Goldberg-Shprintzen Syndrome

Mendelian MONDO:0012280 Pathograph 23 Show in embeddings browser

Goldberg-Shprintzen syndrome (GOSHS) is a rare autosomal recessive neurodevelopmental malformation syndrome caused by biallelic loss-of-function variants in KIFBP (formerly KIAA1279 or KBP), which encodes a kinesin-binding protein that inhibits a subset of kinesin motors and associates with the actin and microtubule cytoskeleton. Core features are microcephaly, intellectual disability and developmental delay, a recognizable facial gestalt, cortical malformation such as polymicrogyria, and axonal neuropathy. Hirschsprung disease is frequent but variable, even between relatives sharing the same variant. Model organisms show defective axon outgrowth and maintenance, delayed enteric neural crest colonization of the gut, and impaired cortical neuron migration; how these defects produce the human malformations is not established. It is distinct from the SKI-related Shprintzen-Goldberg craniosynostosis syndrome.

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1
Inheritance
8
Pathophys.
24
Phenotypes
23
Pathograph
1
Genes
2
Variants
2
Medical Actions
3
Models
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic (homozygous or compound heterozygous) KIFBP variants cause the disorder; several families are consanguineous. Expressivity is variable, most visibly for Hirschsprung disease, which can differ between siblings carrying the same variant.
Autosomal recessive inheritance Expressivity: VARIABLE
Show evidence (3 references)
PMID:15883926 SUPPORT Human Clinical
"We identified, by homozygosity mapping, a novel locus on 10q21.3-q22.1 for Goldberg-Shprintzen syndrome (GOSHS) in a consanguineous Moroccan family."
Homozygosity mapping in a consanguineous family is consistent with recessive inheritance.
PMID:23427148 SUPPORT Human Clinical
"Goldberg-Shprintzen syndrome (GOSHS, MIM #609460) is an autosomal recessive disorder of intellectual disability, specific facial gestalt and Hirschsprung's disease (HSCR)."
States the autosomal recessive mode of inheritance.
PMID:32939943 SUPPORT BACKGROUND Human Clinical
"Homozygosity mapping followed by Sanger sequencing, identified homozygous or compound heterozygous loss of function (LOF) variants in the kinesin binding protein gene (KIFBP, previously known as KIAA1279), as causative for GOSHS"
Both homozygous and compound heterozygous genotypes are reported, i.e. biallelic inheritance.
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Pathophysiology

8
Biallelic KIFBP Loss of Function
Mechanism confidence: Established
Biallelic germline KIFBP variants abolish (truncating alleles) or reduce (missense alleles) KIFBP protein. A threshold level of KIFBP has been proposed to modulate phenotypic variability, but this is not validated.
KIFBP hgnc:23419 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KIFBP (hgnc:23419). hgnc:23419 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context KIFBP hgnc:23419 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns KIFBP (hgnc:23419). hgnc:23419 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Downstream
Loss of KIFBP Kinesin Inhibition and Cytoskeletal Interaction Absence of the protein removes its normal activities; the specific kinesin and cytoskeletal consequences in each developing tissue are not characterized.
Delayed Enteric Neural Crest Colonization of the Gut Shown in Kif1bp knockout mice; the intermediate cellular defect is not identified.
Impaired Cortical Neuron Migration Shown by in utero shRNA knockdown in embryonic mouse cortex, not in a biallelic germline model.
Cortical Neuron Apoptosis Shown by in utero knockdown; the initiating cause of apoptosis is unresolved.
Show evidence (2 references)
PMID:32939943 SUPPORT Human Clinical
"In conclusion, we show that reduced, as well as lack of KIFBP expression can lead to GOSHS, and our results suggest that a threshold expression of KIFBP may modulate phenotypic variability of the disease."
Absent or reduced KIFBP expression is the initiating molecular lesion.
PMID:23427148 SUPPORT Human Clinical
"The homozygous KIAA1279 mutations in these patients (p.Arg90X, p.Ser200X or p.Arg202IlefsX2) led to nonsense-mediated mRNA decay and loss of KBP function."
Patient-derived evidence that truncating alleles remove KIFBP.
Loss of KIFBP Kinesin Inhibition and Cytoskeletal Interaction
Mechanism confidence: Provisional
KIFBP is a tetratricopeptide-repeat alpha-solenoid that binds the motor domains of a subset of kinesins, remodels them and blocks their microtubule attachment; it also interacts with actin filaments and microtubules. Its loss is expected to deregulate these motors and cytoskeletal interactions. This is inferred from normal KIFBP biochemistry; it should not be read as a uniform decrease in kinesin transport, and which deregulated motors matter for each disease feature is unknown. A primary mitochondrial respiratory defect is not supported: patient fibroblasts lacking KIFBP had normal respiratory chain activity.
KIFBP hgnc:23419 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KIFBP (hgnc:23419). hgnc:23419 is a gene from the HUGO Gene Nomenclature Committee.
kinesin binding GO:0019894 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased kinesin binding (GO:0019894). GO:0019894 is a molecular function from the Gene Ontology.
Downstream
Impaired Axon Outgrowth with Axonal Microtubule Disruption Which deregulated kinesin or cytoskeletal interaction disrupts axonal microtubules is not established.
Cytokinesis Failure in Dividing Cells KIFBP depletion alters midbody localization of the kinesins KIF23 and KIF14 and reduces microtubule stability in dividing cultured cells.
Show evidence (4 references)
PMID:33252036 SUPPORT In Vitro
"Kinesin-binding protein (KBP) interacts with a subset of kinesins via their motor domains, inhibits their microtubule (MT) attachment, and blocks their cellular function."
Defines the normal kinesin-inhibitory function lost when KIFBP is absent.
PMID:34797717 SUPPORT In Vitro
"Kinesin-binding protein (KIFBP), which is mutated in Goldberg-Shprintzen syndrome, binds to and inhibits the catalytic motor heads of 8 of 45 kinesin superfamily members, but the mechanism remains poorly defined."
Independent structural work confirming selective kinesin inhibition by the GOSHS protein.
PMID:23427148 SUPPORT In Vitro
"KBP did not co-localize with mitochondria in control human fibroblasts, but interacted with the actin and tubulin cytoskeleton."
Places KIFBP at the cytoskeleton rather than mitochondria.
+ 1 more reference
Impaired Axon Outgrowth with Axonal Microtubule Disruption
Mechanism confidence: Provisional
In kbp mutant zebrafish, early axon outgrowth is slower in peripheral and central neurons and axonal microtubules are disrupted. Kif1bp knockout mice show defective axon extension from some neuronal populations, and cortical KBP knockdown in mice prevents callosal axons from crossing the midline. Human tissue evidence is lacking.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
axon extension GO:0048675 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased axon extension (GO:0048675). GO:0048675 is a biological process from the Gene Ontology. microtubule cytoskeleton organization GO:0000226 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal microtubule cytoskeleton organization (GO:0000226). GO:0000226 is a biological process from the Gene Ontology.
Animal models
Kif1bp knockout mouse Mouse partially recapitulates
kbp mutant zebrafish Zebrafish recapitulates
Downstream
Axon Degeneration In zebrafish, axons that grew abnormally later degenerate; whether degeneration follows from the outgrowth defect or from a separate maintenance role is not resolved.
Hypoplasia of the corpus callosum Failed midline crossing of callosal axons after cortical knockdown in mice is a candidate basis for a thin corpus callosum in patients; not shown in human tissue.
Show evidence (3 references)
PMID:18192286 SUPPORT Model Organism
"In vivo time-lapse analysis of neuronal development shows that the speed of early axonal outgrowth is reduced in both the peripheral and central nervous systems in kbp mutants."
Direct in vivo measurement of reduced axon outgrowth.
PMID:18192286 SUPPORT Model Organism
"Ultrastructural studies reveal that kbp mutants have disruption to axonal microtubules during outgrowth."
Axonal microtubule disruption during outgrowth.
PMID:29192291 SUPPORT Model Organism
"The data show an essential in vivo role for KIF1BP in axon extension from some neurons"
Mouse knockout confirms the axon extension defect in vivo.
Axon Degeneration
Mechanism confidence: Provisional
Later in development, many affected axons in kbp mutant zebrafish degenerate, with mislocalized axonal mitochondria and fewer axons in peripheral, central and enteric nerves.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Animal models
kbp mutant zebrafish Zebrafish recapitulates
Downstream
Peripheral axonal neuropathy Proposed by the zebrafish study as the cellular basis of the nervous system defects; peripheral nerve pathology in patients has not been studied at this level.
Show evidence (1 reference)
PMID:18192286 SUPPORT Model Organism
"Ultrastructural analyses at these stages demonstrate mislocalization of axonal mitochondria and a reduction in axonal number in the peripheral, central and enteric nervous systems."
Axon loss across nervous systems in the zebrafish mutant.
Delayed Enteric Neural Crest Colonization of the Gut
Mechanism confidence: Hypothetical
In Kif1bp knockout mouse embryos the wavefront of migrating enteric neural crest-derived cells lags behind controls, although newborn mice have neurons along the whole bowel. Failure to reach the human distal colon, producing aganglionosis, is an inferred species-sensitive step; neither mouse nor zebrafish models develop a Hirschsprung-like phenotype.
enteric neural crest cell CL:0002607 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves enteric neural crest cell, annotated with migratory enteric neural crest cell (CL:0002607). CL:0002607 is a cell type from the Cell Ontology.
enteric nervous system development GO:0048484 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal enteric nervous system development (GO:0048484). GO:0048484 is a biological process from the Gene Ontology.
enteric nervous system UBERON:0002005 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in enteric nervous system (UBERON:0002005). UBERON:0002005 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Kif1bp knockout mouse Mouse recapitulates
Downstream
Aganglionic megacolon Hypothesized: delayed colonization could leave the distal human colon aganglionic. Not demonstrated in any model, and Hirschsprung disease is absent in some patients sharing a family's variant.
Show evidence (2 references)
PMID:29192291 SUPPORT Model Organism
"Although newborn Kif1bp -/- mice had neurons along the entire bowel, the colonization of the gut by neural crest-derived cells was delayed."
Delayed colonization without distal aganglionosis in knockout mice.
PMID:29192291 SUPPORT BACKGROUND Model Organism
"However, kif1bp mutant zebrafish have neurons along the entire length of the bowel and thus do not develop a Hirschsprung disease-like phenotype"
The zebrafish mutant also lacks aganglionosis, limiting both models for this step.
Impaired Cortical Neuron Migration
Mechanism confidence: Provisional
After in utero KBP knockdown in embryonic mouse cortex, many cells stall in the intermediate zone and about a third of the resulting neurons remain ectopically in the white matter at postnatal day 6; neurons reaching the upper layers show impaired dendritic outgrowth. Neural differentiation itself is not affected. The contribution to human cortical malformations is inferred.
cerebral cortex neuron CL:0010012 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebral cortex neuron (CL:0010012). CL:0010012 is a cell type from the Cell Ontology.
neuron migration GO:0001764 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuron migration (GO:0001764). GO:0001764 is a biological process from the Gene Ontology. dendrite morphogenesis GO:0048813 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dendrite morphogenesis (GO:0048813). GO:0048813 is a biological process from the Gene Ontology.
cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral cortex (UBERON:0000956). UBERON:0000956 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Kbp in utero knockdown mouse cortex Mouse recapitulates
Downstream
Polymicrogyria Proposed by the knockdown study; the step from ectopic neurons to the human gyral malformation is not demonstrated.
Intellectual disability Abnormal cortical organization is a plausible contributor to intellectual disability; not shown directly.
Global developmental delay Abnormal cortical development is a plausible contributor to developmental delay; not shown directly.
Show evidence (1 reference)
PMID:31736709 SUPPORT Model Organism
"Moreover, at postnatal day (P) 6, about one third of the cells, which have become mature neurons, remained ectopically in the white matter (WM), while cells that have reached Layer II/III of the cortex showed impaired dendritic outgrowth and axonal projection."
Migration arrest and impaired dendritic outgrowth of knockdown cortical neurons.
Cortical Neuron Apoptosis
Mechanism confidence: Provisional
KBP knockdown increases apoptosis of cortical neurons during the postnatal period in mice. Neuronal loss is a candidate contributor to reduced brain size; this has not been tested in patients.
cerebral cortex neuron CL:0010012 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebral cortex neuron (CL:0010012). CL:0010012 is a cell type from the Cell Ontology.
apoptotic process GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
Animal models
Kbp in utero knockdown mouse cortex Mouse recapitulates
Downstream
Microcephaly Hypothesized contribution of neuronal loss to small brain size; Kif1bp knockout mice do have smaller brains, but the cause was not traced to apoptosis.
Show evidence (1 reference)
PMID:31736709 SUPPORT Model Organism
"We also found that KBP knockdown induces apoptosis during the postnatal period."
Increased apoptosis after KBP knockdown.
Cytokinesis Failure in Dividing Cells
Mechanism confidence: Hypothetical
KIFBP interacts with citron kinase (encoded by the MCPH17 microcephaly gene), is enriched at the midbody ring and is required for cytokinesis in cultured dividing cells. Reduced neural progenitor output from cytokinesis failure is a proposed, untested route to microcephaly.
cytokinesis GO:0000910 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cytokinesis (GO:0000910). GO:0000910 is a biological process from the Gene Ontology.
Downstream
Microcephaly The authors' proposed clinical link; not demonstrated in neural progenitors in vivo or in patients.
Show evidence (1 reference)
PMID:34100550 SUPPORT In Vitro
"Similar to CITK, KIF1BP is enriched at the midbody ring and is required for cytokinesis."
KIF1BP depletion impairs cytokinesis in cultured cells.
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Pathograph

