that report's own patient.
- name: Impaired Neuronal Dendrite Development
  biological_scale: CELLULAR
  description: >-
    Removing NUP188 in Drosophila produces aberrant dendrite tiling alongside motor deficits
    and seizure susceptibility. This is the only cellular account of the neurological
    phenotype offered so far, and it is an invertebrate one.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: dendrite morphogenesis
    term:
      id: GO:0048813
      label: dendrite morphogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development."
    explanation: The dendritic observation this node records.
  downstream:
  - target: Progressive Encephalopathy with Central Respiratory Control Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A route from disordered neuronal development to the progressive encephalopathy. The
      supporting knockout reproduces motor deficits and seizure susceptibility but only
      partially recapitulates the human neurological phenotype, and the fly has no
      counterpart of the brainstem respiratory control that kills these infants.
    evidence:
    - reference: PMID:32275884
      reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals."
      explanation: States both the neurological recapitulation and its partiality.
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Seizure susceptibility follows NUP188 removal in the fly, and seizures appear in
      affected infants during the first months.
    evidence:
    - reference: PMID:32275884
      reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals."
      explanation: Reports the seizure susceptibility produced by removing NUP188.
- name: Deficient Cerebral White Matter Development and Myelination
  biological_scale: TISSUE
  description: >-
    Loss of periventricular white matter, a thin or hypoplastic corpus callosum and delayed
    myelination together form the imaging signature of the syndrome and are present in
    essentially every reported patient. Whether the primary failure is oligodendroglial or
    axonal has not been established in these patients, so this node is stated at tissue
    level.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: DECREASED
  evidence:
  - reference: PMID:32021605
    reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as loss of periventricular white matter), thin corpus callosum, and delayed myelinization."
    explanation: Establishes the white-matter loss, thin corpus callosum and delayed myelination in the index patients.
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."
    explanation: Independent confirmation of the same white-matter and corpus callosum findings.
  downstream:
  - target: Delayed myelination
    causal_link_type: DIRECT
    description: Deficient myelination presents radiologically as delayed myelination.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "All 6 patients presented with congenital hypotonia, delayed myelination, and white matter abnormalities."
      explanation: Documents delayed myelination in every individual of the defining series.
  - target: Abnormal periventricular white matter morphology
    causal_link_type: DIRECT
    description: Loss of periventricular white matter is the specific white-matter finding reported.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sandestig-Stefanova syndrome is an autosomal recessive developmental syndrome characterized by microcephaly, trigonocephaly, congenital cataracts, microphthalmia, facial findings, camptodactyly, periventricular white matter loss, thin corpus callosum, delayed myelination, and poor prognosis."
      explanation: Names periventricular white matter loss as a defining feature.
  - target: Thin corpus callosum
    causal_link_type: DIRECT
    description: The callosal commissure is thin or hypoplastic on imaging and at postmortem.
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Postnatal MRI showed progression of ventriculomegaly, along with a thin corpus callosum."
      explanation: Documents the thin corpus callosum on postnatal imaging in a molecularly confirmed case.
  - target: Cerebral atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cerebral atrophy develops over the course of the illness and is listed among the most
      important central nervous system findings.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Generalized hypotonia, progressive microcephaly, seizures, cerebral atrophy, thin corpus callosum, and central hypoventilation are the most important CNS findings."
      explanation: Names cerebral atrophy among the cardinal CNS findings.
  - target: Progressive Encephalopathy with Central Respiratory Control Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The white-matter and callosal deficit is the structural correlate of the encephalopathy
      that dominates the clinical course.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Generalized hypotonia, progressive microcephaly, seizures, cerebral atrophy, thin corpus callosum, and central hypoventilation are the most important CNS findings."
      explanation: Groups the structural white-matter findings with the clinical encephalopathy they accompany.
- name: Progressive Encephalopathy with Central Respiratory Control Failure
  biological_scale: ORGANISM
  description: >-
    The clinical convergence point and the cause of death. Generalised hypotonia is present
    from birth, microcephaly is progressive, seizures appear, swallowing is lost, and central
    hypoventilation develops. The respiratory failure is central: no congenital pulmonary or
    tracheal disease has been found in any reported patient, so the lung is not the lesion.
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients die in the early period due to respiratory failure secondary to CNS anomalies. No signs of congenital pulmonary or tracheal disease were detected in the identified patients."
    explanation: Establishes that the fatal respiratory failure is of central nervous system origin.
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals died as a result of respiratory failure, and five of them died within the first year of life."
    explanation: Establishes the uniform terminal event.
  downstream:
  - target: Hypotonia
    causal_link_type: DIRECT
    description: Generalised hypotonia is present congenitally and persists.
    evidence:
    - reference: PMID:32275884
      reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."
      explanation: Names hypotonia as a key clinical feature.
  - target: Central hypoventilation
    causal_link_type: DIRECT
    description: >-
      Loss of central respiratory drive, listed among the cardinal CNS findings and the
      proximate cause of the terminal respiratory failure.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Generalized hypotonia, progressive microcephaly, seizures, cerebral atrophy, thin corpus callosum, and central hypoventilation are the most important CNS findings."
      explanation: Names central hypoventilation among the cardinal CNS findings.
  - target: Respiratory failure
    causal_link_type: DIRECT
    description: Central hypoventilation progresses to respiratory failure, which has killed every reported patient.
    evidence:
    - reference: PMID:32275884
      reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All affected individuals died as a result of respiratory failure, and five of them died within the first year of life."
      explanation: Establishes respiratory failure as the uniform outcome.
  - target: Feeding difficulties
    causal_link_type: DIRECT
    description: >-
      Swallowing is lost over time, so infants who fed orally at birth become dependent on
      nasogastric or orogastric tubes.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As in our patient, patients who are fed orally after birth lose their swallowing function over time and become dependent on nasogastric/orogastric tubes."
      explanation: Documents the progressive loss of swallowing and resulting tube dependence.
  - target: Microcephaly
    causal_link_type: DIRECT
    description: >-
      Microcephaly is present at birth and progresses postnatally, which is what makes it a
      consequence of the encephalopathy as well as of prenatal growth restriction.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Generalized hypotonia, progressive microcephaly, seizures, cerebral atrophy, thin corpus callosum, and central hypoventilation are the most important CNS findings."
      explanation: States that the microcephaly is progressive.
- name: Impaired Lens and Anterior Eye Development
  biological_scale: TISSUE
  description: >-
    Congenital bilateral cataract with microphthalmia. Cataract is one of the two or three
    features that make the syndrome recognizable, and it was present in four of the six
    individuals in the defining series. No lens tissue from an affected individual has been
    examined, so the node asserts the developmental failure without specifying its cellular
    route - in particular, no crystallin aggregation has been demonstrated here.
  evidence:
  - reference: PMID:32021605
    reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as loss of periventricular white matter), thin corpus callosum, and delayed myelinization."
    explanation: Establishes congenital bilateral cataract and microphthalmia together in the index patients.
  downstream:
  - target: Developmental cataract
    causal_link_type: DIRECT
    description: Bilateral lens opacity present at birth.
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Bilateral cataracts were detected on eye examination, and hepatomegaly was observed on abdominal ultrasound."
      explanation: Documents the bilateral cataract on examination in a molecularly confirmed case.
  - target: Microphthalmia
    causal_link_type: DIRECT
    description: Reduced globe size accompanies the cataract.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sandestig-Stefanova syndrome is an autosomal recessive developmental syndrome characterized by microcephaly, trigonocephaly, congenital cataracts, microphthalmia, facial findings, camptodactyly, periventricular white matter loss, thin corpus callosum, delayed myelination, and poor prognosis."
      explanation: Names microphthalmia as a defining feature of the syndrome.
- name: Disrupted Cardiac Morphogenesis
  biological_scale: TISSUE
  description: >-
    Congenital heart disease occurred in five of the six individuals of the defining series
    and in most patients reported since. The lesions are structurally heterogeneous -
    ventricular septal defect, bicuspid aortic valve, patent ductus arteriosus, partial
    anomalous pulmonary venous return, and in one patient tetralogy of Fallot - which is
    what a morphogenetic rather than a single-structure defect looks like.
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Congenital cataracts in 4 patients and congenital heart anomalies including bicuspid aortic valve, partial abnormal pulmonary venous return, and patent ductus arteriosus were seen in 5 patients."
    explanation: >-
      Gives the cardiac lesion spectrum and its frequency in the defining series. The quote
      is this case report summarising that earlier series rather than its own patient.
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patients presented with ToF, expanding the cardiac spectrum of NUP188."
    explanation: Adds tetralogy of Fallot to the cardiac spectrum.
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Congenital heart defects | + | + | + | + | + | Not tested | + | + | + | +"
    explanation: >-
      The report's per-patient comparison table across all ten published cases: a congenital
      heart defect is recorded in nine, with the tenth not tested. This is the denominator
      behind the claim that most patients have one.
  downstream:
  - target: Ventricular septal defect
    causal_link_type: DIRECT
    description: A septal defect among the cardiac lesions reported in biallelic cases.
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Heterozygous truncating variants have been linked to mitral valve prolapse, while patients with bi-allelic variants were reported to have a ventricular septal defect, bicuspid aortic valve, patent ductus arteriosus, partial anomalous pulmonary venous return, and left ventricular hypertrophy"
      explanation: The report's synthesis of the cardiac spectrum across published biallelic cases, where the ventricular septal defect is itemised.
  - target: Bicuspid aortic valve
    causal_link_type: DIRECT
    description: One of the valvar lesions reported in the defining series.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Congenital cataracts in 4 patients and congenital heart anomalies including bicuspid aortic valve, partial abnormal pulmonary venous return, and patent ductus arteriosus were seen in 5 patients."
      explanation: Names bicuspid aortic valve among the reported cardiac lesions.
  - target: Patent ductus arteriosus
    causal_link_type: DIRECT
    description: Persistence of the ductus is among the reported cardiac lesions.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Congenital cataracts in 4 patients and congenital heart anomalies including bicuspid aortic valve, partial abnormal pulmonary venous return, and patent ductus arteriosus were seen in 5 patients."
      explanation: Names patent ductus arteriosus among the reported cardiac lesions.
  - target: Partial anomalous pulmonary venous return
    causal_link_type: DIRECT
    description: An anomalous venous connection reported in the defining series.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Congenital cataracts in 4 patients and congenital heart anomalies including bicuspid aortic valve, partial abnormal pulmonary venous return, and patent ductus arteriosus were seen in 5 patients."
      explanation: Names partial anomalous pulmonary venous return among the reported cardiac lesions.
  - target: Tetralogy of Fallot
    causal_link_type: DIRECT
    description: A conotruncal lesion documented prenatally in one patient and her affected sibling.
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our patient, born to consanguineous parents, presented with tetralogy of Fallot, bilateral congenital cataracts, hydrocephalus, a bifid uvula, a right pelvic kidney, hepatomegaly, facial feature findings, and a history of a similarly affected ex-sibling."
      explanation: Documents tetralogy of Fallot in a molecularly confirmed patient.
- name: Prenatal-Onset Ventriculomegaly and Hydrocephalus
  biological_scale: TISSUE
  description: >-
    Ventricular enlargement begins before birth and is one of the key features of the
    syndrome. In most patients it stays as ventriculomegaly; in one it progressed to overt
    tetraventricular hydrocephalus requiring a shunt, and that report was careful to note
    that concurrent neonatal sepsis may have contributed, so whether progression to frank
    hydrocephalus belongs to the syndrome is not settled.
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."
    explanation: Establishes the prenatal onset of the ventriculomegaly.
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similar to previous reports, prenatal-onset mild ventriculomegaly was identified in our case during the 2nd trimester."
