Galloway-Mowat syndrome (GAMOS) is a rare genetic neuro-renal syndrome defined by the co-occurrence of early-onset nephrotic syndrome, typically steroid-resistant, with microcephaly and structural or developmental brain abnormalities. The parent syndrome is genetically heterogeneous and spans WDR73-related disease, KEOPS/t6A-biogenesis defects, nucleoporin-related disease, WDR4-related disease, and PRDM15-related cases. Across this spectrum, distinct upstream molecular lesions converge on podocyte injury, proteinuria, and impaired brain growth and neuronal maintenance.
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name: Galloway-Mowat syndrome
creation_date: '2026-04-14T08:01:21Z'
updated_date: '2026-05-31T10:45:00Z'
category: Mendelian
synonyms:
- GAMOS
- Galloway syndrome
- nephrosis-microcephaly syndrome
- microcephaly-hiatus hernia-nephrotic syndrome
description: >-
Galloway-Mowat syndrome (GAMOS) is a rare genetic neuro-renal syndrome defined
by the co-occurrence of early-onset nephrotic syndrome, typically
steroid-resistant, with microcephaly and structural or developmental brain
abnormalities. The parent syndrome is genetically heterogeneous and spans
WDR73-related disease, KEOPS/t6A-biogenesis defects, nucleoporin-related
disease, WDR4-related disease, and PRDM15-related cases. Across this spectrum,
distinct upstream molecular lesions converge on podocyte injury, proteinuria,
and impaired brain growth and neuronal maintenance.
disease_term:
preferred_term: Galloway-Mowat syndrome
term:
id: MONDO:0009627
label: Galloway-Mowat syndrome
parents:
- Genetic Kidney Disease
- Neurodevelopmental Disorder
notes: >-
This entry is curated as the syndrome-level parent/root. The pathophysiology
graph emphasizes convergent renal and neurodevelopmental consequences across
heterogeneous gene-defined subtypes rather than exhaustively modeling every
subtype-specific intermediate step. Although MONDO classifies the parent term
under autosomal recessive disease, the syndrome spectrum also includes the
X-linked LAGE3-related subtype.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Most recognized GAMOS subtypes, including WDR73-, KEOPS-, YRDC-, WDR4-,
NUP107-, NUP133-, and PRDM15-related disease, are inherited in an autosomal
recessive pattern.
evidence:
- reference: PMID:40533795
reference_title: Genetics and phenotypic heterogeneity of Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive genetic
disorder that is underrecognized.
explanation: >-
Recent review-level synthesis supports autosomal recessive inheritance for
the majority of the GAMOS spectrum.
- name: X-linked recessive
inheritance_term:
preferred_term: X-linked recessive inheritance
term:
id: HP:0001419
label: X-linked recessive inheritance
description: >-
GAMOS2 is caused by hemizygous or segregating pathogenic variants in LAGE3
and represents an X-linked branch of the broader GAMOS spectrum.
evidence:
- reference: PMID:36755238
reference_title: Diagnosis delay a family of Galloway-Mowat Syndrome caused by a classical splicing mutation of Lage3.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Seven male members died prematurely, and three of them suffered from
nephrotic syndrome, which is consistent with the x-linked gene map of the
disease.
explanation: >-
This LAGE3 family establishes an X-linked recessive subtype within the
broader GAMOS spectrum.
has_subtypes:
- name: GAMOS1
display_name: Galloway-Mowat syndrome 1 (WDR73-related)
classification: gene
description: >-
Classical WDR73-related subtype with postnatal microcephaly, severe
intellectual disability, cerebellar-predominant neurodegeneration, and
later or more variable nephrotic disease.
subtype_term:
preferred_term: Galloway-Mowat syndrome 1
term:
id: MONDO:0033005
label: Galloway-Mowat syndrome 1
genes:
- preferred_term: WDR73
term:
id: hgnc:25928
label: WDR73
evidence:
- reference: PMID:25466283
reference_title: "Loss-of-function mutations in WDR73 are responsible for microcephaly and steroid-resistant nephrotic syndrome: Galloway-Mowat syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular
subset of individuals presenting with late-onset nephrotic syndrome,
postnatal microcephaly, severe intellectual disability, and homogenous
brain MRI features.
explanation: >-
Defines the characteristic WDR73-related clinical subtype within the GAMOS
spectrum.
- name: GAMOS2
display_name: Galloway-Mowat syndrome 2, X-linked (LAGE3-related)
classification: gene
description: >-
X-linked LAGE3-related subtype within the KEOPS pathway, often with a milder
renal trajectory than other KEOPS-associated forms.
subtype_term:
preferred_term: Galloway-Mowat syndrome 2, X-linked
term:
id: MONDO:0033006
label: Galloway-Mowat syndrome 2, X-linked
genes:
- preferred_term: LAGE3
term:
id: hgnc:26058
label: LAGE3
evidence:
- reference: PMID:36755238
reference_title: Diagnosis delay a family of Galloway-Mowat Syndrome caused by a classical splicing mutation of Lage3.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The overall symptoms of the disease due to the LAGE3 mutation were mild
compared to other pathogenic genes.
explanation: >-
Supports LAGE3 as an X-linked GAMOS subtype with comparatively milder
manifestations in this reported family.
- name: GAMOS3
display_name: Galloway-Mowat syndrome 3 (OSGEP-related)
classification: gene
description: >-
OSGEP-related KEOPS subtype that typically presents with very early
steroid-resistant nephrotic syndrome, severe neurodevelopmental involvement,
and short survival.
subtype_term:
preferred_term: Galloway-Mowat syndrome 3
term:
id: MONDO:0033007
label: Galloway-Mowat syndrome 3
genes:
- preferred_term: OSGEP
term:
id: hgnc:18028
label: OSGEP
evidence:
- reference: PMID:30975089
reference_title: "Novel homozygous OSGEP gene pathogenic variants in two unrelated patients with Galloway-Mowat syndrome: case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These two cases, in conjunction with the findings of a literature review,
indicate that OSGEP pathogenic variants are associated with an earlier
onset of nephrotic syndrome and shorter life expectancy than WDR73
pathogenic variants.
explanation: >-
Supports a particularly severe OSGEP-related subtype within the GAMOS
spectrum.
- name: GAMOS4
display_name: Galloway-Mowat syndrome 4 (TP53RK-related)
classification: gene
description: >-
TP53RK-related KEOPS subtype contributing to the early neuro-renal GAMOS
spectrum through defective t6A-related biology.
subtype_term:
preferred_term: Galloway-Mowat syndrome 4
term:
id: MONDO:0033008
label: Galloway-Mowat syndrome 4
genes:
- preferred_term: TP53RK
term:
id: hgnc:16197
label: TP53RK
evidence:
- reference: PMID:31481669
reference_title: Defects in t(6)A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We recently identified autosomal recessive mutations in genes encoding
four of the five subunits of human KEOPS complex, namely LAGE3, OSGEP,
TP53RK, and TPRKB in patients with Galloway-Mowat syndrome (GAMOS,
OMIM#251300).
explanation: >-
This establishes TP53RK as one of the KEOPS-complex genes defining
GAMOS subtypes.