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

24
Cardiovascular 1
Congenital heart defects Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defect, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32939943 SUPPORT BACKGROUND Human Clinical
"with variable severities and additional features, such as iris coloboma, cleft palate/bifid uvula, corneal ulcers, and congenital heart defects"
The introduction lists congenital heart defects among the additional features of reported patients.
PMID:32939943 SUPPORT Human Clinical
"| Cardiac anomalies (ventricular septal defects, aortic valve incompetence) | − | − | + | ? | ? | + | − | + | − |"
Three positive patients in the third block of the per-patient table, naming the lesion types.
Digestive 1
Aganglionic megacolon FREQUENT HP:0002251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hirschsprung disease, annotated with Aganglionic megacolon (HP:0002251). HP:0002251 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:32939943 SUPPORT Human Clinical
"Hirschsprung disease (HSCR) is reported in ~70% of patients with GOSHS, but is considered to be a variable feature."
Frequency and variability of Hirschsprung disease across reported patients.
PMID:32939943 SUPPORT Human Clinical
"The link between GOSHS and HSCR is poorly understood, especially considering the variability of its presence, even between family members sharing the same pathogenic variant."
Intrafamilial variability of Hirschsprung disease.
PMID:32939943 SUPPORT Human Clinical
"We were also unable to find a correlation between common HSCR-associated SNPs, and HSCR development in GOSHS."
Common Hirschsprung modifier alleles do not explain its variable presence.
+ 1 more reference
Ear 1
Macrotia HP:0000400 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Large ears, annotated with Macrotia (HP:0000400). HP:0000400 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32939943 SUPPORT BACKGROUND Human Clinical
"dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose)"
Large ears are listed among the dysmorphic facial features.
Endocrine 1
Hypogonadotropic hypogonadism HP:0000044 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogonadotropic hypogonadism (HP:0000044). HP:0000044 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37903629 SUPPORT Human Clinical
"We report for the first time, early-adulthood-onset progressive ataxia, opthalmoparesis, and hypogonadotropic hypogonadism in GOSHS."
Hypogonadotropic hypogonadism in one affected sibship.
Eye 5
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32939943 SUPPORT BACKGROUND Human Clinical
"dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose)"
Ptosis is listed among the dysmorphic facial features.
PMID:32939943 SUPPORT Human Clinical
"She presented with short stature, typical dysmorphic facial features with bilateral blepharoptosis, and corneal ulcers."
Bilateral ptosis in a patient of the 2020 series.
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32939943 SUPPORT BACKGROUND Human Clinical
"dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose)"
Hypertelorism is listed among the dysmorphic facial features.
Iris coloboma HP:0000612 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Iris coloboma (HP:0000612). HP:0000612 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32939943 SUPPORT BACKGROUND Human Clinical
"with variable severities and additional features, such as iris coloboma, cleft palate/bifid uvula, corneal ulcers, and congenital heart defects"
Iris coloboma listed among additional variable features in reported cases.
Corneal ulceration HP:0012804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corneal ulcers, annotated with Corneal ulceration (HP:0012804). HP:0012804 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32939943 SUPPORT Human Clinical
"She presented with short stature, typical dysmorphic facial features with bilateral blepharoptosis, and corneal ulcers."
Corneal ulcers in a patient of the 2020 series.
Ophthalmoparesis HP:0000597 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ophthalmoparesis (HP:0000597). HP:0000597 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37903629 SUPPORT Human Clinical
"We report for the first time, early-adulthood-onset progressive ataxia, opthalmoparesis, and hypogonadotropic hypogonadism in GOSHS."
Ophthalmoparesis in one affected sibship.
Head and Neck 6
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15883926 SUPPORT Human Clinical
"Phenotypic features of GOSHS in this inbred family included microcephaly and mental retardation, which are both central nervous system defects"
Microcephaly in the original family.
PMID:31736709 SUPPORT BACKGROUND Human Clinical
"characterized by microcephaly, polymicrogyria, intellectual disability, axonal neuropathy, thin corpus callosum and peripheral neuropathy"
Microcephaly listed among the defining features in the mouse study's background summary of patients.
Wide nasal bridge HP:0000431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad nasal bridge, annotated with Wide nasal bridge (HP:0000431). HP:0000431 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32939943 SUPPORT BACKGROUND Human Clinical
"dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose)"
Broad nasal bridge is listed among the dysmorphic facial features.
Synophrys HP:0000664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Synophrys (HP:0000664). HP:0000664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32939943 SUPPORT BACKGROUND Human Clinical
"dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose)"
Synophrys is listed among the dysmorphic facial features.
Highly arched eyebrow HP:0002553 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arched eyebrows, annotated with Highly arched eyebrow (HP:0002553). HP:0002553 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32939943 SUPPORT BACKGROUND Human Clinical
"dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose)"
Arched eyebrows are listed among the dysmorphic facial features.
Prominent nose HP:0000448 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent long nose, annotated with Prominent nose (HP:0000448). HP:0000448 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32939943 SUPPORT BACKGROUND Human Clinical
"dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose)"
A prominent long nose is listed among the dysmorphic facial features.
Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32939943 SUPPORT BACKGROUND Human Clinical
"with variable severities and additional features, such as iris coloboma, cleft palate/bifid uvula, corneal ulcers, and congenital heart defects"
Cleft palate or bifid uvula listed among additional variable features.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32939943 SUPPORT Human Clinical
"| Hypotonia | + | + | ? | ? | ? | ? | ? | ? | + |"
First block of the per-patient table (patients US1 to V-9); later blocks add further positive patients.
PMID:32939943 SUPPORT Human Clinical
"| Hypotonia | + | ? | + | + | + | + | ? | ? | ? |"
Second block of the per-patient table (patients VI-1 to IV-1).
Nervous System 7
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15883926 SUPPORT Human Clinical
"Phenotypic features of GOSHS in this inbred family included microcephaly and mental retardation, which are both central nervous system defects"
Intellectual disability (termed mental retardation) in the original family.
PMID:32939943 SUPPORT Human Clinical
"A common feature in all these patients is the presence of intellectual disability and developmental delays."
Intellectual disability is consistent across the 2020 series.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental delay, annotated with Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32939943 SUPPORT Human Clinical
"A common feature in all these patients is the presence of intellectual disability and developmental delays."
Developmental delay is consistent across the 2020 series.
Polymicrogyria HP:0002126 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polymicrogyria (HP:0002126). HP:0002126 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15883926 SUPPORT Human Clinical
"since bilateral generalized polymicogyria was diagnosed in all patients in this family, this feature might also be considered a key feature of the syndrome"
Polymicrogyria in all affected members of the index family.
Hypoplasia of the corpus callosum HP:0002079 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum, annotated with Hypoplasia of the corpus callosum (HP:0002079). HP:0002079 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31736709 SUPPORT BACKGROUND Human Clinical
"characterized by microcephaly, polymicrogyria, intellectual disability, axonal neuropathy, thin corpus callosum and peripheral neuropathy"
Thin corpus callosum listed among patient features in the study background.
Peripheral axonal neuropathy HP:0003477 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axonal neuropathy, annotated with Peripheral axonal neuropathy (HP:0003477). HP:0003477 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32939943 SUPPORT BACKGROUND Human Clinical
"microcephaly (head circumference < -2.5 SD), and axonal neuropathy"
Axonal neuropathy is among the defining features summarized from the literature.
PMID:32939943 SUPPORT Human Clinical
"In addition, she had scoliosis, lordosis, pes cavus, as well as mild sensory motor neuropathy with both axonal and demyelinating features."
A patient in the series with mixed axonal and demyelinating neuropathy.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32939943 SUPPORT Human Clinical
"| Seizures | + | − | − | − | − | − | − | − | − |"
One positive patient (US1) in the first block of the per-patient table; most others are negative.
PMID:32939943 SUPPORT Human Clinical
"| Seizures | ? | ? | ? | ? | ? | − | + | ? | − |"
A further positive patient (IRN1) in the third block.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive ataxia, annotated with Ataxia (HP:0001251), qualified as course progressive; young adult onset. HP:0001251 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE Onset: YOUNG ADULT
Show evidence (1 reference)
PMID:37903629 SUPPORT Human Clinical
"We report for the first time, early-adulthood-onset progressive ataxia, opthalmoparesis, and hypogonadotropic hypogonadism in GOSHS."
Progressive ataxia in one affected sibship.
Growth 1
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32939943 SUPPORT Human Clinical
"She presented with short stature, typical dysmorphic facial features with bilateral blepharoptosis, and corneal ulcers."
Short stature in a patient of the 2020 series.
🧬

Genetic Associations

1
KIFBP
Gene: KIFBP hgnc:23419 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KIFBP (hgnc:23419). hgnc:23419 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:15883926 SUPPORT Human Clinical
"We demonstrate that homozygous nonsense mutations in KIAA1279 at 10q22.1, encoding a protein with two tetratrico peptide repeats, underlie this syndromic form of Hirschsprung disease and generalized polymicrogyria"
Gene identification in the original consanguineous family.
PMID:32939943 SUPPORT Human Clinical
"Goldberg-Shprintzen syndrome (GOSHS) is caused by loss of function variants in the kinesin binding protein gene (KIFBP)."
Confirms KIFBP loss of function as the cause across additional patients.
Variants (2)
Truncating KIFBP variants
Nonsense, frameshift and exon-deletion alleles, including p.Arg90Ter, p.Ser200Ter and p.Arg202IlefsTer2, which trigger nonsense-mediated mRNA decay and absence of KIFBP protein. Truncating variants in the 2020 series were classified pathogenic under ACMG criteria.
Show evidence (2 references)
PMID:23427148 SUPPORT Human Clinical
"The homozygous KIAA1279 mutations in these patients (p.Arg90X, p.Ser200X or p.Arg202IlefsX2) led to nonsense-mediated mRNA decay and loss of KBP function."
Patient truncating alleles cause transcript decay and loss of function.
PMID:32939943 SUPPORT Human Clinical
"According to the guidelines established by the American College of Medical Genetics (ACMG), all truncating variants identified in our GOSHS patients are classified as pathogenic"
ACMG classification of the truncating alleles in the 2020 series.
KIFBP missense variants
single nucleotide variant
Homozygous p.Pro189Ser and the compound heterozygous p.Glu23Gly/p.Ser427Gly combination reduce KIFBP expression in transfected cells; they were the first missense variants reported in GOSHS.
Show evidence (1 reference)
PMID:32939943 SUPPORT In Vitro
"Our results showed that the missense variants led to reduced expression of KIFBP, while the truncating variants resulted in lack of protein."
Expression assays of the missense alleles in transfected cells.
💊

Medical Actions

2
Saline rectal irrigation
Action: saline rectal irrigationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is saline rectal irrigation, annotated with Enema Administration (NCIT:C28148). NCIT:C28148 is a clinical intervention from the NCI Thesaurus. Ontology label: Enema Administration NCIT:C28148
Platform: Other
Bowel decompression with saline rectal irrigations while the Hirschsprung diagnosis is confirmed and until definitive surgery. The recommendation comes from Hirschsprung disease guidance generally, not from GOSHS-specific studies.
Target Phenotypes: Hirschsprung disease HP:0002251 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hirschsprung disease, annotated with Aganglionic megacolon (HP:0002251). HP:0002251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32586397 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Whilst awaiting the results of the rectal biopsy, saline rectal irrigations should be commenced to overcome the functional bowel obstruction and to enable enteral feeding."
Consensus guidance for Hirschsprung disease generally, applied to GOSHS-associated Hirschsprung disease by inference.
Pull-through surgery for Hirschsprung disease
Action: pull-through surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pull-through surgery, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Resection of the aganglionic segment with a pull-through procedure after histological confirmation, as for Hirschsprung disease generally. Bowel dysfunction and enterocolitis can persist after surgery; no GOSHS-specific outcome data exist.
Target Phenotypes: Hirschsprung disease HP:0002251 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hirschsprung disease, annotated with Aganglionic megacolon (HP:0002251). HP:0002251 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32586397 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"The diagnosis of HSCR should be based on representative rectal histology, and should be confirmed before pull-through surgery."
Consensus guidance placing pull-through surgery after histological confirmation in Hirschsprung disease generally.
PMID:32586397 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Despite an optimal pull-through, impairment of bowel function and enterocolitis are common during the first few years after surgery"
Post-surgical bowel dysfunction and enterocolitis remain common in Hirschsprung disease generally.
📊

Prevalence

1
Published literature
Cases In Literature Rare
No population-based rate exists. A 2020 review counted 37 previously reported patients and added nine new ones; this is a dated count of published cases, not an occurrence estimate.
Show evidence (1 reference)
PMID:32939943 SUPPORT Human Clinical
"To date, 37 patients with GOSHS have been reported. Here, we document nine new patients with variants in KIFBP: seven with nonsense variants and two with missense variants."
Count of published patients at the time of the 2020 case series, the only occurrence measure available.
🐁