    explanation: Independent confirmation of second-trimester ventriculomegaly.
  downstream:
  - target: Ventriculomegaly
    causal_link_type: DIRECT
    description: Ventricular enlargement detectable from the second trimester.
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Similar to previous reports, prenatal-onset mild ventriculomegaly was identified in our case during the 2nd trimester."
      explanation: Documents the prenatal ventriculomegaly.
  - target: Hydrocephalus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Progression from ventriculomegaly to shunt-requiring hydrocephalus, documented once.
      The reporting authors explicitly left open whether the progression is part of the
      syndrome or was driven by the neonatal sepsis their patient also had.
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This study defines Sandestig-Stefanova syndrome with hydrocephalus, liver and kidney malformations, and tetralogy of Fallot for the first time."
      explanation: Records the first documentation of hydrocephalus in this syndrome.
- name: Impaired Craniofacial and Distal Limb Morphogenesis
  biological_scale: TISSUE
  description: >-
    A reproducible dysmorphic gestalt across unrelated families with different alleles:
    trigonocephaly from metopic ridging, small palpebral fissures, a wide nasal bridge and
    nose, micrognathia, palatal clefting or a high arched palate, and distal limb anomalies
    including camptodactyly, clinodactyly and rocker-bottom feet. That two unrelated index
    patients with different nonsense alleles looked alike is what made this a recognizable
    syndrome rather than a collection of malformations.
  evidence:
  - reference: PMID:32021605
    reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients showed very similar facial features such as laterally extended arched eyebrows, wide convex nose with a wide prominent nasal bridge, and prominent angulated antihelix."
    explanation: Documents the reproducible facial gestalt across two unrelated patients.
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies."
    explanation: Independent statement of the same dysmorphic set.
  downstream:
  - target: Trigonocephaly
    causal_link_type: DIRECT
    description: Triangular forehead from metopic ridging.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sandestig-Stefanova syndrome is an autosomal recessive developmental syndrome characterized by microcephaly, trigonocephaly, congenital cataracts, microphthalmia, facial findings, camptodactyly, periventricular white matter loss, thin corpus callosum, delayed myelination, and poor prognosis."
      explanation: Names trigonocephaly as a defining feature.
  - target: Short palpebral fissure
    causal_link_type: DIRECT
    description: Small palpebral fissures are part of the characteristic gestalt.
    evidence:
    - reference: PMID:32275884
      reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies."
      explanation: Names small palpebral fissures among the characteristic dysmorphic features.
  - target: Wide nasal bridge
    causal_link_type: DIRECT
    description: A wide, prominent nasal bridge with a wide convex nose.
    evidence:
    - reference: PMID:32275884
      reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies."
      explanation: Names the wide nasal bridge among the characteristic dysmorphic features.
  - target: Micrognathia
    causal_link_type: DIRECT
    description: A small mandible, part of the characteristic gestalt.
    evidence:
    - reference: PMID:32275884
      reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies."
      explanation: Names micrognathia among the characteristic dysmorphic features.
  - target: Low-set ears
    causal_link_type: DIRECT
    description: Low-set ears with hypoplastic tragus and a prominent angulated antihelix.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In his physical examination, hypotonia, bilateral congenital cataracts, ambiguous genitalia, hypospadias, undescended testis, bifid scrotum, and facial dysmorphic findings (hypertelorism, high palate, micrognathia, microphthalmia, low ear) were recorded"
      explanation: Documents the low-set ears on examination.
  - target: Hypertelorism
    causal_link_type: DIRECT
    description: Increased interocular distance, recorded on examination.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In his physical examination, hypotonia, bilateral congenital cataracts, ambiguous genitalia, hypospadias, undescended testis, bifid scrotum, and facial dysmorphic findings (hypertelorism, high palate, micrognathia, microphthalmia, low ear) were recorded"
      explanation: Documents hypertelorism on examination.
  - target: Orofacial cleft
    causal_link_type: DIRECT
    description: Cleft lip and palate in one index patient.
    evidence:
    - reference: PMID:32021605
      reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as loss of periventricular white matter), thin corpus callosum, and delayed myelinization."
      explanation: States that the index patients had cleft lip and palate or a high-arched palate.
  - target: High palate
    causal_link_type: DIRECT
    description: A high arched palate, the milder end of the same palatal spectrum.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In his physical examination, hypotonia, bilateral congenital cataracts, ambiguous genitalia, hypospadias, undescended testis, bifid scrotum, and facial dysmorphic findings (hypertelorism, high palate, micrognathia, microphthalmia, low ear) were recorded"
      explanation: Documents the high palate on examination.
  - target: Bifid uvula
    causal_link_type: DIRECT
    description: >-
      Incomplete midline fusion of the uvula, at the mildest end of the palatal clefting
      spectrum this node already covers. Reported once, and the reporting authors flagged
      it as a new finding in this syndrome.
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our patient, born to consanguineous parents, presented with tetralogy of Fallot, bilateral congenital cataracts, hydrocephalus, a bifid uvula, a right pelvic kidney, hepatomegaly, facial feature findings, and a history of a similarly affected ex-sibling."
      explanation: Documents the bifid uvula in a molecularly confirmed patient.
  - target: Camptodactyly
    causal_link_type: DIRECT
    description: Fixed flexion of the digits, present in essentially all reported patients.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sandestig-Stefanova syndrome is an autosomal recessive developmental syndrome characterized by microcephaly, trigonocephaly, congenital cataracts, microphthalmia, facial findings, camptodactyly, periventricular white matter loss, thin corpus callosum, delayed myelination, and poor prognosis."
      explanation: Names camptodactyly as a defining feature.
  - target: Clinodactyly
    causal_link_type: DIRECT
    description: Curvature of a digit in the coronal plane, reported alongside camptodactyly.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "phenotypic features such as microcephaly, trigonocephaly, microphthalmia, high-arched palate, retrognathia, clinodactyly, camptodactyly, rocker-bottom feet"
      explanation: Lists clinodactyly among the features shared with the previously reported patients.
  - target: Rocker bottom foot
    causal_link_type: DIRECT
    description: Convex plantar surface with a prominent heel.
    evidence:
    - reference: PMID:32021605
      reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as loss of periventricular white matter), thin corpus callosum, and delayed myelinization."
      explanation: Names rocker-bottom feet among the shared features of the index patients.
- name: Prenatal Growth Restriction
  biological_scale: ORGANISM
  description: >-
    Growth is restricted before birth. Affected infants are born small for gestational age,
    and intrauterine growth restriction has been seen on second-trimester ultrasound.
  evidence:
  - reference: PMID:32021605
    reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They were both born small for gestational age and died shortly after birth at the age of 67 and 140 days, respectively, as a result of central respiratory failure."
    explanation: Establishes small-for-gestational-age birth in the index patients.
  downstream:
  - target: Small for gestational age
    causal_link_type: DIRECT
    description: Birth weight and length below expectation for gestation.
    evidence:
    - reference: PMID:32021605
      reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "They were both born small for gestational age and died shortly after birth at the age of 67 and 140 days, respectively, as a result of central respiratory failure."
      explanation: Documents small-for-gestational-age birth.
  - target: Intrauterine growth retardation
    causal_link_type: DIRECT
    description: Growth restriction detectable on prenatal ultrasound.
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Fetal ultrasound at 23 weeks of gestation revealed intrauterine growth restriction, tetralogy of Fallot (ToF), mild ventriculomegaly, a right pelvic kidney, hyperechogenic bowel (grade III), and an echogenic intracardiac focus in the left ventricle."
      explanation: Documents intrauterine growth restriction on second-trimester ultrasound.
  - target: Microcephaly
    causal_link_type: DIRECT
    description: >-
      Head growth is restricted prenatally as well as postnatally, which is why the
      literature describes the microcephaly as both pre- and postnatal.
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Bi-allelic loss-of-function variants of NUP188 are associated with Sandestig-Stefanova syndrome, which is characterized by pre- and postnatal microcephaly, trigonocephaly, congenital cataracts, periventricular white matter loss, thin corpus callosum, delayed myelination, microphthalmia, camptodactyly, congenital heart disease, and central respiratory failure."
      explanation: States explicitly that the microcephaly is prenatal as well as postnatal.
phenotypes:
- category: Neurologic
  name: Hypotonia
  frequency: VERY_FREQUENT
  description: >-
    Generalised hypotonia is present from birth in essentially every reported patient and
    does not improve.
  phenotype_term:
    preferred_term: Congenital generalized hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
    temporality: CHRONIC
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."
    explanation: Names hypotonia among the key clinical features.
- category: Neurologic
  name: Microcephaly
  frequency: VERY_FREQUENT
  description: >-
    Microcephaly is present at birth and progresses after it. It is one of the features that
    both defining reports place first.
  phenotype_term:
    preferred_term: Pre- and postnatal microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bi-allelic loss-of-function variants of NUP188 are associated with Sandestig-Stefanova syndrome, which is characterized by pre- and postnatal microcephaly, trigonocephaly, congenital cataracts, periventricular white matter loss, thin corpus callosum, delayed myelination, microphthalmia, camptodactyly, congenital heart disease, and central respiratory failure."
    explanation: States that microcephaly is both prenatal and postnatal in this syndrome.
- category: Neurologic
  name: Delayed myelination
  frequency: VERY_FREQUENT
  description: Myelination lags on serial imaging in all reported patients.
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "All 6 patients presented with congenital hypotonia, delayed myelination, and white matter abnormalities."
    explanation: >-
      Documents delayed myelination in all six individuals of the defining series. The quote
      is the later Turkish case report summarising that series rather than reporting its own
      patient.
- category: Neurologic
  name: Abnormal periventricular white matter morphology
  frequency: VERY_FREQUENT
  description: Loss of periventricular white matter, one of the defining imaging findings.
  phenotype_term:
    preferred_term: Loss of periventricular white matter
    term:
      id: HP:0002518
      label: Abnormal periventricular white matter morphology
  evidence:
  - reference: PMID:32021605
    reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as loss of periventricular white matter), thin corpus callosum, and delayed myelinization."
    explanation: Names loss of periventricular white matter among the brain changes shared by the index patients.
- category: Neurologic
  name: Thin corpus callosum
  frequency: VERY_FREQUENT
  description: >-
    The corpus callosum is thin or hypoplastic on imaging and at postmortem examination.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postnatal MRI showed progression of ventriculomegaly, along with a thin corpus callosum."
    explanation: Documents the thin corpus callosum on postnatal MRI.
- category: Neurologic
  name: Ventriculomegaly
  frequency: VERY_FREQUENT
  description: Ventricular enlargement of prenatal onset, detectable from the second trimester.
  phenotype_term:
    preferred_term: Prenatal-onset ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."
    explanation: Names prenatal-onset ventriculomegaly among the key features.
- category: Neurologic
  name: Hydrocephalus
  frequency: OCCASIONAL
  description: >-
    Progression from ventriculomegaly to shunt-requiring tetraventricular hydrocephalus,
    documented in a single patient who also had neonatal sepsis; the authors could not
    separate the two contributions.
  phenotype_term:
    preferred_term: Tetraventricular hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study defines Sandestig-Stefanova syndrome with hydrocephalus, liver and kidney malformations, and tetralogy of Fallot for the first time."
    explanation: Records the first and so far only documentation of hydrocephalus in this syndrome.
- category: Neurologic
  name: Cerebral atrophy
  frequency: FREQUENT
  description: Cerebral atrophy develops during the illness and is a cardinal CNS finding.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generalized hypotonia, progressive microcephaly, seizures, cerebral atrophy, thin corpus callosum, and central hypoventilation are the most important CNS findings."
    explanation: Names cerebral atrophy among the cardinal CNS findings.
- category: Neurologic
  name: Seizure
  frequency: FREQUENT
  description: >-
    Seizures develop during the first months of life and are treated with anticonvulsants.
    Seizure susceptibility is reproduced by NUP188 knockout in Drosophila.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When he had a seizure in the form of a spasm in the upper extremities, levetiracetam was started at the age of 2.5 months."
    explanation: Documents seizure onset in infancy in a molecularly confirmed patient.
- category: Respiratory
  name: Central hypoventilation
  frequency: VERY_FREQUENT
  description: >-
    Loss of central respiratory drive, listed among the cardinal CNS findings and the
    proximate cause of the terminal respiratory failure.
  phenotype_term:
    preferred_term: Central hypoventilation
    term:
      id: HP:0007110
      label: Central hypoventilation
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."
    explanation: Names central hypoventilation among the key clinical features.
- category: Respiratory