- name: GAMOS5
display_name: Galloway-Mowat syndrome 5 (TPRKB-related)
classification: gene
description: >-
TPRKB-related KEOPS subtype contributing to the early-onset
microcephaly-nephrotic syndrome spectrum.
subtype_term:
preferred_term: Galloway-Mowat syndrome 5
term:
id: MONDO:0033009
label: Galloway-Mowat syndrome 5
genes:
- preferred_term: TPRKB
term:
id: hgnc:24259
label: TPRKB
evidence:
- reference: PMID:31481669
reference_title: Defects in t(6)A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We recently identified autosomal recessive mutations in genes encoding
four of the five subunits of human KEOPS complex, namely LAGE3, OSGEP,
TP53RK, and TPRKB in patients with Galloway-Mowat syndrome (GAMOS,
OMIM#251300).
explanation: >-
This establishes TPRKB as one of the KEOPS-complex genes defining
GAMOS subtypes.
- name: GAMOS6
display_name: Galloway-Mowat syndrome 6 (WDR4-related)
classification: gene
description: >-
WDR4-related subtype linking abnormal cerebellar development and
neurodevelopmental failure to the broader GAMOS spectrum.
subtype_term:
preferred_term: Galloway-Mowat syndrome 6
term:
id: MONDO:0032691
label: Galloway-Mowat syndrome 6
genes:
- preferred_term: WDR4
term:
id: hgnc:12756
label: WDR4
evidence:
- reference: PMID:40533795
reference_title: Genetics and phenotypic heterogeneity of Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Although the five subunits that encode the KEOPS complex,
OSGEP/TP53RK/TPRKB/LAGE3/GON7, are known to cause Galloway-Mowat syndrome,
the mutation of the WDR73, WDR4, NUP107, NUP133, and PRDM15 genes can lead
to Galloway-Mowat syndrome, which makes the diagnosis more challenging.
explanation: >-
Recent review evidence explicitly places WDR4-related disease within the
parent GAMOS spectrum.
- name: GAMOS7
display_name: Galloway-Mowat syndrome 7 (NUP107-related)
classification: gene
description: >-
NUP107-related nucleoporin subtype with brain growth failure and
steroid-resistant nephrotic syndrome.
subtype_term:
preferred_term: Galloway-Mowat syndrome 7
term:
id: MONDO:0032692
label: Galloway-Mowat syndrome 7
genes:
- preferred_term: NUP107
term:
id: hgnc:29914
label: NUP107
evidence:
- reference: PMID:28280135
reference_title: Homozygous mutation in NUP107 leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
With the addition of these individuals, we implicate an allele-specific
critical role for NUP107 in the regulation of brain growth and a GAMOS-like
presentation.
explanation: >-
Supports NUP107 as a gene-specific GAMOS subtype with combined renal and
neurodevelopmental involvement.
- name: GAMOS8
display_name: Galloway-Mowat syndrome 8 (NUP133-related)
classification: gene
description: >-
NUP133-related nucleoporin subtype with microcephaly, brain atrophy, and
steroid-resistant nephrotic syndrome.
subtype_term:
preferred_term: Galloway-Mowat syndrome 8
term:
id: MONDO:0032693
label: Galloway-Mowat syndrome 8
genes:
- preferred_term: NUP133
term:
id: hgnc:18016
label: NUP133
evidence:
- reference: PMID:30427554
reference_title: Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These data indicate that the biallelic NUP133 loss-of-function mutation
causes GAMOS.
explanation: >-
Directly establishes NUP133 as a causal gene for a distinct GAMOS subtype.
- name: GAMOS9
display_name: Galloway-Mowat syndrome 9 (GON7-related)
classification: gene
description: >-
GON7-related KEOPS/t6A subtype that is generally milder than YRDC-related
disease, with later proteinuria and slower renal progression.
subtype_term:
preferred_term: Galloway-Mowat syndrome 9
term:
id: MONDO:0030471
label: Galloway-Mowat syndrome 9
genes:
- preferred_term: GON7
term:
id: hgnc:20356
label: GON7
evidence:
- reference: PMID:31481669
reference_title: Defects in t(6)A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we show that mutations in YRDC cause an extremely severe form of
GAMOS whereas mutations in GON7, encoding the fifth KEOPS subunit, lead to
a milder form of the disease.
explanation: >-
Defines GON7-related GAMOS as a milder KEOPS/t6A subtype than YRDC-related
disease.
- name: GAMOS10
display_name: Galloway-Mowat syndrome 10 (YRDC-related)
classification: gene
description: >-
YRDC-related t6A-biogenesis subtype with congenital or infantile
steroid-resistant nephrotic syndrome and severe early neurologic disease.
subtype_term:
preferred_term: Galloway-Mowat syndrome 10
term:
id: MONDO:0030476
label: Galloway-Mowat syndrome 10
genes:
- preferred_term: YRDC
term:
id: hgnc:28905
label: YRDC
evidence:
- reference: PMID:31481669
reference_title: Defects in t(6)A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we show that mutations in YRDC cause an extremely severe form of
GAMOS whereas mutations in GON7, encoding the fifth KEOPS subunit, lead to
a milder form of the disease.
explanation: >-
Defines YRDC-related disease as a particularly severe t6A-biogenesis
subtype within GAMOS.
- name: PRDM15-related
display_name: PRDM15-related GAMOS-type disease
classification: gene
description: >-
PRDM15-related allelic spectrum can produce either isolated nephrotic
syndrome or a GAMOS-type syndromic presentation with additional
neurodevelopmental and extracranial anomalies.
genes:
- preferred_term: PRDM15
term:
id: hgnc:13999
label: PRDM15
evidence:
- reference: PMID:33593823
reference_title: Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome.
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Variants in PRDM15 can cause either isolated nephrotic syndrome or a
GAMOS-type syndrome on an allelic basis.
explanation: >-
Supports PRDM15 as part of the broadened GAMOS allelic spectrum, while
also indicating phenotype divergence toward isolated nephrotic syndrome.
progression:
- phase: Severe congenital or infantile KEOPS/OSGEP disease
subtype: GAMOS3
age_range: Prenatal to infancy
notes: >-
Severe OSGEP-related disease can present prenatally or in early infancy
with microcephaly, pachygyria/hypomyelination, steroid-resistant nephrotic
syndrome, and death before two years.
evidence:
- reference: PMID:30558655
reference_title: "Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Overall, 6 patients from 5 different Taiwanese families were included in
our study; the patients had an identical OSGEP gene mutation (c.740G > A
transition) and all exhibited a uniform clinical phenotype with
early-onset nephrotic syndrome, craniofacial and skeletal dysmorphism,
primary microcephaly with pachygyria, and death before 2 years of age.
explanation: >-
Defines the early severe natural history of a recurrent OSGEP-linked
GAMOS cohort.