Animal Models

3
Kif1bp knockout mouse
Constitutive knockout mice die within hours of birth and have smaller brains, olfactory bulbs and anterior commissures, defective vagal and sympathetic gut innervation, and delayed enteric neural crest colonization, but neurons occupy the entire bowel at birth.
Species
Mouse
Genotype
Kif1bp-/- (CRISPR/Cas9, two independent lines)
Publication
PMID:29192291
Pathograph links
Delayed Enteric Neural Crest Colonization of the Gut recapitulates fidelity: moderate observes: tissue
Limitations: Colonization is delayed but complete by birth, so the model does not reproduce distal aganglionosis; perinatal death prevents study of later outcomes.
Show evidence (1 reference)
PMID:29192291 SUPPORT Model Organism
"Although newborn Kif1bp -/- mice had neurons along the entire bowel, the colonization of the gut by neural crest-derived cells was delayed."
The knockout directly shows the colonization delay.
Impaired Axon Outgrowth with Axonal Microtubule Disruption partially recapitulates fidelity: moderate observes: tissue
Limitations: Axon extension defects affect only some neuronal populations; axonal microtubules were not examined in this model.
Show evidence (1 reference)
PMID:29192291 SUPPORT Model Organism
"The data show an essential in vivo role for KIF1BP in axon extension from some neurons"
In vivo axon extension defect in the knockout.
Show evidence (1 reference)
PMID:29192291 SUPPORT Model Organism
"Mice lacking Kif1bp died shortly after birth, and exhibited smaller brains, olfactory bulbs and anterior commissures, and defects in the vagal and sympathetic innervation of the gut."
Overall phenotype of the knockout model.
kbp mutant zebrafish
Mutants show slowed early axon outgrowth with axonal microtubule disruption, followed by axon degeneration in peripheral, central and enteric nervous systems; neurons are present along the whole bowel.
Species
Zebrafish
Genotype
kbp (kif1bp) loss-of-function mutant
Publication
PMID:18192286
Pathograph links
Impaired Axon Outgrowth with Axonal Microtubule Disruption recapitulates fidelity: moderate observes: cellular
Limitations: Zebrafish axonal biology is not directly equivalent to human cortical and peripheral nerve development.
Show evidence (1 reference)
PMID:18192286 SUPPORT Model Organism
"Ultrastructural studies reveal that kbp mutants have disruption to axonal microtubules during outgrowth."
Axonal microtubule disruption in the mutant.
Axon Degeneration recapitulates fidelity: moderate observes: cellular
Limitations: Degeneration was observed in larvae; whether a comparable process occurs in patients is unknown.
Show evidence (1 reference)
PMID:18192286 SUPPORT Model Organism
"At later stages, we observe that many affected axons degenerate."
Axon degeneration in the mutant.
Show evidence (1 reference)
PMID:18192286 SUPPORT Model Organism
"We show that kbp is required for axonal outgrowth and maintenance."
Summary finding of the zebrafish model.
Kbp in utero knockdown mouse cortex
Focal knockdown in embryonic cortical progenitors impairs neuronal migration, dendritic outgrowth, callosal axon projection and survival, with rescue by shRNA-resistant Kbp.
Species
Mouse
Genotype
Kbp shRNA electroporated in utero at E14
Publication
PMID:31736709
Pathograph links
Impaired Cortical Neuron Migration recapitulates fidelity: moderate observes: cellular
Limitations: Partial, spatially restricted knockdown is not equivalent to a lifelong biallelic germline loss, and the model does not produce polymicrogyria.
Show evidence (1 reference)
PMID:31736709 SUPPORT Model Organism
"Moreover, at postnatal day (P) 6, about one third of the cells, which have become mature neurons, remained ectopically in the white matter (WM), while cells that have reached Layer II/III of the cortex showed impaired dendritic outgrowth and axonal projection."
Migration arrest after knockdown.
Cortical Neuron Apoptosis recapitulates fidelity: unknown observes: cellular
Limitations: Apoptosis has not been assessed in patient brain tissue, so fidelity to the human disease is unknown.
Show evidence (1 reference)
PMID:31736709 SUPPORT Model Organism
"We also found that KBP knockdown induces apoptosis during the postnatal period."
Increased apoptosis after knockdown.
Show evidence (1 reference)
PMID:31736709 SUPPORT Model Organism
"Our findings indicate that loss of KBP function leads to defects in neuronal migration, morphogenesis, maturation, and survival, which may be responsible for brain phenotypes observed in GOSHS."
Summary finding of the knockdown model.
{ }