  name: Respiratory failure
  frequency: OBLIGATE
  description: >-
    Every published patient has died of respiratory failure. The failure is central rather
    than pulmonary - no congenital lung or airway disease has been found in these patients.
  phenotype_term:
    preferred_term: Central respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals died as a result of respiratory failure, and five of them died within the first year of life."
    explanation: Establishes respiratory failure in every affected individual of the defining series.
- category: Gastrointestinal
  name: Feeding difficulties
  frequency: VERY_FREQUENT
  description: >-
    Infants who feed orally at birth lose swallowing function and become dependent on
    nasogastric or orogastric tube feeding.
  phenotype_term:
    preferred_term: Progressive loss of swallowing with tube dependence
    term:
      id: HP:0011968
      label: Feeding difficulties
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As in our patient, patients who are fed orally after birth lose their swallowing function over time and become dependent on nasogastric/orogastric tubes."
    explanation: Documents the progressive loss of swallowing in this syndrome.
- category: Ophthalmologic
  name: Developmental cataract
  frequency: VERY_FREQUENT
  description: >-
    Bilateral lens opacity present at birth, one of the two or three features that make the
    syndrome recognizable. Present in four of the six individuals of the defining series.
  phenotype_term:
    preferred_term: Congenital bilateral cataract
    term:
      id: HP:0000519
      label: Developmental cataract
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation."
    explanation: Names congenital cataract first among the key clinical features.
- category: Ophthalmologic
  name: Microphthalmia
  frequency: FREQUENT
  description: Reduced globe size accompanying the congenital cataract.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sandestig-Stefanova syndrome is an autosomal recessive developmental syndrome characterized by microcephaly, trigonocephaly, congenital cataracts, microphthalmia, facial findings, camptodactyly, periventricular white matter loss, thin corpus callosum, delayed myelination, and poor prognosis."
    explanation: Names microphthalmia among the defining features.
- category: Cardiovascular
  name: Ventricular septal defect
  frequency: FREQUENT
  description: A septal defect among the cardiac lesions reported in biallelic NUP188 cases.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Heterozygous truncating variants have been linked to mitral valve prolapse, while patients with bi-allelic variants were reported to have a ventricular septal defect, bicuspid aortic valve, patent ductus arteriosus, partial anomalous pulmonary venous return, and left ventricular hypertrophy"
    explanation: >-
      The report's synthesis of the cardiac spectrum across published biallelic cases, where
      the ventricular septal defect is itemised.
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "presented two unrelated individuals with bi-allelic truncating variants of NUP188, who exhibited overlapping features including premature birth, pre- and postnatal microcephaly, trigonocephaly, bilateral congenital cataracts, microphthalmia, ventricular septal defect, camptodactyly, clinodactyly, bilateral single transverse crease, rocker-bottom feet, and central nervous involvement comprising enlarged ventricles, loss of periventricular white matter, and thin corpus callosum."
    explanation: >-
      Names ventricular septal defect in both index patients, so the frequency band here is
      supported by a stated count rather than only by the lesion appearing in a spectrum
      list.
- category: Cardiovascular
  name: Bicuspid aortic valve
  frequency: OCCASIONAL
  description: A valvar lesion among the congenital heart defects of the defining series.
  phenotype_term:
    preferred_term: Bicuspid aortic valve
    term:
      id: HP:0001647
      label: Bicuspid aortic valve
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Congenital cataracts in 4 patients and congenital heart anomalies including bicuspid aortic valve, partial abnormal pulmonary venous return, and patent ductus arteriosus were seen in 5 patients."
    explanation: >-
      Itemises the cardiac lesions of the defining series. The quote is the later Turkish
      report summarising that series rather than its own patient.
- category: Cardiovascular
  name: Patent ductus arteriosus
  frequency: OCCASIONAL
  description: Persistence of the ductus arteriosus, reported in the defining series.
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Congenital cataracts in 4 patients and congenital heart anomalies including bicuspid aortic valve, partial abnormal pulmonary venous return, and patent ductus arteriosus were seen in 5 patients."
    explanation: Itemises patent ductus arteriosus among the cardiac lesions of the defining series.
- category: Cardiovascular
  name: Partial anomalous pulmonary venous return
  frequency: OCCASIONAL
  description: An anomalous pulmonary venous connection reported in the defining series.
  phenotype_term:
    preferred_term: Partial anomalous pulmonary venous return
    term:
      id: HP:0010773
      label: Partial anomalous pulmonary venous return
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Congenital cataracts in 4 patients and congenital heart anomalies including bicuspid aortic valve, partial abnormal pulmonary venous return, and patent ductus arteriosus were seen in 5 patients."
    explanation: Itemises partial anomalous pulmonary venous return among the cardiac lesions of the defining series.
- category: Cardiovascular
  name: Tetralogy of Fallot
  frequency: OCCASIONAL
  description: >-
    A conotruncal lesion documented prenatally in one patient and, on second-trimester
    ultrasound, in her similarly affected older brother.
  phenotype_term:
    preferred_term: Tetralogy of Fallot
    term:
      id: HP:0001636
      label: Tetralogy of Fallot
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patients presented with ToF, expanding the cardiac spectrum of NUP188."
    explanation: Records tetralogy of Fallot as a new addition to the cardiac spectrum of this syndrome.
- category: Craniofacial
  name: Trigonocephaly
  frequency: VERY_FREQUENT
  description: Triangular forehead from metopic ridging, one of the defining features.
  phenotype_term:
    preferred_term: Trigonocephaly
    term:
      id: HP:0000243
      label: Trigonocephaly
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bi-allelic loss-of-function variants of NUP188 are associated with Sandestig-Stefanova syndrome, which is characterized by pre- and postnatal microcephaly, trigonocephaly, congenital cataracts, periventricular white matter loss, thin corpus callosum, delayed myelination, microphthalmia, camptodactyly, congenital heart disease, and central respiratory failure."
    explanation: Names trigonocephaly among the characterizing features.
- category: Craniofacial
  name: Short palpebral fissure
  frequency: VERY_FREQUENT
  description: Small, often downslanting palpebral fissures, part of the characteristic gestalt.
  phenotype_term:
    preferred_term: Small palpebral fissures
    term:
      id: HP:0012745
      label: Short palpebral fissure
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies."
    explanation: Names small palpebral fissures as a characteristic dysmorphic feature.
- category: Craniofacial
  name: Wide nasal bridge
  frequency: VERY_FREQUENT
  description: A wide, prominent nasal bridge with a wide convex nose.
  phenotype_term:
    preferred_term: Wide prominent nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies."
    explanation: Names the wide nasal bridge as a characteristic dysmorphic feature.
- category: Craniofacial
  name: Micrognathia
  frequency: VERY_FREQUENT
  description: A small mandible, sometimes described as retrognathia.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies."
    explanation: Names micrognathia as a characteristic dysmorphic feature.
- category: Craniofacial
  name: Low-set ears
  frequency: FREQUENT
  description: Low-set, posteriorly rotated ears with hypoplastic tragus and prominent angulated antihelix.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In his physical examination, hypotonia, bilateral congenital cataracts, ambiguous genitalia, hypospadias, undescended testis, bifid scrotum, and facial dysmorphic findings (hypertelorism, high palate, micrognathia, microphthalmia, low ear) were recorded"
    explanation: Documents the low-set ears on physical examination.
- category: Craniofacial
  name: Hypertelorism
  frequency: OCCASIONAL
  description: Increased interocular distance, recorded on physical examination.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In his physical examination, hypotonia, bilateral congenital cataracts, ambiguous genitalia, hypospadias, undescended testis, bifid scrotum, and facial dysmorphic findings (hypertelorism, high palate, micrognathia, microphthalmia, low ear) were recorded"
    explanation: Documents hypertelorism on physical examination.
- category: Craniofacial
  name: Orofacial cleft
  frequency: OCCASIONAL
  description: Cleft lip and palate, at the severe end of the palatal spectrum in this syndrome.
  phenotype_term:
    preferred_term: Cleft lip and palate
    term:
      id: HP:0000202
      label: Orofacial cleft
  evidence:
  - reference: PMID:32021605
    reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as loss of periventricular white matter), thin corpus callosum, and delayed myelinization."
    explanation: States that the index patients had cleft lip and palate or a high-arched palate.
- category: Craniofacial
  name: High palate
  frequency: FREQUENT
  description: A high, narrow arched palate - the milder end of the palatal spectrum.
  phenotype_term:
    preferred_term: High-arched palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "phenotypic features such as microcephaly, trigonocephaly, microphthalmia, high-arched palate, retrognathia, clinodactyly, camptodactyly, rocker-bottom feet"
    explanation: Lists the high-arched palate among the features shared with previously reported patients.
- category: Craniofacial
  name: Bifid uvula
  frequency: OCCASIONAL
  description: >-
    Incomplete midline fusion of the uvula. Reported once, and flagged by the reporting
    authors as a new finding in this syndrome.
  phenotype_term:
    preferred_term: Bifid uvula
    term:
      id: HP:0000193
      label: Bifid uvula
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patient, born to consanguineous parents, presented with tetralogy of Fallot, bilateral congenital cataracts, hydrocephalus, a bifid uvula, a right pelvic kidney, hepatomegaly, facial feature findings, and a history of a similarly affected ex-sibling."
    explanation: Documents the bifid uvula in a molecularly confirmed patient.
- category: Musculoskeletal
  name: Camptodactyly
  frequency: VERY_FREQUENT
  description: Fixed flexion deformity of the digits, one of the defining features.
  phenotype_term:
    preferred_term: Camptodactyly
    term:
      id: HP:0012385
      label: Camptodactyly
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bi-allelic loss-of-function variants of NUP188 are associated with Sandestig-Stefanova syndrome, which is characterized by pre- and postnatal microcephaly, trigonocephaly, congenital cataracts, periventricular white matter loss, thin corpus callosum, delayed myelination, microphthalmia, camptodactyly, congenital heart disease, and central respiratory failure."
    explanation: Names camptodactyly among the characterizing features.
- category: Musculoskeletal
  name: Clinodactyly
  frequency: OCCASIONAL
  description: Coronal-plane curvature of a digit, reported alongside camptodactyly.
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "phenotypic features such as microcephaly, trigonocephaly, microphthalmia, high-arched palate, retrognathia, clinodactyly, camptodactyly, rocker-bottom feet"
    explanation: Lists clinodactyly among the features shared with previously reported patients.
- category: Musculoskeletal
  name: Rocker bottom foot
  frequency: FREQUENT
  description: Convex plantar surface with prominent heel and vertical talus configuration.
  phenotype_term:
    preferred_term: Rocker-bottom feet
    term:
      id: HP:0001838
      label: Rocker bottom foot
  evidence:
  - reference: PMID:32021605
    reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as loss of periventricular white matter), thin corpus callosum, and delayed myelinization."
    explanation: Names rocker-bottom feet among the shared features of the index patients.
- category: Constitutional
  name: Small for gestational age
  frequency: VERY_FREQUENT
  description: Birth weight and length below expectation for gestational age.
  phenotype_term:
    preferred_term: Small for gestational age
    term:
      id: HP:0001518
      label: Small for gestational age
  evidence:
  - reference: PMID:32021605
    reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They were both born small for gestational age and died shortly after birth at the age of 67 and 140 days, respectively, as a result of central respiratory failure."
    explanation: Documents small-for-gestational-age birth in the index patients.
- category: Constitutional
  name: Intrauterine growth retardation
  frequency: FREQUENT
  description: Growth restriction detectable on second-trimester ultrasound.
  phenotype_term:
    preferred_term: Intrauterine growth restriction
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fetal ultrasound at 23 weeks of gestation revealed intrauterine growth restriction, tetralogy of Fallot (ToF), mild ventriculomegaly, a right pelvic kidney, hyperechogenic bowel (grade III), and an echogenic intracardiac focus in the left ventricle."
    explanation: Documents intrauterine growth restriction on prenatal ultrasound.
- category: Genitourinary
  name: Ambiguous genitalia
  frequency: OCCASIONAL
  description: >-
    Reported in the single male patient published to date, together with hypospadias, bifid
    scrotum and undescended testes. No causal route from the NUP188 lesion to the genital
    phenotype has been proposed, so this phenotype is deliberately left unconnected in the
    causal graph.
  phenotype_term:
    preferred_term: Ambiguous genitalia
    term:
      id: HP:0000062
      label: Ambiguous genitalia
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, immunodeficiency, congenital hypothyroidism, biotinidase deficiency, undescended testis, hypospadias, and ambiguous genitalia are defined for the first time in this syndrome."
    explanation: Records ambiguous genitalia as a first-time finding in this syndrome.
- category: Genitourinary
  name: Hypospadias
  frequency: OCCASIONAL
  description: >-
    Reported in the single male patient published to date. Left unconnected in the causal
    graph for the same reason as the other genital findings.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, immunodeficiency, congenital hypothyroidism, biotinidase deficiency, undescended testis, hypospadias, and ambiguous genitalia are defined for the first time in this syndrome."