- phase: Severe YRDC versus milder GON7 t6A-biogenesis spectrum
notes: >-
YRDC-related disease is reported as extremely severe, whereas GON7-related
disease can be milder and compatible with preserved renal function or a
functioning kidney graft at follow-up.
evidence:
- reference: PMID:31481669
reference_title: Defects in t(6)A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we show that mutations in YRDC cause an extremely severe form of
GAMOS whereas mutations in GON7, encoding the fifth KEOPS subunit, lead to
a milder form of the disease.
explanation: >-
Directly supports subtype-specific severity differences within
t6A-biogenesis GAMOS.
- reference: PMID:31481669
reference_title: Defects in t(6)A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
most of the individuals carrying GON7 mutations were alive at last
follow-up, with either a functioning graft or with normal renal function
despite a mild to heavy proteinuria
explanation: >-
GON7 case follow-up supports the survivable end of the KEOPS-related
spectrum.
- phase: Later-onset WDR73 renal disease
subtype: GAMOS1
age_range: Childhood, often after neurologic presentation
notes: >-
WDR73-related disease often has postnatal progressive microcephaly and
cerebellar-predominant neurologic disease, with proteinuria/nephrotic
syndrome that can appear later in childhood and progress variably.
evidence:
- reference: PMID:27001912
reference_title: Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Microcephaly with nephrotic syndrome has historically been the major GMS
diagnostic criteria, yet in the WDR73-mutation positive group, eight out
of twelve patients had proteinuria with onsets varying from 2 years to 8
years of age (median age 5), later on average compared with the total of
>60 GMS cases reported in the literature [Sano et al., 1995].
explanation: >-
WDR73-positive cases support later and variable renal onset compared with
severe infantile GAMOS.
pathophysiology:
- name: KEOPS and t6A Biogenesis Deficiency
description: >-
GAMOS2-GAMOS5 and GAMOS9-GAMOS10 are caused by defects in KEOPS complex
components or the upstream YRDC enzyme. These lesions reduce t6A tRNA
modification, impair protein synthesis and cell survival, and converge on
early podocyte injury and impaired brain growth.
cell_types:
- preferred_term: podocyte
term:
id: CL:0000653
label: podocyte
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: tRNA modification
term:
id: GO:0006400
label: tRNA modification
modifier: DECREASED
evidence:
- reference: PMID:31481669
reference_title: Defects in t(6)A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We recently identified mutations in genes encoding four out of the five
KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a
clinically heterogeneous autosomal recessive disease characterized by
early-onset steroid-resistant nephrotic syndrome and microcephaly.
explanation: >-
Supports KEOPS-pathway defects as a major genetically heterogeneous cause
of the parent GAMOS syndrome.
- reference: PMID:31481669
reference_title: Defects in t(6)A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
mutations which alter t6A biosynthesis in human cells have an impact on
cell survival through decreased proliferation and protein synthesis,
ultimately leading to apoptosis.
explanation: >-
Directly supports defective t6A biogenesis as a mechanism causing reduced
cell survival in GAMOS-relevant cellular systems.
downstream:
- target: Podocyte Structural Failure
- target: Impaired Brain Growth and Neurodevelopment
- name: WDR73-Dependent Cytoskeletal and RNA-Processing Dysfunction
description: >-
GAMOS1 is caused by WDR73-linked perturbation of cell architecture, cell
survival, focal adhesion biology, Integrator-associated RNA processing, and
cell-cycle regulation in podocytes and neurons.
cell_types:
- preferred_term: podocyte
term:
id: CL:0000653
label: podocyte
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: focal adhesion assembly
term:
id: GO:0048041
label: focal adhesion assembly
modifier: DECREASED
- preferred_term: RNA processing
term:
id: GO:0006396
label: RNA processing
modifier: DYSREGULATED
- preferred_term: cell cycle G1/S phase transition
term:
id: GO:0044843
label: cell cycle G1/S phase transition
modifier: DYSREGULATED
evidence:
- reference: PMID:25466283
reference_title: "Loss-of-function mutations in WDR73 are responsible for microcephaly and steroid-resistant nephrotic syndrome: Galloway-Mowat syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
These data suggest that WDR73 plays a crucial role in the maintenance of
cell architecture and cell survival.
explanation: >-
WDR73 loss perturbs core cellular integrity and viability in GAMOS-linked
experimental systems.
- reference: PMID:33686175
reference_title: Disruption of pathways regulated by Integrator complex in Galloway-Mowat syndrome due to WDR73 mutations.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We also show that WDR73 suppression leads to altered expression of genes
encoding cell cycle regulatory proteins.
explanation: >-
Supports WDR73-linked cell-cycle dysregulation as part of the pathogenic
mechanism.
- reference: PMID:36290302
reference_title: WDR73 Depletion Destabilizes PIP4K2C Activity and Impairs Focal Adhesion Formation in Galloway-Mowat Syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
our study indicated that nephrotic syndrome in GAMOS1 is associated with
disruption of FA caused by WDR73 deficiency.
explanation: >-
Links WDR73 deficiency directly to impaired focal adhesion biology in the
renal arm of GAMOS1.
downstream:
- target: Podocyte Structural Failure
- target: Impaired Brain Growth and Neurodevelopment
- name: Nuclear Pore Dysfunction
description: >-
GAMOS7-GAMOS8 are NUP107- and NUP133-related forms that disrupt nucleoporin
function and spindle biology, converging on abnormal brain growth, glomerular
underdevelopment, and podocyte foot process injury.
cell_types:
- preferred_term: podocyte
term:
id: CL:0000653
label: podocyte
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: spindle assembly
term:
id: GO:0051225
label: spindle assembly
modifier: ABNORMAL
cellular_components:
- preferred_term: nuclear pore
term:
id: GO:0005643
label: nuclear pore
evidence:
- reference: PMID:30427554
reference_title: Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
NUP107 and NUP133 (nucleoporin 133kDa) are interacting subunits of the
nuclear pore complex in the nuclear envelope during interphase, and these
proteins are also involved in centrosome positioning and spindle assembly
during mitosis.
explanation: >-
Supports nuclear pore and spindle biology as the central mechanism for the
nucleoporin-related GAMOS subtypes.