Source YAML

click to show 
name: Goldberg-Shprintzen Syndrome
creation_date: "2026-10-09T12:00:00Z"
description: >-
  Goldberg-Shprintzen syndrome (GOSHS) is a rare autosomal recessive neurodevelopmental malformation syndrome
  caused by biallelic loss-of-function variants in KIFBP (formerly KIAA1279 or KBP), which encodes a
  kinesin-binding protein that inhibits a subset of kinesin motors and associates with the actin and microtubule
  cytoskeleton. Core features are microcephaly, intellectual disability and developmental delay, a recognizable
  facial gestalt, cortical malformation such as polymicrogyria, and axonal neuropathy. Hirschsprung disease is
  frequent but variable, even between relatives sharing the same variant. Model organisms show defective axon
  outgrowth and maintenance, delayed enteric neural crest colonization of the gut, and impaired cortical neuron
  migration; how these defects produce the human malformations is not established. It is distinct from the
  SKI-related Shprintzen-Goldberg craniosynostosis syndrome.
category: Mendelian
disease_term:
  preferred_term: Goldberg-Shprintzen Syndrome
  term:
    id: MONDO:0012280
    label: Goldberg-Shprintzen syndrome
synonyms:
- GOSHS
- Goldberg-Shprintzen megacolon syndrome
- megacolon-microcephaly syndrome
notes: >-
  No GeneReviews chapter exists for Goldberg-Shprintzen syndrome. Not to be confused with Shprintzen-Goldberg
  syndrome (SKI-related craniosynostosis with marfanoid habitus), a different disorder whose features do not
  apply here. Hypotonia, seizures and cardiac anomalies are taken from the per-patient table of the 2020 series
  (PMID:32939943), which compiles 34 published and new patients and marks many features as not assessed. An
  Orphanet citation (ORPHA:66629) was not added because the Orphadata bulk file pinned in data/orphadata no
  longer matches the upstream release, so the structured Orphanet cache cannot be rebuilt without repinning.
prevalence:
- population: Published literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: RARE
  notes: >-
    No population-based rate exists. A 2020 review counted 37 previously reported patients and added nine new
    ones; this is a dated count of published cases, not an occurrence estimate.
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 37 patients with GOSHS have been reported. Here, we document nine new patients with variants in KIFBP: seven with nonsense variants and two with missense variants."
    explanation: Count of published patients at the time of the 2020 case series, the only occurrence measure available.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  expressivity: VARIABLE
  description: >-
    Biallelic (homozygous or compound heterozygous) KIFBP variants cause the disorder; several families are
    consanguineous. Expressivity is variable, most visibly for Hirschsprung disease, which can differ between
    siblings carrying the same variant.
  evidence:
  - reference: PMID:15883926
    reference_title: "Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified, by homozygosity mapping, a novel locus on 10q21.3-q22.1 for Goldberg-Shprintzen syndrome (GOSHS) in a consanguineous Moroccan family."
    explanation: Homozygosity mapping in a consanguineous family is consistent with recessive inheritance.
  - reference: PMID:23427148
    reference_title: "KBP-cytoskeleton interactions underlie developmental anomalies in Goldberg-Shprintzen syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Goldberg-Shprintzen syndrome (GOSHS, MIM #609460) is an autosomal recessive disorder of intellectual disability, specific facial gestalt and Hirschsprung's disease (HSCR)."
    explanation: States the autosomal recessive mode of inheritance.
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Homozygosity mapping followed by Sanger sequencing, identified homozygous or compound heterozygous loss of function (LOF) variants in the kinesin binding protein gene (KIFBP, previously known as KIAA1279), as causative for GOSHS"
    explanation: Both homozygous and compound heterozygous genotypes are reported, i.e. biallelic inheritance.
genetic:
- name: KIFBP
  gene_term:
    preferred_term: KIFBP
    term:
      id: hgnc:23419
      label: KIFBP
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Formerly KIAA1279, KIF1BP or KBP. Most reported alleles are truncating (nonsense, frameshift, exon
    deletions) and abolish protein expression; missense variants reported in two patients reduce expression in
    transfected cells, and one of them was classified likely benign by ACMG criteria, so missense pathogenicity
    is less secure. No correlation between variant position and severity was found.
  variants:
  - name: Truncating KIFBP variants
    description: >-
      Nonsense, frameshift and exon-deletion alleles, including p.Arg90Ter, p.Ser200Ter and p.Arg202IlefsTer2,
      which trigger nonsense-mediated mRNA decay and absence of KIFBP protein. Truncating variants in the 2020
      series were classified pathogenic under ACMG criteria.
    evidence:
    - reference: PMID:23427148
      reference_title: "KBP-cytoskeleton interactions underlie developmental anomalies in Goldberg-Shprintzen syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The homozygous KIAA1279 mutations in these patients (p.Arg90X, p.Ser200X or p.Arg202IlefsX2) led to nonsense-mediated mRNA decay and loss of KBP function."
      explanation: Patient truncating alleles cause transcript decay and loss of function.
    - reference: PMID:32939943
      reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "According to the guidelines established by the American College of Medical Genetics (ACMG), all truncating variants identified in our GOSHS patients are classified as pathogenic"
      explanation: ACMG classification of the truncating alleles in the 2020 series.
  - name: KIFBP missense variants
    description: >-
      Homozygous p.Pro189Ser and the compound heterozygous p.Glu23Gly/p.Ser427Gly combination reduce KIFBP
      expression in transfected cells; they were the first missense variants reported in GOSHS.
    variant_type: single nucleotide variant
    evidence:
    - reference: PMID:32939943
      reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our results showed that the missense variants led to reduced expression of KIFBP, while the truncating variants resulted in lack of protein."
      explanation: Expression assays of the missense alleles in transfected cells.
  evidence:
  - reference: PMID:15883926
    reference_title: "Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We demonstrate that homozygous nonsense mutations in KIAA1279 at 10q22.1, encoding a protein with two tetratrico peptide repeats, underlie this syndromic form of Hirschsprung disease and generalized polymicrogyria"
    explanation: Gene identification in the original consanguineous family.
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Goldberg-Shprintzen syndrome (GOSHS) is caused by loss of function variants in the kinesin binding protein gene (KIFBP)."
    explanation: Confirms KIFBP loss of function as the cause across additional patients.
pathophysiology:
- name: Biallelic KIFBP Loss of Function
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Biallelic germline KIFBP variants abolish (truncating alleles) or reduce (missense alleles) KIFBP protein.
    A threshold level of KIFBP has been proposed to modulate phenotypic variability, but this is not validated.
  genes:
  - preferred_term: KIFBP
    term:
      id: hgnc:23419
      label: KIFBP
  genetic_context:
    genes:
    - preferred_term: KIFBP
      term:
        id: hgnc:23419
        label: KIFBP
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, we show that reduced, as well as lack of KIFBP expression can lead to GOSHS, and our results suggest that a threshold expression of KIFBP may modulate phenotypic variability of the disease."
    explanation: Absent or reduced KIFBP expression is the initiating molecular lesion.
  - reference: PMID:23427148
    reference_title: "KBP-cytoskeleton interactions underlie developmental anomalies in Goldberg-Shprintzen syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The homozygous KIAA1279 mutations in these patients (p.Arg90X, p.Ser200X or p.Arg202IlefsX2) led to nonsense-mediated mRNA decay and loss of KBP function."
    explanation: Patient-derived evidence that truncating alleles remove KIFBP.
  downstream:
  - target: Loss of KIFBP Kinesin Inhibition and Cytoskeletal Interaction
    causal_link_type: DIRECT
    description: >-
      Absence of the protein removes its normal activities; the specific kinesin and cytoskeletal consequences in
      each developing tissue are not characterized.
    evidence:
    - reference: PMID:23427148
      reference_title: "KBP-cytoskeleton interactions underlie developmental anomalies in Goldberg-Shprintzen syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The homozygous KIAA1279 mutations in these patients (p.Arg90X, p.Ser200X or p.Arg202IlefsX2) led to nonsense-mediated mRNA decay and loss of KBP function."
      explanation: Loss of the protein entails loss of its kinesin-regulatory and cytoskeletal functions.
  - target: Delayed Enteric Neural Crest Colonization of the Gut
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Shown in Kif1bp knockout mice; the intermediate cellular defect is not identified.
    evidence:
    - reference: PMID:29192291
      reference_title: "Kif1bp loss in mice leads to defects in the peripheral and central nervous system and perinatal death."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Although newborn Kif1bp -/- mice had neurons along the entire bowel, the colonization of the gut by neural crest-derived cells was delayed."
      explanation: Loss of Kif1bp delays gut colonization by enteric neural crest-derived cells in mice.
  - target: Impaired Cortical Neuron Migration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Shown by in utero shRNA knockdown in embryonic mouse cortex, not in a biallelic germline model.
    evidence:
    - reference: PMID:31736709
      reference_title: "Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg-Shprintzen Syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our findings indicate that loss of KBP function leads to defects in neuronal migration, morphogenesis, maturation, and survival, which may be responsible for brain phenotypes observed in GOSHS."
      explanation: KBP knockdown in mouse cortex causes migration, maturation and survival defects.
  - target: Cortical Neuron Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Shown by in utero knockdown; the initiating cause of apoptosis is unresolved.
    evidence:
    - reference: PMID:31736709
      reference_title: "Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg-Shprintzen Syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We also found that KBP knockdown induces apoptosis during the postnatal period."
      explanation: Knockdown of KBP increases apoptosis of the electroporated cortical cells.
- name: Loss of KIFBP Kinesin Inhibition and Cytoskeletal Interaction
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    KIFBP is a tetratricopeptide-repeat alpha-solenoid that binds the motor domains of a subset of kinesins,
    remodels them and blocks their microtubule attachment; it also interacts with actin filaments and
    microtubules. Its loss is expected to deregulate these motors and cytoskeletal interactions. This is inferred
    from normal KIFBP biochemistry; it should not be read as a uniform decrease in kinesin transport, and which
    deregulated motors matter for each disease feature is unknown. A primary mitochondrial respiratory defect is
    not supported: patient fibroblasts lacking KIFBP had normal respiratory chain activity.
  genes:
  - preferred_term: KIFBP
    term:
      id: hgnc:23419
      label: KIFBP
  molecular_functions:
  - preferred_term: kinesin binding
    modifier: DECREASED
    term:
      id: GO:0019894
      label: kinesin binding
  evidence:
  - reference: PMID:33252036
    reference_title: "The mechanism of kinesin inhibition by kinesin-binding protein."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Kinesin-binding protein (KBP) interacts with a subset of kinesins via their motor domains, inhibits their microtubule (MT) attachment, and blocks their cellular function."
    explanation: Defines the normal kinesin-inhibitory function lost when KIFBP is absent.
  - reference: PMID:34797717
    reference_title: "Kinesin-binding protein remodels the kinesin motor to prevent microtubule binding."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Kinesin-binding protein (KIFBP), which is mutated in Goldberg-Shprintzen syndrome, binds to and inhibits the catalytic motor heads of 8 of 45 kinesin superfamily members, but the mechanism remains poorly defined."
    explanation: Independent structural work confirming selective kinesin inhibition by the GOSHS protein.
  - reference: PMID:23427148
    reference_title: "KBP-cytoskeleton interactions underlie developmental anomalies in Goldberg-Shprintzen syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "KBP did not co-localize with mitochondria in control human fibroblasts, but interacted with the actin and tubulin cytoskeleton."
    explanation: Places KIFBP at the cytoskeleton rather than mitochondria.
  - reference: PMID:23427148
    reference_title: "KBP-cytoskeleton interactions underlie developmental anomalies in Goldberg-Shprintzen syndrome."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Despite the absence of functional KBP, respiratory chain complex activity in patient fibroblasts was normal."
    explanation: Argues against an alternative primary mitochondrial respiratory mechanism.
  downstream:
  - target: Impaired Axon Outgrowth with Axonal Microtubule Disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Which deregulated kinesin or cytoskeletal interaction disrupts axonal microtubules is not established.
    evidence:
    - reference: PMID:18192286
      reference_title: "KBP is essential for axonal structure, outgrowth and maintenance in zebrafish, providing insight into the cellular basis of Goldberg-Shprintzen syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These results together suggest that kbp is an important regulator of the microtubule dynamics that drive the forward propulsion of axons."
      explanation: The zebrafish study interprets the axonal defect as loss of KBP regulation of axonal microtubules.
    - reference: PMID:23427148
      reference_title: "KBP-cytoskeleton interactions underlie developmental anomalies in Goldberg-Shprintzen syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "KBP expression directly affected neurite growth in a neuron-like cell line (human neuroblastoma SH-SY5Y), in keeping with the central (polymicrogyria) and enteric (HSCR) neuronal developmental defects seen in GOSHS patients."
      explanation: KBP levels control neurite growth in a neuron-like cell line.
  - target: Cytokinesis Failure in Dividing Cells
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      KIFBP depletion alters midbody localization of the kinesins KIF23 and KIF14 and reduces microtubule
      stability in dividing cultured cells.
    evidence:
    - reference: PMID:34100550
      reference_title: "Goldberg-Shprintzen syndrome protein KIF1BP is a CITK interactor implicated in cytokinesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "KIF1BP knockdown decreases microtubule stability, increases KIF23 midbody levels and impairs midbody localization of KIF14, as well as of chromosome passenger complex."
      explanation: Links KIF1BP loss to deregulated midbody kinesins in dividing cells.
- name: Impaired Axon Outgrowth with Axonal Microtubule Disruption
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    In kbp mutant zebrafish, early axon outgrowth is slower in peripheral and central neurons and axonal
    microtubules are disrupted. Kif1bp knockout mice show defective axon extension from some neuronal
    populations, and cortical KBP knockdown in mice prevents callosal axons from crossing the midline. Human
    tissue evidence is lacking.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: axon extension
    modifier: DECREASED
    term:
      id: GO:0048675
      label: axon extension
  - preferred_term: microtubule cytoskeleton organization
    modifier: ABNORMAL
    term:
      id: GO:0000226
      label: microtubule cytoskeleton organization
  evidence:
  - reference: PMID:18192286
    reference_title: "KBP is essential for axonal structure, outgrowth and maintenance in zebrafish, providing insight into the cellular basis of Goldberg-Shprintzen syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In vivo time-lapse analysis of neuronal development shows that the speed of early axonal outgrowth is reduced in both the peripheral and central nervous systems in kbp mutants."
    explanation: Direct in vivo measurement of reduced axon outgrowth.
  - reference: PMID:18192286
    reference_title: "KBP is essential for axonal structure, outgrowth and maintenance in zebrafish, providing insight into the cellular basis of Goldberg-Shprintzen syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ultrastructural studies reveal that kbp mutants have disruption to axonal microtubules during outgrowth."
    explanation: Axonal microtubule disruption during outgrowth.
  - reference: PMID:29192291
    reference_title: "Kif1bp loss in mice leads to defects in the peripheral and central nervous system and perinatal death."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The data show an essential in vivo role for KIF1BP in axon extension from some neurons"
    explanation: Mouse knockout confirms the axon extension defect in vivo.
  downstream:
  - target: Axon Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In zebrafish, axons that grew abnormally later degenerate; whether degeneration follows from the
      outgrowth defect or from a separate maintenance role is not resolved.
    evidence:
    - reference: PMID:18192286
      reference_title: "KBP is essential for axonal structure, outgrowth and maintenance in zebrafish, providing insight into the cellular basis of Goldberg-Shprintzen syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "At later stages, we observe that many affected axons degenerate."
      explanation: Degeneration of affected axons follows the outgrowth phase in mutants.
  - target: Hypoplasia of the corpus callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Failed midline crossing of callosal axons after cortical knockdown in mice is a candidate basis for a thin
      corpus callosum in patients; not shown in human tissue.
    evidence:
    - reference: PMID:31736709
      reference_title: "Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg-Shprintzen Syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "On the contrary, axons in KBP-knockdown brains only projected down to the WM and failed to extend across the midline at P6"
      explanation: Callosal axons fail to cross the midline after KBP knockdown in mouse cortex.
- name: Axon Degeneration
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Later in development, many affected axons in kbp mutant zebrafish degenerate, with mislocalized axonal
    mitochondria and fewer axons in peripheral, central and enteric nerves.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:18192286
    reference_title: "KBP is essential for axonal structure, outgrowth and maintenance in zebrafish, providing insight into the cellular basis of Goldberg-Shprintzen syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ultrastructural analyses at these stages demonstrate mislocalization of axonal mitochondria and a reduction in axonal number in the peripheral, central and enteric nervous systems."
    explanation: Axon loss across nervous systems in the zebrafish mutant.
  downstream:
  - target: Peripheral axonal neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed by the zebrafish study as the cellular basis of the nervous system defects; peripheral nerve
      pathology in patients has not been studied at this level.
    evidence:
    - reference: PMID:18192286
      reference_title: "KBP is essential for axonal structure, outgrowth and maintenance in zebrafish, providing insight into the cellular basis of Goldberg-Shprintzen syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "We propose that kbp is an important regulator of axonal development and that axonal cytoskeletal defects underlie the nervous system defects in GSS."
      explanation: The authors' proposed link from axonal defects to the human neurological features.
- name: Delayed Enteric Neural Crest Colonization of the Gut
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    In Kif1bp knockout mouse embryos the wavefront of migrating enteric neural crest-derived cells lags behind
    controls, although newborn mice have neurons along the whole bowel. Failure to reach the human distal colon,
    producing aganglionosis, is an inferred species-sensitive step; neither mouse nor zebrafish models develop a
    Hirschsprung-like phenotype.
  cell_types:
  - preferred_term: enteric neural crest cell
    term:
      id: CL:0002607
      label: migratory enteric neural crest cell
  biological_processes:
  - preferred_term: enteric nervous system development
    modifier: ABNORMAL
    term:
      id: GO:0048484
      label: enteric nervous system development
  locations:
  - preferred_term: enteric nervous system
    term:
      id: UBERON:0002005
      label: enteric nervous system
  evidence:
  - reference: PMID:29192291
    reference_title: "Kif1bp loss in mice leads to defects in the peripheral and central nervous system and perinatal death."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Although newborn Kif1bp -/- mice had neurons along the entire bowel, the colonization of the gut by neural crest-derived cells was delayed."
    explanation: Delayed colonization without distal aganglionosis in knockout mice.
  - reference: PMID:29192291
    reference_title: "Kif1bp loss in mice leads to defects in the peripheral and central nervous system and perinatal death."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "However, kif1bp mutant zebrafish have neurons along the entire length of the bowel and thus do not develop a Hirschsprung disease-like phenotype"
    explanation: The zebrafish mutant also lacks aganglionosis, limiting both models for this step.
  downstream:
  - target: Aganglionic megacolon
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hypothesized: delayed colonization could leave the distal human colon aganglionic. Not demonstrated in any
      model, and Hirschsprung disease is absent in some patients sharing a family's variant.
    evidence:
    - reference: PMID:29192291
      reference_title: "Kif1bp loss in mice leads to defects in the peripheral and central nervous system and perinatal death."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Although newborn Kif1bp -/- mice had neurons along the entire bowel, the colonization of the gut by neural crest-derived cells was delayed."
      explanation: Delayed colonization is the closest modeled precursor of aganglionosis; the mice themselves are not aganglionic.
- name: Impaired Cortical Neuron Migration
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    After in utero KBP knockdown in embryonic mouse cortex, many cells stall in the intermediate zone and about a
    third of the resulting neurons remain ectopically in the white matter at postnatal day 6; neurons reaching
    the upper layers show impaired dendritic outgrowth. Neural differentiation itself is not affected. The
    contribution to human cortical malformations is inferred.
  cell_types:
  - preferred_term: cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  biological_processes:
  - preferred_term: neuron migration
    modifier: DECREASED
    term:
      id: GO:0001764
      label: neuron migration
  - preferred_term: dendrite morphogenesis
    modifier: DECREASED
    term:
      id: GO:0048813
      label: dendrite morphogenesis
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:31736709
    reference_title: "Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg-Shprintzen Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Moreover, at postnatal day (P) 6, about one third of the cells, which have become mature neurons, remained ectopically in the white matter (WM), while cells that have reached Layer II/III of the cortex showed impaired dendritic outgrowth and axonal projection."
    explanation: Migration arrest and impaired dendritic outgrowth of knockdown cortical neurons.
  downstream:
  - target: Polymicrogyria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed by the knockdown study; the step from ectopic neurons to the human gyral malformation is not
      demonstrated.
    evidence:
    - reference: PMID:31736709
      reference_title: "Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg-Shprintzen Syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Our findings indicate that loss of KBP function leads to defects in neuronal migration, morphogenesis, maturation, and survival, which may be responsible for brain phenotypes observed in GOSHS."
      explanation: Authors propose the migration defect underlies GOSHS brain phenotypes.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal cortical organization is a plausible contributor to intellectual disability; not shown directly.
    evidence:
    - reference: PMID:31736709
      reference_title: "Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg-Shprintzen Syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Our findings indicate that loss of KBP function leads to defects in neuronal migration, morphogenesis, maturation, and survival, which may be responsible for brain phenotypes observed in GOSHS."
      explanation: Authors propose the cortical defects underlie GOSHS brain phenotypes.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal cortical development is a plausible contributor to developmental delay; not shown directly.
    evidence:
    - reference: PMID:31736709
      reference_title: "Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg-Shprintzen Syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Our findings indicate that loss of KBP function leads to defects in neuronal migration, morphogenesis, maturation, and survival, which may be responsible for brain phenotypes observed in GOSHS."
      explanation: Authors propose the cortical defects underlie GOSHS brain phenotypes.
- name: Cortical Neuron Apoptosis