    explanation: Records hypospadias as a first-time finding in this syndrome.
- category: Genitourinary
  name: Cryptorchidism
  frequency: OCCASIONAL
  description: Undescended testes in the single male patient published to date.
  phenotype_term:
    preferred_term: Undescended testis
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, immunodeficiency, congenital hypothyroidism, biotinidase deficiency, undescended testis, hypospadias, and ambiguous genitalia are defined for the first time in this syndrome."
    explanation: Records undescended testis as a first-time finding in this syndrome.
- category: Genitourinary
  name: Ectopic kidney
  frequency: OCCASIONAL
  description: >-
    A right pelvic kidney seen prenatally and confirmed postmortem in one patient. The
    reporting authors stated that further reports are needed before this is accepted as part
    of the disease spectrum, so it is left unconnected in the causal graph.
  phenotype_term:
    preferred_term: Pelvic ectopic kidney
    term:
      id: HP:0000086
      label: Ectopic kidney
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional novel clinical findings include hepatomegaly and a pelvic ectopic kidney; however, further reports are required to confirm these associations within the disease spectrum."
    explanation: Records the pelvic ectopic kidney together with the authors' own caveat about its status.
- category: Gastrointestinal
  name: Hepatomegaly
  frequency: OCCASIONAL
  description: >-
    Enlarged liver on abdominal ultrasound in one patient, reported with the same caveat as
    the ectopic kidney and left unconnected in the causal graph for the same reason.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional novel clinical findings include hepatomegaly and a pelvic ectopic kidney; however, further reports are required to confirm these associations within the disease spectrum."
    explanation: Records the hepatomegaly together with the authors' own caveat about its status.
- category: Immunologic
  name: Combined immunodeficiency
  frequency: OCCASIONAL
  description: >-
    Low CD8 proportion, lymphopenia, hypogammaglobulinemia and failure to seroconvert after
    hepatitis B vaccination, in one patient who required intravenous immunoglobulin. No
    mechanistic route from the NUP188 lesion has been proposed, so this is left unconnected
    in the causal graph.
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the cluster of differentiation (CD) panel, CD8 was low (9.9%), and the patient had lymphopenia. The patient was followed up with the diagnosis of combined immunodeficiency."
    explanation: Documents the immunological findings and the diagnosis made from them.
- category: Endocrine
  name: Congenital hypothyroidism
  frequency: OCCASIONAL
  description: >-
    Diagnosed in one patient and treated with levothyroxine. Reported as a first-time
    finding in this syndrome, so it is left unconnected in the causal graph.
  phenotype_term:
    preferred_term: Congenital hypothyroidism
    term:
      id: HP:0000851
      label: Congenital hypothyroidism
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With the diagnosis of congenital hypothyroidism, levothyroxine treatment was started."
    explanation: Documents the diagnosis and its treatment in a molecularly confirmed patient.
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic NUP188 variants. Consanguinity is common among reported families, sibship
    recurrence has been documented, and parents are heterozygous carriers without the
    phenotype. Heterozygous carriers of the truncating alleles are unaffected, including for
    the cardiac phenotype: the parents and carrier sibling of one proband with tetralogy of
    Fallot had no detectable cardiac abnormality.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sandestig-Stefanova syndrome is an autosomal recessive developmental syndrome characterized by microcephaly, trigonocephaly, congenital cataracts, microphthalmia, facial findings, camptodactyly, periventricular white matter loss, thin corpus callosum, delayed myelination, and poor prognosis."
    explanation: States the mode of inheritance.
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial segregation analysis using Sanger sequencing revealed that both the healthy brother and the parents carried this variant in a heterozygous state"
    explanation: Documents heterozygous carriage in unaffected parents and a healthy sibling, which is what recessive segregation looks like.
genetic:
- name: NUP188
  gene_term:
    preferred_term: NUP188
    term:
      id: hgnc:17859
      label: NUP188
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    NUP188 is the only gene implicated in this syndrome; no second locus has been reported.
    Every disease allele published to date is truncating - nonsense, frameshift, or a
    canonical splice-acceptor change - and no missense allele has been shown to cause the
    recessive syndrome. Heterozygous NUP188 variants have separately been reported in
    cardiovascular cohorts and in an unrelated developmental presentation, but those
    associations were not established; that is a different genetic claim from the biallelic
    loss-of-function syndrome curated here.
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Bi-allelic loss-of-function variants of NUP188 are associated with Sandestig-Stefanova syndrome, which is characterized by pre- and postnatal microcephaly, trigonocephaly, congenital cataracts, periventricular white matter loss, thin corpus callosum, delayed myelination, microphthalmia, camptodactyly, congenital heart disease, and central respiratory failure."
      explanation: States that the disease alleles are biallelic and loss-of-function.
  variants:
  - name: Homozygous c.287dupA p.(Tyr96Ter) and homozygous c.337C>T p.(Gln113Ter)
    description: >-
      The two alleles of the index patients: different homozygous nonsense variants in two
      unrelated girls whose phenotypes were nonetheless strikingly alike, which is what made
      the syndrome recognizable.
    evidence:
    - reference: PMID:32021605
      reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "For the first time, we report 2 unrelated patients with 2 different homozygous nonsense gene variants of NUP188, p.Tyr96* and p.Gln113*, respectively."
      explanation: Names the two index alleles.
  - name: Compound heterozygous c.904_907delATTT p.(Ile302Valfs*7) and c.3144C>G p.(Tyr1048Ter)
    description: >-
      The Ashkenazi Jewish founder pair, shared by three individuals from two families. Both
      alleles are enriched in gnomAD's Ashkenazi Jewish population, and a targeted screen of
      3,225 healthy Ashkenazi Jewish individuals confirmed the enrichment.
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Three individuals from two different families were of Ashkenazi Jewish descent, and all three individuals shared the same two variants in compound heterozygous state, c.904_907delATTT; p.(Ile302Valfs*7) and c.3144C>G; p.(Tyr1048Ter), in NUP188."
      explanation: Names the two founder alleles and the families carrying them, as itemised by the later report's review of the literature.
    - reference: PMID:32275884
      reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals."
      explanation: Establishes the population enrichment of these two alleles and the screen that confirmed it.
  - name: Homozygous c.1087C>T p.(Gln363Ter)
    description: >-
      The allele of the first reported male patient, from a consanguineous Turkish family;
      novel at the time of report, absent from gnomAD, ClinVar and dbSNP, and classified
      pathogenic on PVS1, PM2, PP3 and PP4.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In our patient, a homozygous c.1087C>T (p.Gln363Ter) variant was detected in exon 11 of the NUP188 (NM_015354.3) gene."
      explanation: Names the allele and its exon.
  - name: Homozygous c.124C>T p.(Arg42Ter)
    description: >-
      An early nonsense allele in exon 3 of 44, expected to trigger nonsense-mediated decay,
      in a consanguineous Turkish family with a second similarly affected child.
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole exome sequence analysis in the index case revealed a novel homozygous variant NM_015354.2: c.124C>T/p.(Arg42Ter) in the NUP188 gene."
      explanation: Names the allele and how it was found.
  - name: Homozygous c.1962-2A>C splice acceptor variant
    description: >-
      A canonical splice-acceptor allele in a Saudi patient. RT-PCR gave no detectable
      product in the proband while both parents showed two bands, which is direct transcript
      evidence that the allele abolishes the normal message.
    evidence:
    - reference: PMID:40859750
      reference_title: A Novel Homozygous Splice Variant in the NUP188 Gene Causing Sandestig-Stefanova Syndrome in a Saudi Patient.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "RT-PCR analysis showed no detectable amplification in the proband, while parental samples displayed two bands, indicating carrier status."
      explanation: Gives the transcript-level consequence of this splice allele and the parental carrier status.
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype."
    explanation: The gene-disease claim in the authors' own summary.
  - reference: PMID:32021605
    reference_title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings strongly suggest a correlation between the homozygous nonsense gene variants of NUP188 and a severe phenotype of a new developmental syndrome with poor prognosis resulting from nucleoporin 188 homolog protein insufficiency."
    explanation: The independent gene-disease claim from the first report.
animal_models:
- name: NUP188 CRISPR knockout Drosophila
  species: Drosophila melanogaster
  genotype: CRISPR-mediated NUP188 knockout
  publication: PMID:32275884
  description: >-
    A fly knockout generated alongside the human genetics, used to ask whether removing
    NUP188 produces a neurological phenotype at all. It does - motor deficits and seizure
    susceptibility - and it also revealed aberrant dendrite tiling, which is the origin of
    the dendritic-development hypothesis for this syndrome.
  modeled_mechanisms:
  - target: Impaired Neuronal Dendrite Development
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Dendrite tiling is disrupted by NUP188 removal, which is the observation the node
      records.
    limitations: >-
      Drosophila dendritic arborisation neurons are not a model of human cortical or
      brainstem circuitry, and no dendritic abnormality has been demonstrated in tissue from
      an affected individual.
    evidence:
    - reference: PMID:32275884
      reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development."
      explanation: The dendritic result that grounds this link.
  - target: Progressive Encephalopathy with Central Respiratory Control Failure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Motor deficits and seizure susceptibility reproduce part of the human neurological
      picture, and the authors describe the recapitulation as partial.
    limitations: >-
      The fly has no counterpart of the brainstem respiratory control whose failure kills
      these infants, and no counterpart of the progressive microcephaly, white-matter loss,
      or corpus callosum hypoplasia. The model speaks to neuronal excitability and motor
      output, not to the fatal element of the syndrome.
    evidence:
    - reference: PMID:32275884
      reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals."
      explanation: States both the recapitulation and its partiality, in the authors' own words.
- name: Xenopus Nup188 morpholino knockdown
  species: Xenopus
  genotype: Nup188 morpholino knockdown
  publication: PMID:27593162
  description: >-
    Morpholino depletion of Nup188 in Xenopus, used to test whether a nucleoporin can cause
    congenital heart disease through cilia rather than through nuclear transport. Cilia are
    lost at the left-right organizer and in mammalian cell lines while nuclear pore function
    stays largely intact - which is what makes the ciliary model a distinct proposal rather
    than a downstream consequence of a transport deficit.
  modeled_mechanisms:
  - target: Loss of Cilia and Ciliary-Base NUP188 Function
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The model is the source of this node: it shows that depleting Nup188 costs cells their
      cilia.
    limitations: >-
      Morpholino knockdown is a partial, transient depletion rather than the biallelic
      germline truncation that causes the human syndrome, and the human genetic observation
      that motivated the work was a NUP188 duplication in a heterotaxy patient, not a
      loss-of-function allele. No patient with this syndrome has had ciliation assayed.
    evidence:
    - reference: PMID:27593162
      reference_title: Congenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we show that knockdown of Nup188 or its binding partner Nup93 leads to a loss of cilia during embryonic development while leaving NPC function largely intact."
      explanation: The primary result grounding this link.
experimental_models:
- name: Patient-derived skin fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary fibroblasts from affected individuals, used both to establish the protein-level
    consequence of the truncating alleles and to measure nuclear protein import. These are
    the only patient-derived cells in which the mechanism has been assayed.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: patient-derived skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  publication: PMID:32275884
  modeled_mechanisms:
  - target: Reduced Nucleocytoplasmic Protein Import
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Nuclear protein import was measured in patient fibroblasts and found to be reduced.
    limitations: >-
      A dermal fibroblast is not a lens, cardiomyocyte, or neuron. The measurement
      establishes that the transport deficit exists in a patient cell, not that it is the
      deficit that produces the malformations in the tissues that are actually affected.
    evidence:
    - reference: PMID:32275884
      reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism."
      explanation: The measurement this link records.
diagnosis:
- name: Exome sequencing
  description: >-
    Every published diagnosis has been made by exome sequencing, typically after normal
    karyotype and chromosomal microarray. NUP188 is not on targeted panels for any of the
    presenting features, so the diagnosis is a sequencing rather than a clinical one.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metabolic screening tests and chromosome and microarray analyses of the patient were found to be normal. Thereupon whole-exome sequencing (WES) analysis was performed."
    explanation: Documents the diagnostic sequence - normal karyotype and microarray first, then exome sequencing.
- name: Chromosomal microarray
  description: >-
    Performed before sequencing in reported cases and normal in each, which is part of why
    the diagnosis requires sequencing.
  diagnosis_term:
    preferred_term: chromosomal microarray analysis
    term:
      id: NCIT:C18477
      label: Microarray Analysis