- reference: PMID:28280135
reference_title: Homozygous mutation in NUP107 leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The founder mutation was associated with concomitant reduction in NUP107
protein and in the obligate binding partner NUP133 protein, as well as
density of nuclear pores in patient cells.
explanation: >-
Patient-cell evidence supports defective nuclear pore biology in
NUP107-related GAMOS.
- reference: PMID:30427554
reference_title: Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
A nup133-knockdown zebrafish model exhibited microcephaly, fewer neuronal
cells, underdeveloped glomeruli, and fusion of the foot processes of the
podocytes, which mimicked human GAMOS features.
explanation: >-
Model-organism evidence shows how nucleoporin loss converges on both brain
and kidney pathology in GAMOS.
downstream:
- target: Podocyte Structural Failure
- target: Impaired Brain Growth and Neurodevelopment
- name: WDR4-CUL4 Cerebellar Developmental Dysfunction
description: >-
GAMOS6 is WDR4-related disease linking CUL4 E3-ligase adaptor dysfunction to
impaired cerebellar development, granule-neuron progenitor cell-cycle
maintenance, gait phenotypes, and the broader GAMOS neurodevelopmental
spectrum.
genes:
- preferred_term: WDR4
term:
id: hgnc:12756
label: WDR4
biological_processes:
- preferred_term: cell cycle G1/S phase transition
term:
id: GO:0044843
label: cell cycle G1/S phase transition
modifier: DYSREGULATED
evidence:
- reference: PMID:36681682
reference_title: Wdr4 promotes cerebellar development and locomotion through Arhgap17-mediated Rac1 activation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Wdr4 deficiency in granule neuron progenitors (GNPs) not only reduces
foliation and the sizes of external and internal granular layers but also
compromises Purkinje neuron organization and the size of the molecular
layer, leading to locomotion defects.
explanation: >-
Model-organism evidence links WDR4 loss to cerebellar development and
locomotor abnormalities relevant to GAMOS6.
- reference: PMID:36681682
reference_title: Wdr4 promotes cerebellar development and locomotion through Arhgap17-mediated Rac1 activation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with mutations of WDR4, a substrate adaptor of the CUL4 E3 ligase
complex, develop cerebellar atrophy and gait phenotypes.
explanation: >-
Human disease context supports WDR4/CUL4 adaptor dysfunction as a
GAMOS6-relevant mechanism.
downstream:
- target: Impaired Brain Growth and Neurodevelopment
- name: Podocyte Structural Failure
description: >-
Despite upstream gene heterogeneity, the cross-subtype renal effector
phenotype converges on podocyte dysfunction with proteinuria, foot process
injury, and steroid-resistant nephrotic syndrome. Histopathology spans
minimal change disease, focal segmental glomerulosclerosis, collapsing
lesions, and diffuse mesangial sclerosis.
cell_types:
- preferred_term: podocyte
term:
id: CL:0000653
label: podocyte
biological_processes:
- preferred_term: focal adhesion assembly
term:
id: GO:0048041
label: focal adhesion assembly
modifier: DECREASED
locations:
- preferred_term: kidney
term:
id: UBERON:0002113
label: kidney
evidence:
- reference: PMID:11793093
reference_title: Podocyte proteins in Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Synaptopodin, GLEPP1, and nephrin expression was present, although reduced
in Galloway-Mowat syndrome.
explanation: >-
Direct human kidney-tissue evidence of podocyte structural protein
disturbance in GAMOS.
- reference: PMID:30427554
reference_title: Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
A nup133-knockdown zebrafish model exhibited microcephaly, fewer neuronal
cells, underdeveloped glomeruli, and fusion of the foot processes of the
podocytes, which mimicked human GAMOS features.
explanation: >-
Provides direct model support for podocyte foot process injury and
underdeveloped glomeruli as convergent renal lesions in GAMOS.
- name: Impaired Brain Growth and Neurodevelopment
description: >-
Brain growth failure is the shared cross-subtype neurologic effector
phenotype across the syndrome and includes microcephaly, brain atrophy, gyral
abnormalities, cerebellar involvement, hypotonia, developmental delay, and
seizures.
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: cell cycle G1/S phase transition
term:
id: GO:0044843
label: cell cycle G1/S phase transition
modifier: DYSREGULATED
locations:
- preferred_term: brain
term:
id: UBERON:0000955
label: brain
evidence:
- reference: PMID:30558655
reference_title: "Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Neurological findings consisted of microcephaly, hypotonia, developmental
delay, and seizures.
explanation: >-
Human case-series evidence supports the core neurodevelopmental syndrome
components.
- reference: PMID:30558655
reference_title: "Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Brain imaging studies all showed pachygyria and hypomyelination.
explanation: >-
Supports consistent structural brain abnormalities in a severe OSGEP-linked
GAMOS cohort.
- reference: PMID:30427554
reference_title: Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
A nup133-knockdown zebrafish model exhibited microcephaly, fewer neuronal
cells, underdeveloped glomeruli, and fusion of the foot processes of the
podocytes, which mimicked human GAMOS features.
explanation: >-
Model-organism evidence links impaired neuronal cell number to the shared
microcephalic phenotype.
phenotypes:
- name: Microcephaly
description: >-
Microcephaly is a defining feature of the syndrome and may be primary,
postnatal progressive, or accompanied by structural brain malformations.
phenotype_term:
preferred_term: Microcephaly
term:
id: HP:0000252
label: Microcephaly
evidence:
- reference: PMID:40533795
reference_title: Genetics and phenotypic heterogeneity of Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The phenotype is heterogeneous, but it is now widely accepted that
early-onset nephrotic syndrome (SRNS) and microcephaly with brain
malformation are characteristic features of Galloway-Mowat syndrome.
explanation: >-
Recent review-level synthesis identifies microcephaly with brain
malformation as a characteristic syndrome feature.
- name: Steroid-resistant nephrotic syndrome
description: >-
Early-onset proteinuric kidney disease is the renal hallmark of GAMOS and is
commonly steroid-resistant.
phenotype_term:
preferred_term: steroid-resistant nephrotic syndrome
term:
id: HP:0012588
label: Steroid-resistant nephrotic syndrome
evidence:
- reference: PMID:36755238
reference_title: Diagnosis delay a family of Galloway-Mowat Syndrome caused by a classical splicing mutation of Lage3.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Galloway-Mowat syndrome (GAMOS) is a group of rare hereditary diseases by
the combination of early onset steroid-resistant nephrotic syndrome (SRNS)
and microcephaly with brain anomalies caused by WDR73, LAGE3, OSGEP,
TP53RK, TPRKB, GON7, WDR4 or NUP133 mutations.
explanation: >-
Case-based literature synthesis identifies early steroid-resistant
nephrotic syndrome as a defining cross-subtype renal phenotype.