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    KBP knockdown increases apoptosis of cortical neurons during the postnatal period in mice. Neuronal loss is a
    candidate contributor to reduced brain size; this has not been tested in patients.
  cell_types:
  - preferred_term: cerebral cortex neuron
    term:
      id: CL:0010012
      label: cerebral cortex neuron
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:31736709
    reference_title: "Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg-Shprintzen Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We also found that KBP knockdown induces apoptosis during the postnatal period."
    explanation: Increased apoptosis after KBP knockdown.
  downstream:
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hypothesized contribution of neuronal loss to small brain size; Kif1bp knockout mice do have smaller
      brains, but the cause was not traced to apoptosis.
    evidence:
    - reference: PMID:29192291
      reference_title: "Kif1bp loss in mice leads to defects in the peripheral and central nervous system and perinatal death."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Mice lacking Kif1bp died shortly after birth, and exhibited smaller brains, olfactory bulbs and anterior commissures, and defects in the vagal and sympathetic innervation of the gut."
      explanation: Loss of Kif1bp reduces brain size in mice, consistent with microcephaly, without identifying the cellular cause.
- name: Cytokinesis Failure in Dividing Cells
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    KIFBP interacts with citron kinase (encoded by the MCPH17 microcephaly gene), is enriched at the midbody
    ring and is required for cytokinesis in cultured dividing cells. Reduced neural progenitor output from
    cytokinesis failure is a proposed, untested route to microcephaly.
  biological_processes:
  - preferred_term: cytokinesis
    modifier: DECREASED
    term:
      id: GO:0000910
      label: cytokinesis
  evidence:
  - reference: PMID:34100550
    reference_title: "Goldberg-Shprintzen syndrome protein KIF1BP is a CITK interactor implicated in cytokinesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Similar to CITK, KIF1BP is enriched at the midbody ring and is required for cytokinesis."
    explanation: KIF1BP depletion impairs cytokinesis in cultured cells.
  downstream:
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The authors' proposed clinical link; not demonstrated in neural progenitors in vivo or in patients.
    evidence:
    - reference: PMID:34100550
      reference_title: "Goldberg-Shprintzen syndrome protein KIF1BP is a CITK interactor implicated in cytokinesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "These data indicate that KIF1BP is a CITK interactor involved in midbody maturation and abscission, and suggest that cytokinesis failure may contribute to the microcephaly phenotype observed in GOSHS."
      explanation: Proposes cytokinesis failure as a contributor to microcephaly.
phenotypes:
- name: Aganglionic megacolon
  category: Gastrointestinal
  frequency: FREQUENT
  description: >-
    Hirschsprung disease, absence of enteric ganglia in the distal colon, is reported in about 70% (24/34) of
    patients compiled in 2020. It is variable even between family members sharing the same pathogenic variant, and
    selected common RET, SEMA3A and NRG1 Hirschsprung risk SNPs did not explain its presence.
  phenotype_term:
    preferred_term: Hirschsprung disease
    term:
      id: HP:0002251
      label: Aganglionic megacolon
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hirschsprung disease (HSCR) is reported in ~70% of patients with GOSHS, but is considered to be a variable feature."
    explanation: Frequency and variability of Hirschsprung disease across reported patients.
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The link between GOSHS and HSCR is poorly understood, especially considering the variability of its presence, even between family members sharing the same pathogenic variant."
    explanation: Intrafamilial variability of Hirschsprung disease.
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We were also unable to find a correlation between common HSCR-associated SNPs, and HSCR development in GOSHS."
    explanation: Common Hirschsprung modifier alleles do not explain its variable presence.
  - reference: PMID:15883926
    reference_title: "Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotypic features of GOSHS in this inbred family included microcephaly and mental retardation, which are both central nervous system defects, as well as Hirschsprung disease, an enteric nervous system defect."
    explanation: Hirschsprung disease in the original molecularly defined family.
- name: Microcephaly
  category: Neurological
  description: >-
    Congenital or early microcephaly, with head circumference below -2.5 SD in the clinical definition used for
    diagnosis.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:15883926
    reference_title: "Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotypic features of GOSHS in this inbred family included microcephaly and mental retardation, which are both central nervous system defects"
    explanation: Microcephaly in the original family.
  - reference: PMID:31736709
    reference_title: "Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg-Shprintzen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "characterized by microcephaly, polymicrogyria, intellectual disability, axonal neuropathy, thin corpus callosum and peripheral neuropathy"
    explanation: Microcephaly listed among the defining features in the mouse study's background summary of patients.
- name: Intellectual disability
  category: Neurological
  description: >-
    Intellectual disability, often described as moderate, is present in reported patients.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:15883926
    reference_title: "Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phenotypic features of GOSHS in this inbred family included microcephaly and mental retardation, which are both central nervous system defects"
    explanation: Intellectual disability (termed mental retardation) in the original family.
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A common feature in all these patients is the presence of intellectual disability and developmental delays."
    explanation: Intellectual disability is consistent across the 2020 series.
- name: Global developmental delay
  category: Neurological
  description: >-
    Developmental delay is a common feature across reported patients.
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A common feature in all these patients is the presence of intellectual disability and developmental delays."
    explanation: Developmental delay is consistent across the 2020 series.
- name: Polymicrogyria
  category: Neurological
  description: >-
    Bilateral generalized polymicrogyria was present in all affected members of the original family and was
    proposed as a key feature; cortical malformations vary between families.
  phenotype_term:
    preferred_term: Polymicrogyria
    term:
      id: HP:0002126
      label: Polymicrogyria
  evidence:
  - reference: PMID:15883926
    reference_title: "Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "since bilateral generalized polymicogyria was diagnosed in all patients in this family, this feature might also be considered a key feature of the syndrome"
    explanation: Polymicrogyria in all affected members of the index family.
- name: Hypoplasia of the corpus callosum
  category: Neurological
  description: >-
    A thin corpus callosum is reported among the brain anomalies of GOSHS.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  evidence:
  - reference: PMID:31736709
    reference_title: "Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg-Shprintzen Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "characterized by microcephaly, polymicrogyria, intellectual disability, axonal neuropathy, thin corpus callosum and peripheral neuropathy"
    explanation: Thin corpus callosum listed among patient features in the study background.
- name: Peripheral axonal neuropathy
  category: Neurological
  description: >-
    Axonal neuropathy is part of the clinical definition; individual patients have mixed axonal and
    demyelinating sensorimotor neuropathy.
  phenotype_term:
    preferred_term: Axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "microcephaly (head circumference < -2.5 SD), and axonal neuropathy"
    explanation: Axonal neuropathy is among the defining features summarized from the literature.
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, she had scoliosis, lordosis, pes cavus, as well as mild sensory motor neuropathy with both axonal and demyelinating features."
    explanation: A patient in the series with mixed axonal and demyelinating neuropathy.
- name: Ptosis
  category: Craniofacial
  description: Ptosis is part of the characteristic facial gestalt.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose)"
    explanation: Ptosis is listed among the dysmorphic facial features.
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She presented with short stature, typical dysmorphic facial features with bilateral blepharoptosis, and corneal ulcers."
    explanation: Bilateral ptosis in a patient of the 2020 series.
- name: Hypertelorism
  category: Craniofacial
  description: Widely spaced eyes are part of the facial gestalt.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose)"
    explanation: Hypertelorism is listed among the dysmorphic facial features.
- name: Wide nasal bridge
  category: Craniofacial
  description: A broad nasal bridge is part of the facial gestalt.
  phenotype_term:
    preferred_term: Broad nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose)"
    explanation: Broad nasal bridge is listed among the dysmorphic facial features.
- name: Synophrys
  category: Craniofacial
  description: Synophrys is part of the facial gestalt.
  phenotype_term:
    preferred_term: Synophrys
    term:
      id: HP:0000664
      label: Synophrys
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose)"
    explanation: Synophrys is listed among the dysmorphic facial features.
- name: Highly arched eyebrow
  category: Craniofacial
  description: Arched eyebrows are part of the facial gestalt.
  phenotype_term:
    preferred_term: Arched eyebrows
    term:
      id: HP:0002553
      label: Highly arched eyebrow
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose)"
    explanation: Arched eyebrows are listed among the dysmorphic facial features.
- name: Macrotia
  category: Craniofacial
  description: Large ears are part of the facial gestalt.
  phenotype_term:
    preferred_term: Large ears
    term:
      id: HP:0000400
      label: Macrotia
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose)"
    explanation: Large ears are listed among the dysmorphic facial features.
- name: Prominent nose
  category: Craniofacial
  description: A prominent, long nose is part of the facial gestalt.
  phenotype_term:
    preferred_term: Prominent long nose
    term:
      id: HP:0000448
      label: Prominent nose
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "dysmorphic facial features (arched eyebrows, dense eyelashes, broad nasal bridge, hypertelorism, synophrys, ptosis, large ears, and a prominent long nose)"
    explanation: A prominent long nose is listed among the dysmorphic facial features.
- name: Iris coloboma
  category: Ophthalmological
  description: Iris coloboma is an additional, variable feature.
  phenotype_term:
    preferred_term: Iris coloboma
    term:
      id: HP:0000612
      label: Iris coloboma
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "with variable severities and additional features, such as iris coloboma, cleft palate/bifid uvula, corneal ulcers, and congenital heart defects"
    explanation: Iris coloboma listed among additional variable features in reported cases.
- name: Corneal ulceration
  category: Ophthalmological
  description: Corneal ulcers are an additional, variable feature.
  phenotype_term:
    preferred_term: Corneal ulcers
    term:
      id: HP:0012804
      label: Corneal ulceration
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She presented with short stature, typical dysmorphic facial features with bilateral blepharoptosis, and corneal ulcers."
    explanation: Corneal ulcers in a patient of the 2020 series.
- name: Cleft palate
  category: Craniofacial
  description: Cleft palate or bifid uvula is an additional, variable feature.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "with variable severities and additional features, such as iris coloboma, cleft palate/bifid uvula, corneal ulcers, and congenital heart defects"
    explanation: Cleft palate or bifid uvula listed among additional variable features.
- name: Hypotonia
  category: Neurological
  description: >-
    Hypotonia is recorded as present in 13 of the 34 patients in the 2020 compiled table, absent in 2 and not
    assessed in the other 19, so it is common among patients examined for it but its true frequency is unknown.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Hypotonia | + | + | ? | ? | ? | ? | ? | ? | + |"
    explanation: First block of the per-patient table (patients US1 to V-9); later blocks add further positive patients.
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Hypotonia | + | ? | + | + | + | + | ? | ? | ? |"
    explanation: Second block of the per-patient table (patients VI-1 to IV-1).
- name: Seizure
  category: Neurological
  description: >-
    Seizures are an occasional feature, recorded in 3 of the 34 patients in the 2020 compiled table, absent in 22
    and not assessed in 9.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Seizures | + | − | − | − | − | − | − | − | − |"
    explanation: One positive patient (US1) in the first block of the per-patient table; most others are negative.
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Seizures | ? | ? | ? | ? | ? | − | + | ? | − |"
    explanation: A further positive patient (IRN1) in the third block.
- name: Congenital heart defects
  category: Cardiovascular
  description: >-
    Cardiac anomalies, namely ventricular septal defects and aortic valve incompetence, are recorded in 5 of the
    34 patients in the 2020 compiled table, absent in 22 and not assessed in 7. The table does not say which
    patient had which lesion, so the general term is bound.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "with variable severities and additional features, such as iris coloboma, cleft palate/bifid uvula, corneal ulcers, and congenital heart defects"
    explanation: The introduction lists congenital heart defects among the additional features of reported patients.
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Cardiac anomalies (ventricular septal defects, aortic valve incompetence) | − | − | + | ? | ? | + | − | + | − |"
    explanation: Three positive patients in the third block of the per-patient table, naming the lesion types.
- name: Short stature
  category: Growth
  description: Short stature is reported in several patients.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:32939943
    reference_title: "Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She presented with short stature, typical dysmorphic facial features with bilateral blepharoptosis, and corneal ulcers."
    explanation: Short stature in a patient of the 2020 series.
- name: Ataxia
  category: Neurological
  description: >-
    Early-adulthood-onset progressive ataxia was first reported in four siblings of one consanguineous family
    with a homozygous KIFBP variant; its frequency is unknown.
  phenotype_term:
    preferred_term: Progressive ataxia
    term:
      id: HP:0001251
      label: Ataxia
    clinical_course: PROGRESSIVE
    onset:
      onset_category: YOUNG_ADULT
  evidence:
  - reference: PMID:37903629
    reference_title: "Progressive ataxia, ophthalmoparesis, and hypogonadotropic hypogonadism in a family with a novel variant in the KIFBP gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report for the first time, early-adulthood-onset progressive ataxia, opthalmoparesis, and hypogonadotropic hypogonadism in GOSHS."
    explanation: Progressive ataxia in one affected sibship.
- name: Ophthalmoparesis
  category: Neurological
  description: >-
    Ophthalmoparesis was reported with adult-onset progression in one sibship; its frequency is unknown.
  phenotype_term:
    preferred_term: Ophthalmoparesis
    term:
      id: HP:0000597
      label: Ophthalmoparesis
  evidence:
  - reference: PMID:37903629
    reference_title: "Progressive ataxia, ophthalmoparesis, and hypogonadotropic hypogonadism in a family with a novel variant in the KIFBP gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report for the first time, early-adulthood-onset progressive ataxia, opthalmoparesis, and hypogonadotropic hypogonadism in GOSHS."
    explanation: Ophthalmoparesis in one affected sibship.
- name: Hypogonadotropic hypogonadism
  category: Endocrine
  description: >-
    Hypogonadotropic hypogonadism was reported in one sibship; its frequency is unknown.
  phenotype_term:
    preferred_term: Hypogonadotropic hypogonadism
    term:
      id: HP:0000044
      label: Hypogonadotropic hypogonadism
  evidence:
  - reference: PMID:37903629
    reference_title: "Progressive ataxia, ophthalmoparesis, and hypogonadotropic hypogonadism in a family with a novel variant in the KIFBP gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report for the first time, early-adulthood-onset progressive ataxia, opthalmoparesis, and hypogonadotropic hypogonadism in GOSHS."
    explanation: Hypogonadotropic hypogonadism in one affected sibship.
treatments:
- name: Saline rectal irrigation
  description: >-
    Bowel decompression with saline rectal irrigations while the Hirschsprung diagnosis is confirmed and until
    definitive surgery. The recommendation comes from Hirschsprung disease guidance generally, not from
    GOSHS-specific studies.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: saline rectal irrigation
    term:
      id: NCIT:C28148
      label: Enema Administration
  target_phenotypes:
  - preferred_term: Hirschsprung disease
    term:
      id: HP:0002251
      label: Aganglionic megacolon
  evidence:
  - reference: PMID:32586397
    reference_title: "ERNICA guidelines for the management of rectosigmoid Hirschsprung's disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: "Whilst awaiting the results of the rectal biopsy, saline rectal irrigations should be commenced to overcome the functional bowel obstruction and to enable enteral feeding."
    explanation: Consensus guidance for Hirschsprung disease generally, applied to GOSHS-associated Hirschsprung disease by inference.
- name: Pull-through surgery for Hirschsprung disease
  description: >-
    Resection of the aganglionic segment with a pull-through procedure after histological confirmation, as for
    Hirschsprung disease generally. Bowel dysfunction and enterocolitis can persist after surgery; no
    GOSHS-specific outcome data exist.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: pull-through surgery
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Hirschsprung disease
    term:
      id: HP:0002251
      label: Aganglionic megacolon
  evidence:
  - reference: PMID:32586397
    reference_title: "ERNICA guidelines for the management of rectosigmoid Hirschsprung's disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: "The diagnosis of HSCR should be based on representative rectal histology, and should be confirmed before pull-through surgery."
    explanation: Consensus guidance placing pull-through surgery after histological confirmation in Hirschsprung disease generally.
  - reference: PMID:32586397
    reference_title: "ERNICA guidelines for the management of rectosigmoid Hirschsprung's disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: "Despite an optimal pull-through, impairment of bowel function and enterocolitis are common during the first few years after surgery"
    explanation: Post-surgical bowel dysfunction and enterocolitis remain common in Hirschsprung disease generally.
animal_models:
- name: Kif1bp knockout mouse
  species: Mouse
  genotype: Kif1bp-/- (CRISPR/Cas9, two independent lines)
  publication: PMID:29192291
  description: >-
    Constitutive knockout mice die within hours of birth and have smaller brains, olfactory bulbs and anterior
    commissures, defective vagal and sympathetic gut innervation, and delayed enteric neural crest colonization,
    but neurons occupy the entire bowel at birth.
  modeled_mechanisms:
  - target: Delayed Enteric Neural Crest Colonization of the Gut
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    limitations: >-
      Colonization is delayed but complete by birth, so the model does not reproduce distal aganglionosis; perinatal
      death prevents study of later outcomes.
    evidence:
    - reference: PMID:29192291
      reference_title: "Kif1bp loss in mice leads to defects in the peripheral and central nervous system and perinatal death."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Although newborn Kif1bp -/- mice had neurons along the entire bowel, the colonization of the gut by neural crest-derived cells was delayed."
      explanation: The knockout directly shows the colonization delay.
  - target: Impaired Axon Outgrowth with Axonal Microtubule Disruption
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    limitations: >-
      Axon extension defects affect only some neuronal populations; axonal microtubules were not examined in this
      model.
    evidence:
    - reference: PMID:29192291
      reference_title: "Kif1bp loss in mice leads to defects in the peripheral and central nervous system and perinatal death."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The data show an essential in vivo role for KIF1BP in axon extension from some neurons"
      explanation: In vivo axon extension defect in the knockout.
  evidence:
  - reference: PMID:29192291
    reference_title: "Kif1bp loss in mice leads to defects in the peripheral and central nervous system and perinatal death."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice lacking Kif1bp died shortly after birth, and exhibited smaller brains, olfactory bulbs and anterior commissures, and defects in the vagal and sympathetic innervation of the gut."
    explanation: Overall phenotype of the knockout model.
- name: kbp mutant zebrafish
  species: Zebrafish
  genotype: kbp (kif1bp) loss-of-function mutant
  publication: PMID:18192286
  description: >-
    Mutants show slowed early axon outgrowth with axonal microtubule disruption, followed by axon degeneration in
    peripheral, central and enteric nervous systems; neurons are present along the whole bowel.
  modeled_mechanisms:
  - target: Impaired Axon Outgrowth with Axonal Microtubule Disruption
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    limitations: >-
      Zebrafish axonal biology is not directly equivalent to human cortical and peripheral nerve development.
    evidence:
    - reference: PMID:18192286
      reference_title: "KBP is essential for axonal structure, outgrowth and maintenance in zebrafish, providing insight into the cellular basis of Goldberg-Shprintzen syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Ultrastructural studies reveal that kbp mutants have disruption to axonal microtubules during outgrowth."
      explanation: Axonal microtubule disruption in the mutant.
  - target: Axon Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    limitations: >-
      Degeneration was observed in larvae; whether a comparable process occurs in patients is unknown.
    evidence:
    - reference: PMID:18192286
      reference_title: "KBP is essential for axonal structure, outgrowth and maintenance in zebrafish, providing insight into the cellular basis of Goldberg-Shprintzen syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "At later stages, we observe that many affected axons degenerate."
      explanation: Axon degeneration in the mutant.
  evidence:
  - reference: PMID:18192286
    reference_title: "KBP is essential for axonal structure, outgrowth and maintenance in zebrafish, providing insight into the cellular basis of Goldberg-Shprintzen syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that kbp is required for axonal outgrowth and maintenance."
    explanation: Summary finding of the zebrafish model.
- name: Kbp in utero knockdown mouse cortex
  species: Mouse
  genotype: Kbp shRNA electroporated in utero at E14
  publication: PMID:31736709
  description: >-
    Focal knockdown in embryonic cortical progenitors impairs neuronal migration, dendritic outgrowth, callosal
    axon projection and survival, with rescue by shRNA-resistant Kbp.
  modeled_mechanisms:
  - target: Impaired Cortical Neuron Migration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    limitations: >-
      Partial, spatially restricted knockdown is not equivalent to a lifelong biallelic germline loss, and the
      model does not produce polymicrogyria.
    evidence:
    - reference: PMID:31736709
      reference_title: "Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg-Shprintzen Syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Moreover, at postnatal day (P) 6, about one third of the cells, which have become mature neurons, remained ectopically in the white matter (WM), while cells that have reached Layer II/III of the cortex showed impaired dendritic outgrowth and axonal projection."
      explanation: Migration arrest after knockdown.
  - target: Cortical Neuron Apoptosis
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: CELLULAR
    limitations: >-
      Apoptosis has not been assessed in patient brain tissue, so fidelity to the human disease is unknown.
    evidence:
    - reference: PMID:31736709
      reference_title: "Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg-Shprintzen Syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We also found that KBP knockdown induces apoptosis during the postnatal period."
      explanation: Increased apoptosis after knockdown.
  evidence:
  - reference: PMID:31736709
    reference_title: "Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg-Shprintzen Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings indicate that loss of KBP function leads to defects in neuronal migration, morphogenesis, maturation, and survival, which may be responsible for brain phenotypes observed in GOSHS."
    explanation: Summary finding of the knockdown model.
📚