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metabolic screening tests and chromosome and microarray analyses of the patient were found to be normal. Thereupon whole-exome sequencing (WES) analysis was performed."
    explanation: Documents that the microarray was normal before sequencing was undertaken.
- name: Sanger sequencing for variant confirmation and family segregation
  description: >-
    Candidate variants are confirmed by Sanger sequencing and segregation is checked in the
    parents, who are heterozygous carriers.
  diagnosis_term:
    preferred_term: Sanger sequencing
    term:
      id: NCIT:C19641
      label: Dideoxy Chain Termination DNA Sequencing
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial segregation analysis using Sanger sequencing revealed that both the healthy brother and the parents carried this variant in a heterozygous state"
    explanation: Documents the confirmatory and segregation role of Sanger sequencing.
- name: Brain magnetic resonance imaging
  description: >-
    MRI establishes the imaging signature - ventriculomegaly, thin corpus callosum, loss of
    periventricular white matter, delayed myelination, and later cerebral atrophy.
  diagnosis_term:
    preferred_term: brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postnatal MRI showed progression of ventriculomegaly, along with a thin corpus callosum."
    explanation: Documents the role of MRI in establishing the intracranial findings.
- name: Ophthalmologic examination
  description: Eye examination detects the bilateral congenital cataract and microphthalmia.
  diagnosis_term:
    preferred_term: eye examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral cataracts were detected on eye examination, and hepatomegaly was observed on abdominal ultrasound."
    explanation: Documents cataract detection by eye examination.
- name: Fetal ultrasound
  description: >-
    Second-trimester ultrasound can show growth restriction, ventriculomegaly and the
    cardiac and renal malformations before birth, which is the earliest point at which the
    syndrome can be suspected.
  diagnosis_term:
    preferred_term: fetal ultrasound imaging
    term:
      id: NCIT:C222238
      label: Fetal Ultrasound Imaging
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fetal ultrasound at 23 weeks of gestation revealed intrauterine growth restriction, tetralogy of Fallot (ToF), mild ventriculomegaly, a right pelvic kidney, hyperechogenic bowel (grade III), and an echogenic intracardiac focus in the left ventricle."
    explanation: Documents what second-trimester ultrasound detected in a molecularly confirmed case.
- name: When to consider the diagnosis
  description: >-
    The clinical trigger stated in the literature: an infant with neurological deficits,
    congenital cataract, congenital heart defect and unexplained respiratory failure should
    have NUP188 evaluated.
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Evaluation of NUP188 should be considered in infants with neurologic deficits, congenital cataracts, congenital heart defects, and unexplained respiratory failure."
    explanation: States the diagnostic trigger for considering this gene.
treatments:
- name: Genetic counseling and recurrence-risk assessment
  description: >-
    There is no disease-modifying therapy. Counselling about the one-in-four recurrence risk
    is the intervention with the largest effect on families, several of whom have had more
    than one affected child - one reported proband had a similarly affected older brother
    who died at 42 days without a molecular diagnosis.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial segregation analysis using Sanger sequencing revealed that both the healthy brother and the parents carried this variant in a heterozygous state"
    explanation: >-
      Documents the carrier testing on which recurrence-risk counselling in these families
      is based. The recurrence risk itself follows from the recessive inheritance recorded
      in the inheritance block.
- name: Cataract surgery
  description: Extraction of the congenital cataract, performed in at least one reported patient.
  treatment_term:
    preferred_term: Cataract Surgery
    term:
      id: NCIT:C157809
      label: Cataract Surgery
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Developmental cataract
    treatment_effect: MODULATES
    description: Symptomatic surgery addressing the lens opacity itself, not its cause.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "He underwent surgery on his left eye due to a congenital cataract."
      explanation: Documents cataract surgery in a molecularly confirmed patient.
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He underwent surgery on his left eye due to a congenital cataract."
    explanation: Documents that cataract surgery is used in this syndrome.
- name: Anticonvulsant therapy
  description: >-
    Levetiracetam was started for infantile spasm-like seizures in one reported patient. No
    published series reports seizure outcome, so no efficacy claim is made here.
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Seizure
    treatment_effect: INHIBITS
    description: Symptomatic anticonvulsant treatment of the seizures.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "When he had a seizure in the form of a spasm in the upper extremities, levetiracetam was started at the age of 2.5 months."
      explanation: Documents the drug and the indication in a molecularly confirmed patient.
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When he had a seizure in the form of a spasm in the upper extremities, levetiracetam was started at the age of 2.5 months."
    explanation: Documents anticonvulsant use in this syndrome.
- name: Levothyroxine replacement
  description: >-
    Started in the one patient found to have congenital hypothyroidism. Whether the
    hypothyroidism belongs to the syndrome is unresolved, so this is recorded as management
    of a reported comorbidity rather than of a syndrome feature.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levothyroxine
      term:
        id: CHEBI:18332
        label: L-thyroxine
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Congenital hypothyroidism
    treatment_effect: MODULATES
    description: Hormone replacement for the hypothyroidism found in that patient.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "With the diagnosis of congenital hypothyroidism, levothyroxine treatment was started."
      explanation: Documents the treatment and its indication.
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With the diagnosis of congenital hypothyroidism, levothyroxine treatment was started."
    explanation: Documents levothyroxine use in a patient with this syndrome.
- name: Ventriculoperitoneal shunt placement
  description: >-
    A shunt was placed on day 38 in the one patient whose ventriculomegaly progressed to
    tetraventricular hydrocephalus. It did not alter the outcome; she died at 72 days.
  treatment_term:
    preferred_term: Ventriculoperitoneal Shunt Placement
    term:
      id: NCIT:C168483
      label: Ventriculoperitoneal Shunt Placement
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Hydrocephalus
    treatment_effect: MODULATES
    description: Cerebrospinal fluid diversion for the hydrocephalus.
    evidence:
    - reference: PMID:39911172
      reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "On the 38th day of life, a shunt was placed due to tetraventricular hydrocephalus."
      explanation: Documents the shunt and its indication.
  evidence:
  - reference: PMID:39911172
    reference_title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On the 38th day of life, a shunt was placed due to tetraventricular hydrocephalus."
    explanation: Documents shunt placement in a patient with this syndrome.
- name: Respiratory support
  description: >-
    Escalating support for the central hypoventilation - high-flow nasal cannula, then
    intubation and mechanical ventilation. It is life-prolonging, not life-saving: every
    published patient has died of respiratory failure regardless.
  treatment_term:
    preferred_term: Mechanical Ventilation
    term:
      id: NCIT:C70909
      label: Mechanical Ventilation
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Central hypoventilation
    treatment_effect: MODULATES
    description: Mechanical support substituting for absent central respiratory drive.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "He was followed up in the PICU for a total of 2 months, 3 weeks with a high-flow nasal cannula and 5 weeks as intubated."
      explanation: Documents the escalating respiratory support given.
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was followed up in the PICU for a total of 2 months, 3 weeks with a high-flow nasal cannula and 5 weeks as intubated."
    explanation: Documents the respiratory support used in this syndrome.
- name: Enteral tube feeding
  description: >-
    Patients lose swallowing function and become dependent on nasogastric or orogastric tube
    feeding.
  treatment_term:
    preferred_term: Nasogastric Intubation
    term:
      id: NCIT:C91836
      label: Nasogastric Intubation
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Feeding difficulties
    treatment_effect: MODULATES
    description: Tube feeding substituting for lost swallowing function.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As in our patient, patients who are fed orally after birth lose their swallowing function over time and become dependent on nasogastric/orogastric tubes."
      explanation: Documents the tube dependence and what it substitutes for.
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As in our patient, patients who are fed orally after birth lose their swallowing function over time and become dependent on nasogastric/orogastric tubes."
    explanation: Documents enteral tube feeding as standard management in this syndrome.
- name: Intravenous immunoglobulin
  description: >-
    Given twice for hypogammaglobulinemia in the one patient with documented combined
    immunodeficiency. A single case, not established management.
  treatment_term:
    preferred_term: Intravenous Immunoglobulin Therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
  therapeutic_modality: PROTEIN_REPLACEMENT
  target_mechanisms:
  - target: Combined immunodeficiency
    treatment_effect: MODULATES
    description: Immunoglobulin replacement for the hypogammaglobulinemia in that patient.
    evidence:
    - reference: PMID:36158057
      reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Intravenous immunoglobulin was given twice due to hypogammaglobulinemia."
      explanation: Documents the treatment and its indication.
  evidence:
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intravenous immunoglobulin was given twice due to hypogammaglobulinemia."
    explanation: Documents immunoglobulin use in a patient with this syndrome.
discussions:
- discussion_id: transport_versus_ciliary_mechanism
  prompt: >-
    Is Sandestig-Stefanova syndrome a nucleocytoplasmic transport disorder, a ciliopathy, or
    both?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Nucleocytoplasmic Protein Import
  - pathophysiology#Loss of Cilia and Ciliary-Base NUP188 Function
  rationale: >-
    The only measurement in patient material is reduced nuclear protein import in
    fibroblasts, and its authors called it a possible mechanism rather than an established
    one. Meanwhile the clinical picture contains features a transport deficit does not
    obviously explain - structurally heterogeneous congenital heart disease, hydrocephalus,
    and heterotaxy-like findings in some patients - and there is direct evidence that
    depleting Nup188 abolishes cilia while the nuclear pore keeps working. That experiment
    is the crux: it means a ciliary phenotype is not a downstream consequence of a transport
    phenotype, so the two are genuinely competing accounts and not two descriptions of one
    lesion. No patient with this syndrome has had ciliation assayed, and no rescue
    experiment has been reported, so the question is open.
  evidence:
  - reference: PMID:27593162
    reference_title: Congenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we show that knockdown of Nup188 or its binding partner Nup93 leads to a loss of cilia during embryonic development while leaving NPC function largely intact."
    explanation: Establishes that the two candidate lesions are dissociable, which is what makes this a real question.
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism."
    explanation: The hedged patient-cell measurement that is the sole direct support for the transport account.
- discussion_id: drosophila_model_translational_validity
  prompt: >-
    Does the Drosophila NUP188 knockout tell us anything about the brainstem respiratory
    failure that kills these infants?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Progressive Encephalopathy with Central Respiratory Control Failure
  - animal_models#Drosophila melanogaster
  rationale: >-
    The fly knockout is the only in vivo model of NUP188 loss with a neurological readout,
    and its authors describe the recapitulation as partial. What it reproduces is motor
    deficit and seizure susceptibility. What kills affected infants is failure of central
    respiratory drive, and the fly has no brainstem respiratory control to fail. It also has
    no counterpart of the progressive microcephaly, periventricular white-matter loss, or
    corpus callosum hypoplasia that dominate the human imaging. So the model supports the
    claim that NUP188 is required for normal neuronal function, and supports no claim about
    the specific lesion that is lethal. A vertebrate model with a brainstem, or human neural
    tissue, would be needed to close this.
  evidence:
  - reference: PMID:32275884
    reference_title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals."
    explanation: The authors' own statement that the recapitulation is partial, which is the mismatch this discussion records.
  - reference: PMID:36158057
    reference_title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients die in the early period due to respiratory failure secondary to CNS anomalies. No signs of congenital pulmonary or tracheal disease were detected in the identified patients."
    explanation: Establishes that the lethal lesion is central respiratory control, the element the fly model cannot address.
references:
- reference: PMID:32021605
  title: "NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?"
- reference: PMID:32275884
  title: "Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities."
- reference: PMID:36158057
  title: A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.
- reference: PMID:39911172
  title: A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.
- reference: PMID:40859750
  title: A Novel Homozygous Splice Variant in the NUP188 Gene Causing Sandestig-Stefanova Syndrome in a Saudi Patient.
- reference: PMID:27593162
  title: Congenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia.
notes: >-
  Entry-type decision. Curated as a standalone DISEASE. MONDO:0032926 has one causal gene
  (RO:0004003 HGNC:17859, NUP188), no descendants, and a single is_a parent (hereditary
  disease), so there is nothing here to lump or split.