- name: Global developmental delay
description: >-
Developmental delay is common across reported gene-defined subtypes and
reflects the shared neurodevelopmental burden of the syndrome.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:30558655
reference_title: "Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Neurological findings consisted of microcephaly, hypotonia, developmental
delay, and seizures.
explanation: >-
Human case-series evidence supports developmental delay as a core
neurologic manifestation.
- name: Axial hypotonia
description: >-
Generalized or axial hypotonia is frequent in severe infantile forms and
accompanies developmental impairment.
phenotype_term:
preferred_term: Axial hypotonia
term:
id: HP:0008936
label: Axial hypotonia
evidence:
- reference: PMID:30975089
reference_title: "Novel homozygous OSGEP gene pathogenic variants in two unrelated patients with Galloway-Mowat syndrome: case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both patients showed a similar clinical presentation, with early-onset
nephrotic syndrome, microcephaly, brain atrophy, developmental delay,
axial hypotonia, and early fatality.
explanation: >-
Supports axial hypotonia as part of the severe infantile neurologic
presentation.
- name: Seizures
description: >-
Seizures occur in a subset of severe subtypes and accompany the structural
and developmental brain phenotype.
phenotype_term:
preferred_term: Seizures
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:30558655
reference_title: "Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Neurological findings consisted of microcephaly, hypotonia, developmental
delay, and seizures.
explanation: >-
Supports seizures as a recurring neurologic feature in severe OSGEP-linked
disease and the broader GAMOS spectrum.
- name: Pachygyria
description: >-
Gyral simplification or pachygyria is a recurrent imaging abnormality in
severe GAMOS subtypes.
phenotype_term:
preferred_term: Pachygyria
term:
id: HP:0001302
label: Pachygyria
evidence:
- reference: PMID:30558655
reference_title: "Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Brain imaging studies all showed pachygyria and hypomyelination.
explanation: >-
Provides direct imaging evidence for pachygyria in a severe OSGEP-related
cohort.
- name: Brain atrophy
description: >-
Cerebral or cerebellar atrophy is common in severe cases and contributes to
the progressive neurologic phenotype.
phenotype_term:
preferred_term: Brain atrophy
term:
id: HP:0012444
label: Brain atrophy
evidence:
- reference: PMID:30975089
reference_title: "Novel homozygous OSGEP gene pathogenic variants in two unrelated patients with Galloway-Mowat syndrome: case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both patients showed a similar clinical presentation, with early-onset
nephrotic syndrome, microcephaly, brain atrophy, developmental delay,
axial hypotonia, and early fatality.
explanation: >-
Supports brain atrophy as part of the severe neuroimaging phenotype in
GAMOS.
- name: Cerebellar atrophy
description: >-
Cerebellar atrophy is especially prominent in WDR73-related GAMOS and is
also linked to WDR4-related cerebellar development defects.
phenotype_term:
preferred_term: Cerebellar atrophy
term:
id: HP:0001272
label: Cerebellar atrophy
evidence:
- reference: PMID:27001912
reference_title: Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Cerebellar atrophy seen in MR imaging is also consistent within our
series, and correlated with symptoms of truncal ataxia, hypotonia, and
dysmetria in some individuals.
explanation: >-
WDR73-positive cases support cerebellar atrophy as a subtype-distinguishing
MRI feature.
- reference: PMID:36681682
reference_title: Wdr4 promotes cerebellar development and locomotion through Arhgap17-mediated Rac1 activation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with mutations of WDR4, a substrate adaptor of the CUL4 E3 ligase
complex, develop cerebellar atrophy and gait phenotypes.
explanation: >-
WDR4 literature supports cerebellar atrophy in the GAMOS6-related
spectrum.
- name: Thin corpus callosum
subtype: GAMOS1
description: Thin corpus callosum is a recurrent WDR73-related brain MRI feature.
phenotype_term:
preferred_term: Thin corpus callosum
term:
id: HP:0033725
label: Thin corpus callosum
evidence:
- reference: PMID:27001912
reference_title: Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Other common pathologies observed in cranial MRI were thinning of corpus
callosum in half of the patients and brain stem hypoplasia in 80%.
explanation: >-
WDR73 case synthesis supports thin corpus callosum as a frequent subtype
feature.
- name: Hypoplasia of the brainstem
subtype: GAMOS1
description: Brainstem hypoplasia is frequent in WDR73-related GAMOS.
phenotype_term:
preferred_term: Hypoplasia of the brainstem
term:
id: HP:0002365
label: Hypoplasia of the brainstem
evidence:
- reference: PMID:27001912
reference_title: Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Other common pathologies observed in cranial MRI were thinning of corpus
callosum in half of the patients and brain stem hypoplasia in 80%.
explanation: >-
WDR73 case synthesis supports brainstem hypoplasia as a frequent subtype
feature.
- name: CNS hypomyelination
subtype: GAMOS3
description: Hypomyelination is a recurrent MRI feature in severe OSGEP-related GAMOS.
phenotype_term:
preferred_term: CNS hypomyelination
term:
id: HP:0003429
label: CNS hypomyelination
evidence:
- reference: PMID:30558655
reference_title: "Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Brain imaging studies all showed pachygyria and hypomyelination.
explanation: >-
OSGEP-linked cases support CNS hypomyelination as part of the severe
imaging phenotype.
- name: Hiatus hernia
description: >-
Hiatal hernia is part of the classic syndrome description, but reported
WDR73-linked cases lacked this feature and should not be assumed to have it.
phenotype_term:
preferred_term: Hiatus hernia
term:
id: HP:0002036
label: Hiatus hernia
evidence:
- reference: PMID:27001912
reference_title: Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Galloway–Mowat syndrome (GMS; OMIM 251300) was first described in 1968 in
two siblings presenting with nephrotic syndrome, microcephaly, and hiatal
hernia [Galloway and Mowat, 1968].
explanation: >-
This supports hiatal hernia as a classic historical feature, not a
universal finding across molecular subtypes.
- name: Optic atrophy
description: Optic atrophy and other ocular malformations are reported in GAMOS.
phenotype_term:
preferred_term: Optic atrophy
term:
id: HP:0000648
label: Optic atrophy
evidence:
- reference: PMID:27001912
reference_title: Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Epilepsy was variable, as was optic atrophy.
explanation: >-
WDR73-positive case synthesis supports optic atrophy as a variable
subtype feature.
- name: Coarse facial features
description: Coarse facial features or dysmorphic facies are recurrent in some GAMOS subtypes.
phenotype_term:
preferred_term: Coarse facial features
term:
id: HP:0000280
label: Coarse facial features
evidence:
- reference: PMID:27001912
reference_title: Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Another interesting observation was the presence of coarse facial features
in five patients from three families (2027, 2286, and 2889) in our cohort.
explanation: >-
WDR73-related cases support coarse facial features as a recurrent subtype
manifestation.