References & Deep Research

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Evaluations and curation notes (1)

Create: Goldberg-Shprintzen_Syndrome · 2026-10-09T21:19:38Z · View source

New entry for Goldberg-Shprintzen syndrome (MONDO:0012280; KIFBP, autosomal recessive), curated from the Perplexity deep-research report research/Goldberg-Shprintzen_Syndrome-deep-research-perplexity.md (preflight-dr PASS, KIFBP mentioned 27 times). Lumped as a single DISEASE entry with no subtypes. The SKI-related Shprintzen-Goldberg syndrome is a different disorder; one SKI paper the report linked (PMID:39638120) was fetched, found to be about that disorder, and not used. The two references flagged off-topic by the report's validator (PMID:33252036 and PMC12905500/PMID:41604282) are kinesin-inhibition mechanism papers; PMID:33252036 was read and cited for normal KIFBP function, PMC12905500 was not used. Orphanet ORPHA:66629 could not be cached (fetch-reference has no ORPHA source and the pinned Orphadata snapshot has drifted), so Orphanet-only signs (hypotonia, seizures) were left out. Pathophysiology is an 8-node chain from biallelic KIFBP loss through loss of kinesin inhibition and cytoskeletal interaction to axon outgrowth failure and degeneration (zebrafish), delayed enteric neural crest colonization (Kif1bp knockout mouse), impaired cortical neuron migration and apoptosis (in utero knockdown), and a hypothetical cytokinesis route to microcephaly; model-to-human steps are marked INDIRECT_UNKNOWN_INTERMEDIATES. 21 phenotypes with HPO bindings, 2 Hirschsprung treatments citing ERNICA guidance as indirect evidence, 3 animal models. Validation: just validate, validate-terms, count-verified-snippets (80/80), check-entity-refs, check-causal-targets, check-genereviews (NO_CHAPTER) and validate-disorders all passed; 7/21 phenotypes causally connected.

Perplexity ▸
Goldberg–Shprintzen syndrome: disease-characteristics research report
sonar-deep-research 61 citations 2026-10-09T20:59:43.618672

Goldberg–Shprintzen syndrome: disease-characteristics research report

Goldberg–Shprintzen syndrome (GOSHS; MONDO:0012280) is a rare, autosomal-recessive neurodevelopmental disorder caused by biallelic loss-of-function variants in KIFBP. Its defining clinical pattern combines microcephaly, developmental impairment and characteristic facial features; many, but not all, affected people also have Hirschsprung disease and malformations of cerebral cortical development. It is not Shprintzen–Goldberg syndrome, the distinct SKI-associated condition. [3][23][51]

Evidence boundary. This is an aggregated, disease-level synthesis of published patients, experimental studies, and curated resources—not an analysis of individual electronic health records. The small, inconsistently ascertained case literature supports clinical descriptions but seldom supports population-wide frequencies, treatment-response rates, or survival estimates. In particular, Orphanet’s description says 24 published cases, whereas a 2020 paper identified 37 previously reported people and added nine; those counts should not be combined as if they were contemporaneous estimates. [1][37]

1. Disease information and identifiers

Identifier or name Value and interpretation
MONDO MONDO:0012280. [3]
OMIM phenotype 609460, Goldberg–Shprintzen megacolon syndrome. The associated KIFBP gene entry is OMIM 609367. [51][88]
Orphanet ORPHA:66629. [1]
MeSH C537279, as cross-referenced by Orphanet. [1]
ICD-10; ICD-11 Q87.8; LD2F.1Y, respectively, as listed by Orphanet; these are classification mappings rather than GOSHS-specific molecular diagnoses. [1]
UMLS/MedGen; SNOMED CT C1836123 / MedGen 332131; SNOMED CT 717822006. [3]
Synonyms Goldberg–Shprintzen megacolon syndrome; megacolon–microcephaly syndrome; GOSHS. [1][3]
Crucial disambiguation Shprintzen–Goldberg syndrome is SKI-associated and has a different OMIM/Orphanet entry; its craniosynostosis/connective-tissue phenotype should not be imported into this entry. [21][32]

The original molecular study, published 9 May 2005, linked homozygous KIAA1279—the former name for KIFBP—nonsense variants to central and enteric nervous-system malformations. Its abstract states: “homozygous nonsense mutations in KIAA1279 … underlie this syndromic form of Hirschsprung disease and generalized polymicrogyria.” PMID: 15883926. [151]

2. Etiology: causal, risk, protective, and environmental factors

Established cause: pathogenic variants affecting both germline KIFBP alleles, usually nonsense, frameshift, splice-disrupting or exon-deletion variants; some missense variants reduce protein abundance. A 2020 human-patient and transfected-cell study found that truncating variants produced no detectable KIFBP protein, while the tested missense variants reduced expression. The authors concluded: “reduced, as well as lack of KIFBP expression can lead to GOSHS.” Published 16 September 2020; PMID: 32939943. [37][154]