  One entity, two independent descriptions. Sandestig et al. (PMID:32021605, two unrelated
  girls) and Muir et al. (PMID:32275884, six individuals from four families) published
  within months of each other; the phenotypes and the allele class are the same, and every
  subsequent report treats them as one condition and counts patients cumulatively across
  both series. That is why the ten-patient census in PMID:39911172 and PMID:40859750 spans
  both. The "NUP188-related disorder" of the Muir title - the neurologic, ocular and
  cardiac syndrome - is therefore SANDSTEF, not a separate entity. PMID:36158057 states
  this directly: Muir et al. "also defined the same syndrome".

  Not the nucleoporin fetal akinesia disorder. Biallelic nucleoporin variants do cause a
  lethal fetal akinesia deformation sequence, but that is NUP88 (PMID:30543681), a
  different gene. A PubMed search for NUP188 combined with akinesia or arthrogryposis
  returns nothing. The camptodactyly and rocker-bottom feet of this syndrome are distal
  contractures, not the generalised arthrogryposis of a fetal akinesia sequence, and no
  report describes reduced fetal movement.

  GeneReviews. No GeneReviews chapter exists for this condition or for NUP188. This was
  checked offline against the committed Bookshelf index (cache/bookshelf/genereviews.csv
  and statpearls.csv), which carries every PubMed-indexed chapter of both collections; a
  case-insensitive search for "NUP188" and "sandestig" matches nothing in either file. That
  is an expected absence for a disorder with roughly ten published patients, not a curation
  gap.