- name: Proteinuria
description: Proteinuria can be present even when nephrotic syndrome timing and severity vary by subtype.
phenotype_term:
preferred_term: Proteinuria
term:
id: HP:0000093
label: Proteinuria
evidence:
- reference: PMID:36755238
reference_title: Diagnosis delay a family of Galloway-Mowat Syndrome caused by a classical splicing mutation of Lage3.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Due to the heterogeneity of the renal phenotype, regular proteinuria
screening is recommended for all patients diagnosed with GAMOS.
explanation: >-
The recommendation for cross-subtype proteinuria screening supports
proteinuria as an important variable renal manifestation.
- name: Focal segmental glomerulosclerosis
description: FSGS, including collapsing FSGS, is a reported renal-biopsy pattern in GAMOS.
phenotype_term:
preferred_term: Focal segmental glomerulosclerosis
term:
id: HP:0000097
label: Focal segmental glomerulosclerosis
evidence:
- reference: PMID:27001912
reference_title: Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Four of these patients had renal biopsies, two with collapsing type focal
segmental glomerulosclerosis (FSGS), one with non-collapsing FSGS, and one
diffuse mesangial sclerosis pathology.
explanation: >-
WDR73-positive renal biopsies directly document FSGS as a renal
histopathology pattern.
- name: Diffuse mesangial sclerosis
description: Diffuse mesangial sclerosis is another reported GAMOS renal-biopsy pattern.
phenotype_term:
preferred_term: Diffuse mesangial sclerosis
term:
id: HP:0001967
label: Diffuse mesangial sclerosis
evidence:
- reference: PMID:27001912
reference_title: Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Four of these patients had renal biopsies, two with collapsing type focal
segmental glomerulosclerosis (FSGS), one with non-collapsing FSGS, and one
diffuse mesangial sclerosis pathology.
explanation: >-
WDR73-positive renal biopsies directly document diffuse mesangial
sclerosis as a renal histopathology pattern.
diagnosis:
- name: Clinical neuro-renal syndrome recognition
presence: Early-onset SRNS or proteinuria with microcephaly and brain malformation.
description: >-
GAMOS should be suspected when nephrotic-range proteinuria or
steroid-resistant nephrotic syndrome co-occurs with microcephaly and
structural brain abnormalities.
diagnosis_term:
preferred_term: neurodevelopmental assessment
term:
id: MAXO:0035041
label: neurodevelopmental assessment
evidence:
- reference: PMID:40533795
reference_title: Genetics and phenotypic heterogeneity of Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The phenotype is heterogeneous, but it is now widely accepted that
early-onset nephrotic syndrome (SRNS) and microcephaly with brain
malformation are characteristic features of Galloway-Mowat syndrome.
explanation: >-
Recent review synthesis defines the clinical dyad used to recognize
GAMOS.
- name: Gene panel or exome sequencing
presence: Biallelic or hemizygous pathogenic variants in a GAMOS-associated gene.
description: >-
Molecular workup should cover KEOPS/t6A genes, WDR73, WDR4, NUP107, NUP133,
PRDM15, and LAGE3/X-linked analysis, with exome sequencing useful when
targeted panels are unrevealing.
diagnosis_term:
preferred_term: gene panel testing
term:
id: MAXO:0001615
label: gene panel testing
evidence:
- reference: PMID:40533795
reference_title: Genetics and phenotypic heterogeneity of Galloway-Mowat syndrome.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Although the five subunits that encode the KEOPS complex,
OSGEP/TP53RK/TPRKB/LAGE3/GON7, are known to cause Galloway-Mowat syndrome,
the mutation of the WDR73, WDR4, NUP107, NUP133, and PRDM15 genes can lead
to Galloway-Mowat syndrome, which makes the diagnosis more challenging.
explanation: >-
The gene heterogeneity supports broad panel or exome-based molecular
testing.
- reference: PMID:27001912
reference_title: Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Taking a “sequence first” approach, we screened this cohort with exome
sequencing, and identified patients with homozygous deleterious WDR73
mutations.
explanation: >-
Demonstrates exome sequencing utility in identifying WDR73-related GAMOS
within a neurodevelopmental cohort.
- name: Brain MRI for subtype patterning
presence: Cerebellar atrophy, corpus-callosum/brainstem abnormalities, pachygyria, or hypomyelination.
description: >-
Brain MRI supports diagnosis and subtype patterning: WDR73 disease has
cerebellar atrophy with corpus-callosum and brainstem abnormalities, whereas
severe OSGEP disease is associated with pachygyria and hypomyelination.
diagnosis_term:
preferred_term: MRI of the brain
term:
id: MAXO:0000427
label: MRI of the brain
evidence:
- reference: PMID:27001912
reference_title: Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Other common pathologies observed in cranial MRI were thinning of corpus
callosum in half of the patients and brain stem hypoplasia in 80%.
explanation: >-
WDR73 cases support corpus-callosum and brainstem MRI clues.
- reference: PMID:30558655
reference_title: "Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Brain imaging studies all showed pachygyria and hypomyelination.
explanation: >-
OSGEP cases support pachygyria and hypomyelination as severe-subtype MRI
clues.
- name: Proteinuria and kidney function testing
presence: Proteinuria, nephrotic syndrome, or reduced kidney function.
description: >-
Proteinuria screening and kidney-function assessment are important because
renal onset can be variable and may lag behind neurologic presentation in
some subtypes.
diagnosis_term:
preferred_term: urine protein measurement
term:
id: MAXO:0000851
label: urine protein measurement
evidence:
- reference: PMID:36755238
reference_title: Diagnosis delay a family of Galloway-Mowat Syndrome caused by a classical splicing mutation of Lage3.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Due to the heterogeneity of the renal phenotype, regular proteinuria
screening is recommended for all patients diagnosed with GAMOS.
explanation: >-
Supports proteinuria screening across genetically heterogeneous GAMOS.
- name: Kidney biopsy for renal histopathology
presence: FSGS, diffuse mesangial sclerosis, minimal-change pattern, or related glomerular lesions.
description: >-
Kidney biopsy can document the glomerular lesion pattern when clinically
indicated, but histopathology is descriptive and not a standalone molecular
subtype assignment.
diagnosis_term:
preferred_term: biopsy of kidney
term:
id: MAXO:0001121
label: biopsy of kidney
evidence:
- reference: PMID:27001912
reference_title: Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Renal biopsies have revealed various histopathology including diffuse
mesangial sclerosis, focal segmental glomerulosclerosis, mesangial
proliferation, increased mesangial matrix, and minimal change disease
[Meyers et al., 1999; Steiss et al., 2005; Sartelet et al., 2008].
explanation: >-
Supports renal biopsy as a way to characterize GAMOS glomerular
histopathology.