Risk and variation: having two disease-causing alleles is the established genetic risk; family history and consanguinity can increase the chance that both parents transmit the same rare recessive allele. Hirschsprung disease is variably expressed even among siblings carrying the same KIFBP variant. Proposed genetic or stochastic modifiers remain unconfirmed: in a small analysis, selected common RET, NRG1, and SEMA3A SNPs did not significantly explain Hirschsprung status (p=0.526). A mouse study found a Kif1bp–Ret interaction affecting vagal stomach innervation, but did not demonstrate an interaction explaining delayed enteric neural-crest migration. [37][38][151]

Not established: no protective allele, protective diet, toxin, lifestyle exposure, pathogen, or reproducible gene–environment interaction has been identified for GOSHS onset. Nutrition, infection prevention, and bowel care can influence complications; they do not correct the inherited cause. No GOSHS-specific epigenetic mechanism has been demonstrated. [37][1]

3. Phenotypes

The table distinguishes cohort observations from resource descriptions. The strongest numerical disease-specific estimate is Hirschsprung disease in 24/34 people (~71%) in the 2020 literature-assembled dataset; this is not a population prevalence. Orphanet describes cerebral MRI abnormalities in about half of patients. Its HPO sign page places terms in frequency groupings, but its initially listed signs have no visible frequency-group heading in the retrieved page; they should not be interpreted as 100% penetrant. [37][1][226]

Phenotype type Phenotype and suggested HPO term Onset, severity, course, frequency, and functional impact
Physical manifestation Microcephaly — HP:0000252 Congenital or early infancy; prominent but severity varies. Small brain/head size accompanies developmental disability; an exact unbiased frequency is unavailable. [1][37][226]
Gastrointestinal sign/pathology Aganglionic megacolon / Hirschsprung disease — HP:0002251 Congenital; 24/34 (~71%) in a published-case compilation. Presentation ranges from constipation to neonatal obstruction; untreated obstruction can threaten life and bowel function. [37][1][226]
Developmental/behavioral manifestation Global developmental delay — HP:0001263 Recognized in infancy or childhood; often substantial, particularly for expressive language. Affects communication, schooling, and independence; no validated syndrome-wide percentage or quality-of-life score. [1][141]
Neurocognitive manifestation Intellectual disability — HP:0001249 Childhood recognition; commonly moderate to severe in clinical descriptions, with variable expressivity. Long-term support needs vary. [1][226]
Neuromuscular sign Hypotonia — HP:0001252 Usually early-life; Orphanet’s HPO listing calls it very frequent, but no reliable patient denominator is supplied. Can compound motor and feeding difficulties. [1][226]
Brain-imaging sign Polymicrogyria — HP:0002126 Congenital cortical malformation, sometimes focal or generalized; variable among families. Potential developmental and seizure burden should be assessed individually. [1][185]
Brain-imaging sign Pachygyria — HP:0001302 Congenital; Orphanet HPO listing calls it frequent. An imaging finding, not a separate disease stage. [226][37]
Brain-imaging sign Corpus-callosum hypoplasia — HP:0002079 Congenital; frequent in Orphanet’s HPO listing. Possible contribution to impaired interhemispheric connectivity is mechanistic inference. [226][151]
Brain-imaging sign Ventriculomegaly — HP:0002119 Prenatally or postnatally detectable; frequent in Orphanet’s HPO listing; clinical effect depends on context. [226][136]
Neurological sign Seizures — HP:0001250 Variable onset and occurrence; frequent in Orphanet’s HPO listing, but present in only some individually described patients. Episode severity and burden vary. [226][37]
Peripheral-neurological sign Peripheral, including axonal, neuropathy Childhood or later detection; sensory/motor impact varies. Some reported patients had mixed axonal/demyelinating findings; no dependable syndrome-wide frequency or single specific HPO subtype is established here. [37][145]
Craniofacial signs Ptosis — HP:0000508; hypertelorism — HP:0000316; wide nasal bridge — HP:0000431; pointed chin — HP:0000307 Typically apparent at birth, sometimes clearer with age. Features aid recognition but are not independently diagnostic; ptosis may affect vision and warrants eye assessment. [1][226]
Eye manifestations Iris coloboma — HP:0000612; hypermetropia, megalocornea, corneal disease Variable; vision or corneal symptoms may require treatment. Iris coloboma is listed as very frequent by Orphanet HPO, while individual clinical series differ in ascertainment. [226][1][37]
Growth/skeletal findings Short stature — HP:0004322; scoliosis and digital anomalies Growth concerns emerge in childhood; highly variable. Scoliosis or limb findings may affect mobility. [1][37][226]
Cardiovascular/urogenital findings Ventricular septal defect; aortic regurgitation; vesicoureteral reflux; genital or renal anomalies Congenital and variable, not defining findings. Their presence determines organ-specific monitoring and intervention. [1][3]
Newly reported adult manifestations Progressive ataxia, ophthalmoparesis, hypogonadotropic hypogonadism Reported in four affected siblings with a homozygous KIFBP variant; early-adulthood-onset progression was described for the first time. These findings must not be treated as established frequencies or the universal course. Published February 2024, online 30 October 2023; PMID: 37903629. [24]

Quality-of-life evidence: no GOSHS-specific EQ-5D, SF-36, or PROMIS cohort estimate was identified in these sources. Effects on continence, communication, mobility, learning, and caregiver burden are clinically plausible and individually important, but should not be presented as measured GOSHS outcomes. Orphanet explicitly recommends individualized developmental assessment to improve quality of life. [1][125]

4. Genetic and molecular information

Gene or variant class Evidence and knowledge-base interpretation
Causal gene: KIFBP (HGNC:23419; NCBI Gene:26128; OMIM:609367), 10q22.1 Also called KIAA1279 or KIF1BP in older papers. The associated phenotype is OMIM:609460. Use current approved symbol KIFBP, not SKI. [82][86][136]
Germline truncating variants Established recessive loss-of-function class; examples include c.268C>T (p.Arg90Ter), c.250G>T (p.Glu84Ter), c.604_605delAG (p.Arg202IlefsTer2), and exon deletions. The 2020 study reports its truncating patient variants as pathogenic by ACMG assessment. These are germline, not tumor-somatic drivers. [37][50]
Functionally investigated missense variants c.565C>T (p.Pro189Ser) was reported homozygous and pathogenic in the study, absent from its cited gnomAD exome and genome samples (AC 0 in each). c.68A>G (p.Glu23Gly) and c.1279A>G (p.Ser427Gly) occurred together in another patient, reduced expression in transfected cells, but were described as likely benign by the stated ACMG assessment; their role must not be upgraded to definitively pathogenic solely from that experiment. Reported 2020 gnomAD exome allele frequencies were 0.001707 and 2.44×10⁻⁵, respectively—not current universal frequencies. [37]
2024 case-level variants An August 2024 case report labeled homozygous c.1694_1695del (p.Glu565AlafsTer16) likely pathogenic; however, a related exon-7 deletion had been catalogued earlier, so it is not securely a novel recurrent allele. An October 2024 report described homozygous p.Glu98Ter but supplied inconsistent notation and lacked parental segregation testing. These reports broaden individual observations, not population estimates. [48][37][47]
Modifiers, epigenetics, chromosomal findings No validated GOSHS-specific modifier gene, protective variant, DNA-methylation signature, anticipation mechanism, or characteristic aneuploidy/translocation. Intragenic exon deletions are relevant structural KIFBP alleles; a chromosome-wide rearrangement is not the established cause. [37][51]

The 2020 authors found no clear variant-position/severity correlation and proposed a KIFBP-expression threshold as one explanation for variable presentation. That proposal is mechanistically plausible, not a validated prognostic biomarker or individual-patient prediction rule. PMID: 32939943. [37]

5. Environmental information

No environmental toxin, radiation exposure, smoking pattern, diet, occupational exposure, or infectious agent is established as a cause of GOSHS. Infections can instead occur downstream of complications: a 2024 patient report describes bacteremia during severe bowel/respiratory illness, which does not make the bacterium a cause of the genetic syndrome. Likewise, nutrition and access to surgical care can alter outcomes without changing genotype. No GOSHS-specific CheBI exposure or prophylactic chemical should be annotated as etiologic. [48][1]

6. Mechanism and pathophysiology

Ordered causal chain — demonstrated steps and inferences separated:

  1. Biallelic germline KIFBP loss-of-function leads to absent or reduced KIFBP protein; this is supported by patient genetics and variant-expression experiments. [37][151]
  2. Altered KIFBP abundance leads to dysregulation of interactions with selected kinesin motors and the actin–microtubule cytoskeleton; protein interactions and motor inhibition are experimentally demonstrated, but the exact effects of each patient allele in each developing tissue remain inferred. [234][211][234]
  3. Cytoskeletal/motor dysregulation leads to impaired neurite extension, axonal organization, and neuronal migration/survival in zebrafish and mouse perturbation models; extension of every modeled effect to human tissue is inferred. [92][225]
  4. Enteric branch: impaired development leads to delayed enteric neural-crest colonization in knockout mouse embryos; failure to populate the human distal bowel is the inferred species-sensitive step, resulting in aganglionosis → dysmotility, constipation or obstruction. Mouse and zebrafish bowel can be fully ganglionated at birth despite model defects. [38][151]
  5. Cerebral branch: impaired neuronal migration, dendritic growth, callosal axon extension, and survival leads to abnormal cortical organization/connectivity in models; their contribution to human polymicrogyria, callosal hypoplasia, microcephaly and developmental disability is inferred, not proven lesion by lesion. [225]
  6. Possible parallel cerebral branch: KIFBP depletion leads to midbody/cytokinesis defects in cultured dividing cells; reduced neural-progenitor production may lead to microcephaly, but that final link remains a hypothesis, not a demonstrated GOSHS patient mechanism. [224]

At the protein level, cryo-EM and biochemical work showed that KIFBP can bind and remodel selected kinesin motor heads, obstructing their microtubule-binding surface. This describes normal KIFBP molecular activity: loss of an inhibitor can have complex, context-dependent developmental consequences and should not be simplified to “all kinesin transport decreases.” PMID: 33252036 (2020); PMID: 34797717 (2021). [219][211]

Experimental detail and annotation candidates:

Mechanistic process Evidence level; cells and candidate ontology terms
Neuronal migration and morphogenesis Mouse in vivo / cultured neurons: embryonic cortical Kbp shRNA impaired migration; at postnatal day 6, 34.3% ± 4.9% of labeled cells remained ectopic in white matter, with reduced dendritic and callosal axon growth. Rescue by shRNA-resistant Kbp supported perturbation specificity. Candidate GO:0001764 neuron migration; GO:0007409 axonogenesis; CL:0002609 neuron of cerebral cortex. PMID: 31736709 (2019). [225][180][183]
Axonal microtubules and enteric development Zebrafish mutant / mouse knockout: axonal microtubule disorganization, reduced outgrowth and later degeneration in fish; delayed Sox10-positive enteric neural-crest-cell wavefront in mouse embryos. Candidate GO:0007017 microtubule-based process; CL:0002607 enteric neural crest cell. Fish: PMID: 18192286 (2008); mouse: PMID: 29192291 (2017). [92][151][179]
Cytokinesis and possible microcephaly mechanism Cultured-cell interaction/knockdown: KIFBP interacts with CITK, localizes to the midbody and is needed for normal midbody maturation and abscission. Abstract: “cytokinesis failure may contribute to the microcephaly phenotype”—the authors’ proposed clinical link. Candidate GO:0000910 cytokinesis. PMID: 34100550 (2021). [224][182]
Cell survival Mouse cortical-neuron perturbation: increased cleaved caspase-3 after Kbp knockdown; the initiating cause of apoptosis is unresolved. Candidate GO:0006915 apoptosis. PMID: 31736709. [225][182]
Mitochondrial/metabolic hypothesis Human fibroblasts: three reported truncating variants led to transcript decay and protein loss, yet respiratory-chain-complex activity was normal and KIFBP did not colocalize with mitochondria in control fibroblasts. Consequently, a primary oxidative-phosphorylation deficiency is not established. PMID: 23427148 (2013). [223]

Not established as disease mechanisms: a GOSHS-specific Wnt/MAPK/mTOR/PI3K-AKT cascade, immune or inflammatory primary lesion, disease-specific metabolomic/lipidomic or epigenomic signature, single-cell or spatial-transcriptomic disease atlas, or validated multi-omics diagnostic profile. Cultured-cell, imaging, proteomic-interaction, and cryo-EM results should not be relabeled as such profiles. [225][224][211]

7. Anatomical structures affected

Level Structures, localization, and suggested ontology terms
Primary organ/system Brain and nervous system—particularly cerebral cortex (UBERON:0000956), callosal pathways (UBERON:0002336), and peripheral nerves; distal large intestine/enteric nervous system when Hirschsprung disease occurs. Suggested cells: cortical neuron CL:0002609, enteric neural crest cell CL:0002607. [1][151][167][179]
Tissue/cell Cortical neural progenitors and migrating neurons; embryonic enteric neural-crest-derived cells, enteric ganglion cells, and developing autonomic axons. These are developmental populations, not evidence of an acquired inflammatory attack. [225][151]
Secondary involvement Eye/cornea, cardiac structures, kidneys/urinary tract, skeletal tissues, growth, and respiratory health variably; these are not required to establish the molecular diagnosis. [1][37]
Subcellular Cytoplasmic microtubules and actin-associated structures, axonal projections, and the midbody during cell division. Earlier mitochondrial-localization proposals are not uniformly supported by patient-fibroblast experiments. Appropriate GO cellular-component labels include cytoplasm, microtubule and midbody; assign exact accession IDs only after ontology-version validation. [223][224][211]
Lateralization No consistent right-versus-left disease localization is established. Cerebral malformations may be focal or generalized; a 2024 individual had bilaterally asymmetric periventricular volume loss. [1][47]