  Orphanet. MONDO records no Orphanet cross-reference for MONDO:0032926 (its xrefs are
  DOID:0081272, MEDGEN:1718072, OMIM:618804 and UMLS:C5394118), so no ORPHA record was
  cited.

  Module conformance. No conforms_to was declared, and three candidates were considered and
  rejected on specific grounds rather than for lack of a search.
  cataract_lens_opacification requires the conforming node to carry the crystallin
  solubility, aggregation and light-scatter chain; nothing has been measured in lens tissue
  from a patient with this syndrome, so declaring it would assert a mechanism no source
  supports. cns_myelin_failure is built on an oligodendrocyte-lineage or myelin-membrane
  insult with differentiation arrest and death; the delayed myelination here is documented
  radiologically only, and whether the primary failure is oligodendroglial or axonal is
  unknown. ciliopathy_dysfunction is the closest fit and is the one to revisit - but its
  entry node is basal body and transition zone dysfunction, and the ciliary evidence for
  NUP188 is Xenopus morpholino knockdown plus a duplication allele in an unrelated
  heterotaxy patient, not this disease's biallelic truncating alleles. That case is
  recorded as the EMERGING ciliary_nup188_model hypothesis group instead, which is what the
  hypothesis machinery is for. If ciliation is ever assayed in patient cells, the
  conformance should be reconsidered.