- reference: PMID:40533795
reference_title: Genetics and phenotypic heterogeneity of Galloway-Mowat syndrome.
supports: PARTIAL
evidence_source: OTHER
snippet: >-
Although glomerular injury is frequently documented in biopsies of
patients with Galloway-Mowat syndrome, there is currently no reliable
evidence that renal biopsy has diagnostic or prognostic value.
explanation: >-
Qualifies biopsy findings as supportive/descriptive rather than
definitive for diagnosis or prognosis.
- name: Prenatal imaging and familial variant testing
presence: Prenatal microcephaly, growth restriction, oligohydramnios, gyral/myelin abnormalities, or known familial variant.
description: >-
In families with prior affected children or known familial variants,
prenatal ultrasound, fetal MRI, genetic counseling, and mutation analysis
can support early prenatal diagnosis.
diagnosis_term:
preferred_term: fetal MRI
term:
id: MAXO:0001478
label: fetal MRI
evidence:
- reference: PMID:30558655
reference_title: "Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Prenatal ultrasound findings, fetal MRI, genetic counseling, and mutation
analysis may be useful for an early prenatal diagnosis.
explanation: >-
OSGEP cohort evidence supports prenatal imaging and variant testing in
at-risk pregnancies.
treatments:
- name: Genetic counseling
description: >-
Early molecular diagnosis supports family counseling, recurrence-risk
assessment, and prenatal testing or imaging in future pregnancies.
treatment_term:
preferred_term: genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
evidence:
- reference: PMID:30558655
reference_title: "Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Prenatal ultrasound findings, fetal MRI, genetic counseling, and mutation
analysis may be useful for an early prenatal diagnosis.
explanation: >-
Supports genetic counseling as a practical management step for affected
families and future pregnancies.
- name: Proteinuria and kidney-function surveillance
description: >-
Regular urine protein and kidney-function monitoring is important across the
GAMOS spectrum because renal onset and severity vary by gene and subtype.
treatment_term:
preferred_term: urine protein measurement
term:
id: MAXO:0000851
label: urine protein measurement
target_phenotypes:
- preferred_term: Proteinuria
term:
id: HP:0000093
label: Proteinuria
- preferred_term: Steroid-resistant nephrotic syndrome
term:
id: HP:0012588
label: Steroid-resistant nephrotic syndrome
evidence:
- reference: PMID:36755238
reference_title: Diagnosis delay a family of Galloway-Mowat Syndrome caused by a classical splicing mutation of Lage3.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Due to the heterogeneity of the renal phenotype, regular proteinuria
screening is recommended for all patients diagnosed with GAMOS.
explanation: >-
Directly supports ongoing proteinuria screening as a GAMOS management
action.
- name: Renal failure management and dialysis bridge
description: >-
Children who progress to end-stage renal disease require nephrology-led
renal replacement planning, which may include dialysis as a bridge or
alternative to transplant depending on neurologic severity and subtype.
treatment_term:
preferred_term: renal replacement therapy
term:
id: MAXO:0000600
label: renal replacement therapy
target_phenotypes:
- preferred_term: Chronic kidney disease
term:
id: HP:0012622
label: Chronic kidney disease
- preferred_term: Steroid-resistant nephrotic syndrome
term:
id: HP:0012588
label: Steroid-resistant nephrotic syndrome
evidence:
- reference: PMID:31481669
reference_title: Defects in t(6)A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
SRNS is typically detected in the first months of life and most often
rapidly progresses to end-stage renal disease (ESRD) within a few months;
however, there are rarer cases with preserved renal function in adulthood.
explanation: >-
Natural-history evidence supports planning for renal failure management,
while the citation does not test a specific dialysis strategy.
- name: Seizure-directed pharmacotherapy
description: >-
Seizures should be managed symptomatically by neurology with antiseizure
medication individualized to seizure type and comorbid renal status.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
target_phenotypes:
- preferred_term: Seizures
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:27001912
reference_title: Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: EEG at 4 years documented generalized epileptiform activity, treated with carbamazepine therapy.
explanation: >-
Case-level WDR73 evidence documents antiseizure pharmacotherapy use, but
does not establish a subtype-specific preferred drug.
- name: Nutrition and growth support
description: >-
Nutrition assessment and growth support are part of supportive care for
infants and children with poor feeding, growth restriction, nephrotic
syndrome, and severe neurodevelopmental disability.
treatment_term:
preferred_term: nutrition assessment
term:
id: MAXO:0000624
label: nutrition assessment
evidence:
- reference: PMID:27001912
reference_title: Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: She was referred for evaluation at 6 months of age due to weakness and poor feeding.
explanation: >-
Poor feeding in a WDR73-related case supports nutrition-focused supportive
assessment, although not a treatment trial.
- reference: PMID:36755238
reference_title: Diagnosis delay a family of Galloway-Mowat Syndrome caused by a classical splicing mutation of Lage3.
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
We present the clinical and genetic features of a two-year-old boy with
early nephrotic syndrome, microcephaly, growth retardation hypotonia and
hypothyroidism.
explanation: >-
Growth retardation and nephrotic disease support nutrition/growth
monitoring as supportive management.
- name: Neurodevelopmental rehabilitation
description: >-
Early physical, occupational, and speech/communication supports should be
matched to hypotonia, motor impairment, developmental delay, and severe
intellectual disability.
treatment_term:
preferred_term: occupational therapy
term:
id: MAXO:0001351
label: occupational therapy
target_phenotypes:
- preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
- preferred_term: Axial hypotonia
term:
id: HP:0008936
label: Axial hypotonia
evidence:
- reference: PMID:30558655
reference_title: "Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Neurological findings consisted of microcephaly, hypotonia, developmental
delay, and seizures.
explanation: >-
Core neurologic disability supports rehabilitative care, though the
citation is natural-history evidence rather than a therapy trial.
- name: Kidney transplantation
description: >-
Selected children who survive to end-stage kidney disease may undergo kidney
transplantation, but this treats only the renal component and reported
success is subtype-dependent.
treatment_term:
preferred_term: kidney transplantation
term:
id: MAXO:0010039
label: organ transplantation
located_in:
preferred_term: kidney
term:
id: UBERON:0002113
label: kidney
notes: >-
Human evidence is strongest in the milder GON7-related subtype and should
not be interpreted as disease-modifying for the neurologic component.
evidence:
- reference: PMID:31481669
reference_title: Defects in t(6)A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
most of the individuals carrying GON7 mutations were alive at last
follow-up, with either a functioning graft or with normal renal function
despite a mild to heavy proteinuria
explanation: >-
Supports the feasibility of renal transplantation in selected milder
GON7-related cases after renal failure, while not implying benefit for the
neurologic phenotype.