8. Temporal development

GOSHS begins prenatally as a developmental disorder; microcephaly and bowel obstruction may become apparent in the neonatal period, whereas intellectual disability becomes measurable through childhood. Facial differences can become more recognizable with age. The condition is lifelong rather than relapsing–remitting, but individual manifestations differ: congenital structural findings are generally persistent; bowel symptoms may improve after treatment; and progressive adult ataxia was newly reported in one family in 2023/2024. There is no validated mild/intermediate/end-stage classification, progression rate, or spontaneous-remission estimate. Prenatal neural and enteric development, neonatal bowel decompression, and early developmental support are the most evident intervention windows. [1][24][125]

9. Inheritance and population

Population or inheritance measure Best-supported assessment
Inheritance; recurrence Autosomal recessive. When both parents are heterozygous carriers of the familial pathogenic variants, each pregnancy has 25% affected, 50% carrier, 25% neither probabilities under the standard Mendelian model. [1][151]
Penetrance and expressivity Penetrance of the entire molecular syndrome is not precisely estimated. Hirschsprung disease has incomplete/variable expression: 24/34 reported individuals in the 2020 compilation had it, including families discordant for the bowel phenotype. Do not equate its penetrance with syndrome penetrance. [37]
Prevalence Orphanet estimates <1 per 1,000,000, equivalent to <0.1 per 100,000; ascertainment is uncertain. [1]
Incidence; carrier frequency; sex ratio No reliable disease-specific estimate identified. Hirschsprung disease’s general-population sex ratio must not be substituted for a GOSHS ratio. [1][125]
Geography, founder effects, anticipation, mosaicism Families from multiple geographic backgrounds have been reported; no validated worldwide founder allele, geographic incidence pattern, genetic anticipation, or quantified germline-mosaicism risk. Consanguinity aided identification in some families but is not required. [151][37]

10. Diagnostics

Clinical suspicion: microcephaly and developmental delay with Hirschsprung disease or cortical malformation—or the neural phenotype without Hirschsprung disease—warrant molecular evaluation. No standalone consensus diagnostic score or syndrome-specific circulating biomarker is established. [3][37]

Test or assessment Purpose and interpretation
KIFBP sequencing, with deletion/duplication assessment Molecular confirmation: identify and classify two pathogenic/likely pathogenic variants in trans, or a homozygous causal variant; examine segregation where possible. A phenotype alone or a single VUS does not establish the same molecular certainty. Targeted single-gene testing is reasonable when findings and familial variants are known. [37][151]
Neurodevelopmental/Hirschsprung or brain-malformation multigene panel; trio WES/WGS Useful when signs overlap other syndromes, Hirschsprung disease is absent, or the causal gene is unclear. WES identified an atypical 2020 patient and was used in 2024 case reports. WGS can assess coding and otherwise difficult-to-detect variants when earlier testing is unrevealing; a GOSHS-specific incremental diagnostic yield is unavailable. [37][48][47]
Copy-number analysis Include KIFBP exon-level deletions where indicated. Chromosomal microarray can evaluate broader developmental-delay differentials, but a normal CMA does not exclude sequence-level KIFBP disease. Routine karyotype/FISH, mitochondrial DNA, and repeat-expansion testing do not target the established cause. [37][51]
Rectal suction or surgical biopsy Confirm suspected Hirschsprung disease by adequate submucosal sampling and absent ganglion cells; appropriate histology may include H&E and calretinin/peripherin assessment. The underlying Hirschsprung guideline recommends histologic confirmation before pull-through. PMID: 32586397 (2020). [125][1]
Abdominal radiograph/contrast enema; anorectal manometry Evaluate obstruction, the likely transition zone, or an absent recto-anal inhibitory reflex; none replaces diagnostic rectal histology. [125][37]
Brain MRI; examination and targeted tests Characterize cortical, callosal and other malformations. Use developmental assessment, ophthalmology, growth/nutrition review, neurological examination ± nerve studies, EEG if seizures are suspected, and cardiac/renal assessment according to findings. These evaluate manifestations, not the causal genotype. [1][37][47]

Differential: especially ZEB2-related Mowat–Wilson syndrome and Baraitser–Winter syndrome for overlapping microcephaly/developmental and facial findings; consider other genetic causes of syndromic Hirschsprung disease and cortical malformations. Do not substitute the SKI-associated Shprintzen–Goldberg diagnosis, which has a different defining constellation. Molecular testing resolves ambiguous presentations. [1][3][21]

No validated GOSHS-specific RNA-seq, proteomic, metabolomic, methylation, or liquid-biopsy clinical diagnostic exists. Symptom-directed investigation in an affected child is distinct from population newborn screening. [37][1]

11. Outcome and prognosis

There are no reliable GOSHS-specific five- or ten-year survival rates, mortality rates, or life-expectancy estimates. Orphanet says long-term prognosis depends on the nature and severity of associated birth defects. Individual clinical reports document survival into adulthood—including a 28-year-old in the 2020 study and the adult-affected family reported in 2024—but cannot define average survival. A neonatal sibling death from postoperative sepsis in one family illustrates potential complication severity, not an estimated mortality rate. [1][37][24]

Long-term morbidity can involve developmental disability, speech difficulty, neuropathy, visual problems, and treated or persistent bowel dysfunction. Hirschsprung-specific guidance notes that constipation, incontinence, and enterocolitis can continue after surgery, but its outcome percentages must not be relabeled as GOSHS-specific rates. Neither variant position, KIFBP protein level, nor a serum marker is validated to forecast an individual GOSHS course. [1][125][37]

12. Treatment and real-world implementation

Treatment is complication-directed; no therapy is established to restore KIFBP function. The following are care approaches or, where indicated, extrapolations from Hirschsprung disease guidelines—not GOSHS-specific efficacy trials. [1][125]

Clinical need Intervention and suggested NCIt annotation Evidence, outcomes, and cautions
Confirmed Hirschsprung disease with obstruction Specialist bowel decompression, often saline rectal irrigations before definitive pull-through surgery; a stoma when decompression fails or complications require it. Suggested broad NCIt Surgical Procedure C15329; use a more specific, verified procedure term in a coded record. ERNICA recommends histologic confirmation, decompression and surgery once stable and growing. Its rectosigmoid guidance is not a GOSHS-specific trial; operative approach depends on disease extent and clinical status. [125][209]
Hirschsprung-associated enterocolitis Urgent surgical assessment; admitted patients may require IV fluids, broad-spectrum antibiotics and rectal washouts. Suggested broad NCIt Therapeutic Procedure C49236 where a more specific verified term is unavailable. Treat as a potentially severe downstream complication, not as an infectious cause of GOSHS. ERNICA guidance provides the management basis; drug selection depends on clinical setting. [125][181]
Developmental, speech and motor impairment Individualized early intervention, education, speech-language and physical/occupational rehabilitation. Candidate NCIt Physical Therapy C15302 and Speech Language Therapy C159273; verify local terminology version. Supported as individualized supportive care by Orphanet; no syndrome-specific response percentage exists. [1][208][209]
Ocular, cardiac, renal, skeletal, neurological complications Specialist assessment and manifestation-specific treatment; antiseizure medication only if clinically indicated, not universal prophylaxis. Orphanet recommends multidisciplinary care; there is no established GOSHS-specific drug or pharmacogenomic prescribing rule. [1][37]
Family planning Genetic counseling; candidate NCIt Genetic Counseling C15240. Confirm molecular findings and explain recessive reproductive risks, testing options, and phenotype variability. [1][208]

Investigational status: no disease-modifying drug, gene replacement/editing, RNA therapy, cell therapy, immunotherapy, genotype-directed medication, or established GOSHS-specific treatment response rate is supported by the retrieved clinical evidence. Orphanet’s website category count for “clinical trial(s)” is not evidence that an interventional KIFBP trial exists; no verified GOSHS-specific NCT identifier is supplied here. In vitro restoration of expression in an experimental model is not a patient therapy. [1][225]

13. Prevention

Prevention level Disease-specific interpretation
Primary There is no demonstrated vaccine, diet, exposure avoidance, or medication that prevents a child who inherits two causal variants from having GOSHS. For a family with known variants, offer counseling and discuss carrier, prenatal, or preimplantation genetic testing according to preferences and local practice; these are reproductive options, not treatment of an affected person. [1]
Secondary Targeted family testing and prompt assessment of neonatal stooling/obstruction, growth, vision and development can enable earlier recognition and management. Orphanet notes that prenatal molecular diagnosis is possible once familial variants are known; ultrasound suspicion alone is difficult and requires confirmation. No established population newborn-screening program is identified. [1][125]
Tertiary Manage confirmed bowel aganglionosis and promptly recognize enterocolitis; provide developmental support and monitoring tailored to actual cardiac, ocular, urogenital or skeletal abnormalities. Routine age-appropriate immunization remains ordinary healthcare, not GOSHS-specific prophylaxis. [1][125]

14. Other species and naturally occurring disease

Confirmed syndrome: humans, Homo sapiens (NCBI Taxon:9606). Ortholog-based experimental phenotypes have been studied in house mouse, Mus musculus (Taxon:10090; Kifbp, NCBI Gene:72320, MGI:1919570), and zebrafish, Danio rerio (Taxon:7955; kifbp, ZFIN:ZDB-GENE-070117-1989). These are models, not documented naturally occurring Goldberg–Shprintzen syndrome in an animal breed. No verified veterinary breed/VBO association, animal-to-human transmission, or zoonotic potential applies to this inherited disorder. [107][111][151][92]

15. Model organisms and research applications

Model Recapitulated findings, limitations, and application
CRISPR/Cas9 Kif1bp exon-1 knockout mice, two independent lines Model evidence: smaller brains and olfactory bulbs, thin anterior commissure, defective vagal/sympathetic innervation and delayed embryonic enteric-neural-crest colonization. Both lines died within 3–4 hours of birth with respiratory failure signs. Important limitation: ganglion cells occupied the entire bowel by birth—not a faithful human Hirschsprung phenotype; mice cannot model long-term adult human outcomes. Useful for developmental neurobiology and species comparison. PMID: 29192291 (2017); MGI:1919570. [151][107]
Zebrafish kifbp mutant, including ZFIN-listed kifbp^st23/st23^ Model evidence: reduced early axonal-outgrowth speed, disrupted axonal microtubules and later axonal degeneration. Limitation: no full human-like distal-bowel aganglionosis demonstrated. Useful for live imaging and axon-growth mechanisms. PMID: 18192286 (2008); ZFIN:ZDB-GENE-070117-1989. [92][111][151]
Mouse embryonic cortical shRNA and primary-neuron cultures Model evidence: migration, arborization, axonal-projection and apoptosis findings; shRNA-resistant Kbp rescued the tested migration phenotype. Limitation: partial, spatially restricted knockdown is not a patient’s lifelong biallelic genotype. Useful for distinguishing cell-development processes. PMID: 31736709 (2019). [225]
Human fibroblasts; SH-SY5Y and transfected HEK293T cells; dividing-cell assays In vitro evidence: patient-variant transcript/protein effects, actin–microtubule associations, neurite growth, and CITK/midbody function. Limitation: these assays do not replicate a developing human enteric or cerebral tissue or prove treatment efficacy. PMID: 23427148; PMID: 32939943; PMID: 34100550. [223][37][224]

Knowledge-base conclusion: annotate KIFBP biallelic germline loss of function as the established initiating cause; annotate developmental cytoskeletal, enteric-neural-crest and cortical-neuron processes with their model or in-vitro evidence provenance; and keep hypothesized cytokinesis-to-microcephaly and expression-threshold effects separate from demonstrated human causal steps. Record Hirschsprung disease as variable, not obligatory, and do not merge this entry with SKI-associated Shprintzen–Goldberg syndrome. [37][151][224][21]

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 18
Resolved 18
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 18
On topic 4
Off topic 2

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:33252036 (2 mentions) - The mechanism of kinesin inhibition by kinesin-binding protein.
  • shared terms: molecular, cell
  • PMC:PMC12905500 (1 mention) - Rules of the road: how to turn off kinesin motors.
  • shared terms: molecular, cell

Weighed against this report's own most characteristic terms: kifbp, disease, variant, gosh, developmental, established, goshs-specific, bowel, hirschsprung, phenotype, patient, molecular, genetic, syndrome, cause, individual, validated, cell, clinical, assessment.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

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

Outcome Count
Terms checked 36
Resolved 25
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 10

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • CL:0002609 (obsolete neuron of cerebral cortex) (2 mentions) - replaced by CL:0010012

Prefixes with no resolver

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

25 of 36 terms resolved to a current term; the rest could not be looked up either way.