  Unconnected phenotypes. Seven phenotypes are deliberately left with no incoming causal
  edge: ambiguous genitalia, hypospadias, cryptorchidism, combined immunodeficiency,
  congenital hypothyroidism, hepatomegaly and ectopic kidney. Each was reported in exactly
  one patient and flagged by its own authors as a first-time or unconfirmed association -
  the hepatomegaly and ectopic kidney explicitly so ("further reports are required to
  confirm these associations within the disease spectrum"). No route from the NUP188 lesion
  to any of them has been proposed in the literature, and inventing a node to hold them
  would assert a mechanism nobody has claimed. Bifid uvula is the one exception and is
  wired, to the craniofacial node, because midline palatal fusion failure is already within
  that node's scope via the cleft palate this syndrome causes.

  Phenotype frequency bands. With about ten published patients the HPO frequency bands carry
  very little information: a finding in one patient is 10 percent, which is OCCASIONAL
  (5-29%) rather than VERY_RARE (<5%), so every single-case finding here is banded
  OCCASIONAL and its own description says how many patients it was seen in. Read the
  description, not the band.

  Biotinidase deficiency was reported in the same single patient as the hypothyroidism and
  immunodeficiency. It is not curated as a phenotype here: it was a newborn-screening
  result in a consanguineous Turkish family, biotinidase deficiency is itself a recessive
  condition in its own right, and the report does not establish it as anything other than a
  coincidental second diagnosis.

  Death in infancy is not curated as a phenotype. HPO places `Death in infancy`
  (HP:0001522) under clinical course rather than under phenotypic abnormality, so it falls
  outside the schema's PhenotypeTerm enum and binding it there fails validation. The
  mortality is carried by the "Death from central respiratory failure" progression phase and
  by the Respiratory failure phenotype instead.

  Two editorials on NUP188 by M. Poot (PMID:32256295, PMID:36158058) are indexed in PubMed
  but their records carry no retrievable body, so nothing from them could be quoted and
  they are not cited.

📚

References & Deep Research

References

6

PMID:32021605

NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?

No top-level findings curated for this source.

PMID:32275884

Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities.

No top-level findings curated for this source.

PMID:36158057

A Boy with Sandestig-Stefanova Syndrome and Genital Abnormalities.

No top-level findings curated for this source.

PMID:39911172

A Novel Truncating Variant in Sandestig-Stefanova Syndrome with Hydrocephalus.

No top-level findings curated for this source.

PMID:40859750

A Novel Homozygous Splice Variant in the NUP188 Gene Causing Sandestig-Stefanova Syndrome in a Saudi Patient.

No top-level findings curated for this source.

PMID:27593162

Congenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia.

No top-level findings curated for this source.

Sandestig-Stefanova Syndrome

Ask OpenScientist

OpenScientist Report

Mappings

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Clinical Burden

Experimental Models

Animal Models

Source YAML

References & Deep Research

References