MONDO:0009627 Galloway-Mowat syndromeWDR73LAGE3, OSGEP, TP53RK, TPRKB, GON7, YRDCNUP107, NUP133WDR4, PRDM15Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive genetic disorder that is underrecognized.
The phenotype is heterogeneous, but it is now widely accepted that early-onset nephrotic syndrome (SRNS) and microcephaly with brain malformation are characteristic features of Galloway-Mowat syndrome.
Galloway-Mowat syndrome (GAMOS) is a group of rare hereditary diseases by the combination of early onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies caused by WDR73, LAGE3, OSGEP, TP53RK, TPRKB, GON7, WDR4 or NUP133 mutations.
Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment.
These data suggest that WDR73 plays a crucial role in the maintenance of cell architecture and cell survival.
Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features.
We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly.
Here we show that mutations in YRDC cause an extremely severe form of GAMOS whereas mutations in GON7, encoding the fifth KEOPS subunit, lead to a milder form of the disease.
mutations which alter t6A biosynthesis in human cells have an impact on cell survival through decreased proliferation and protein synthesis, ultimately leading to apoptosis.
Overall, 6 patients from 5 different Taiwanese families were included in our study; the patients had an identical OSGEP gene mutation (c.740G > A transition) and all exhibited a uniform clinical phenotype with early-onset nephrotic syndrome, craniofacial and skeletal dysmorphism, primary microcephaly with pachygyria, and death before 2 years of age.
Neurological findings consisted of microcephaly, hypotonia, developmental delay, and seizures.
Brain imaging studies all showed pachygyria and hypomyelination.
All patients developed early-onset nephrotic syndrome. The proteinuria was steroid-resistant and eventually resulted in renal function impairment.
These two cases, in conjunction with the findings of a literature review, indicate that OSGEP pathogenic variants are associated with an earlier onset of nephrotic syndrome and shorter life expectancy than WDR73 pathogenic variants.
Seven male members died prematurely, and three of them suffered from nephrotic syndrome, which is consistent with the x-linked gene map of the disease.
The overall symptoms of the disease due to the LAGE3 mutation were mild compared to other pathogenic genes.
Due to the heterogeneity of the renal phenotype, regular proteinuria screening is recommended for all patients diagnosed with GAMOS.
The founder mutation was associated with concomitant reduction in NUP107 protein and in the obligate binding partner NUP133 protein, as well as density of nuclear pores in patient cells.
With the addition of these individuals, we implicate an allele-specific critical role for NUP107 in the regulation of brain growth and a GAMOS-like presentation.
NUP107 and NUP133 (nucleoporin 133kDa) are interacting subunits of the nuclear pore complex in the nuclear envelope during interphase, and these proteins are also involved in centrosome positioning and spindle assembly during mitosis.
A nup133-knockdown zebrafish model exhibited microcephaly, fewer neuronal cells, underdeveloped glomeruli, and fusion of the foot processes of the podocytes, which mimicked human GAMOS features.
These data indicate that the biallelic NUP133 loss-of-function mutation causes GAMOS.
Synaptopodin, GLEPP1, and nephrin expression was present, although reduced in Galloway-Mowat syndrome.
our study indicated that nephrotic syndrome in GAMOS1 is associated with disruption of FA caused by WDR73 deficiency.
Although the five subunits that encode the KEOPS complex, OSGEP/TP53RK/TPRKB/LAGE3/GON7, are known to cause Galloway-Mowat syndrome, the mutation of the WDR73, WDR4, NUP107, NUP133, and PRDM15 genes can lead to Galloway-Mowat syndrome, which makes the diagnosis more challenging.
Variants in PRDM15 can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis.
Patients with mutations of WDR4, a substrate adaptor of the CUL4 E3 ligase complex, develop cerebellar atrophy and gait phenotypes.
Prenatal ultrasound findings, fetal MRI, genetic counseling, and mutation analysis may be useful for an early prenatal diagnosis.
most of the individuals carrying GON7 mutations were alive at last follow-up, with either a functioning graft or with normal renal function despite a mild to heavy proteinuria
Parent/root framing:
The parent MONDO term already has explicit subtype children (GAMOS1 through GAMOS10) and recent review evidence confirms broader genetic heterogeneity. The disorder YAML should therefore represent the syndrome as the root disease and keep gene-defined subtypes inside has_subtypes.
Inheritance modeling:
The literature still commonly describes GAMOS as autosomal recessive, but LAGE3 creates a real X-linked branch. The YAML should therefore keep both Autosomal recessive and X-linked recessive inheritance entries, with a note explaining the spectrum.
Mechanism modeling: The most defensible disease graph is convergent:
tRNA modificationWDR73 defects -> disrupted focal adhesion, RNA processing, and cell-cycle controlNUP107 / NUP133 defects -> nuclear pore and spindle dysfunctionall of the above -> podocyte failure + impaired brain growth
Phenotype selection: The safest high-signal phenotype set for the initial disease-level entry is:
HP:0000252 MicrocephalyHP:0012588 Steroid-resistant nephrotic syndromeHP:0001263 Global developmental delayHP:0008936 Axial hypotoniaHP:0001250 SeizureHP:0001302 PachygyriaHP:0012444 Brain atrophy
Treatment selection: The literature supports conservative treatment assertions only:
MAXO:0000079 genetic counselingMAXO:0010039 organ transplantation, localized to kidney, only as subtype-limited renal rescue after ESRDMONDO:0009627 Galloway-Mowat syndromeMONDO:0033005 Galloway-Mowat syndrome 1MONDO:0033006 Galloway-Mowat syndrome 2, X-linkedMONDO:0033007 Galloway-Mowat syndrome 3MONDO:0033008 Galloway-Mowat syndrome 4MONDO:0033009 Galloway-Mowat syndrome 5MONDO:0032691 Galloway-Mowat syndrome 6MONDO:0032692 Galloway-Mowat syndrome 7MONDO:0032693 Galloway-Mowat syndrome 8MONDO:0030471 Galloway-Mowat syndrome 9MONDO:0030476 Galloway-Mowat syndrome 10
Cell and anatomy terms:
CL:0000653 podocyteCL:0000540 neuronUBERON:0002113 kidneyUBERON:0000955 brain
Biological process and component terms:
GO:0006400 tRNA modificationGO:0006396 RNA processingGO:0048041 focal adhesion assemblyGO:0044843 cell cycle G1/S phase transitionGO:0051225 spindle assemblyGO:0005643 nuclear pore
Treatment terms:
MAXO:0000079 genetic counselingMAXO:0010039 organ transplantation