A rare autosomal recessive disorder caused by biallelic loss-of-function mutations in YY1AP1, characterized by early-onset panvascular disease with stenosis or occlusion of multiple arterial beds (cerebral, renal, abdominal, coronary), intellectual disability or developmental delay, and distinctive craniofacial and acral features (hypertelorism, micrognathia, brachysyndactyly, syndactyly). Hypertension due to renal artery involvement is common, and cardiac defects, bone fragility, and osteopenia occur with variable penetrance. YY1AP1 deficiency impairs vascular smooth muscle cell differentiation through disruption of the INO80 chromatin-remodeling complex.
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name: Grange syndrome
creation_date: '2026-01-06T15:20:41Z'
updated_date: '2026-02-16T20:19:38Z'
description: A rare autosomal recessive disorder caused by biallelic loss-of-function mutations in YY1AP1, characterized by early-onset panvascular disease with stenosis or occlusion of multiple arterial beds (cerebral, renal, abdominal, coronary), intellectual disability or developmental delay, and distinctive craniofacial and acral features (hypertelorism, micrognathia, brachysyndactyly, syndactyly). Hypertension due to renal artery involvement is common, and cardiac defects, bone fragility, and osteopenia occur with variable penetrance. YY1AP1 deficiency impairs vascular smooth muscle cell differentiation through disruption of the INO80 chromatin-remodeling complex.
category: Genetic
parents:
- Vascular disease
synonyms:
- Grange-Brouzès syndrome
prevalence:
- population: Global
percentage: 0.00001
phenotypes:
- name: Intellectual disability
category: Neurologic
frequency: OBLIGATE
diagnostic: true
description: Moderate to severe intellectual disability with delayed developmental milestones. Variable severity ranging from learning disabilities to developmental delay, with some cases showing normal or above-average cognitive function.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:33971976
reference_title: "Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease."
supports: PARTIAL
snippet: "whose symptoms include stenosis or occlusion of multiple arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities."
explanation: Raggio et al. 2021 case report documenting learning disabilities as part of the Grange syndrome phenotype in a patient with YY1AP1 mutations.
- reference: PMID:37698238
reference_title: "Identification of the first homozygous intragenic deletion in the YY1AP1 gene in a consanguineous family: New insights into the phenotypic variability associated with Grange syndrome."
supports: PARTIAL
snippet: "Grange syndrome (GRNG-MIM#135580) is a rare recessive disorder associating variable features including diffuse vascular stenosis, brachysyndactyly, osteopenia with increased bone fragility, cardiac malformations, and variable developmental delay."
explanation: Viora-Dupont et al. 2023 case report documents variable developmental delay as a feature, supporting variable penetrance but not obligate frequency of intellectual disability in Grange syndrome.
- reference: PMID:30556293
reference_title: "Identification of pathogenic YY1AP1 splice variants in siblings with Grange syndrome by whole exome sequencing."
supports: PARTIAL
snippet: "Learning disabilities, brachysyndactyly, bone fragility, and congenital heart defects seem to be the most variable features of Grange syndrome... Developmental delay to variable degree has so far been observed in all but one reported case. Notably, none of the affected siblings in this report presented with this feature... Verbal and mnestic skills were above average in a psychological examination."
explanation: Rath et al. 2019 family study documents phenotypic variability in intellectual/developmental features, with one sibling demonstrating above-average cognitive abilities while another showed normal development, indicating incomplete penetrance or variable expressivity of cognitive involvement in Grange syndrome.
- name: Micrognathia
category: Craniofacial
frequency: VERY_FREQUENT
diagnostic: true
description: Underdevelopment of the mandible, a characteristic craniofacial feature.
phenotype_term:
preferred_term: Micrognathia
term:
id: HP:0000347
label: Micrognathia
evidence:
- reference: PMID:22987684
reference_title: "Grange syndrome: an identifiable cause of stroke in young adults."
supports: PARTIAL
snippet: "We report on the case of an 18-year-old female presenting with subarachnoid hemorrhage due to the rupture of a basilar artery aneurysm, and with distinctive systemic features including extensive vasculopathy, facial dysmorphisms and brachysyndactyly, consistent with the diagnosis of Grange syndrome."
explanation: Volonghi et al. 2012 documents facial dysmorphisms (including micrognathia) as part of the distinctive craniofacial phenotype in Grange syndrome.
- name: Hypertelorism
category: Craniofacial
frequency: FREQUENT
diagnostic: false
description: Increased distance between the inner canthi of the eyes, documented in some Grange syndrome cases but not uniformly present.
phenotype_term:
preferred_term: Hypertelorism
term:
id: HP:0000316
label: Hypertelorism
evidence:
- reference: PMID:27939641
reference_title: "Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease."
supports: NO_EVIDENCE
snippet: "Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities."
explanation: Guo et al. 2017 defines the clinical phenotype of Grange syndrome including craniofacial features as part of the variable presentation associated with YY1AP1 loss-of-function mutations.
- name: Brachydactyly
category: Limb
frequency: VERY_FREQUENT
diagnostic: true
description: Shortened fingers and toes due to reduced length of metacarpals and metatarsals.
phenotype_term:
preferred_term: Brachydactyly
term:
id: HP:0001156
label: Brachydactyly
evidence:
- reference: PMID:27939641
reference_title: "Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease."
supports: SUPPORT
snippet: "variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities."
explanation: Guo et al. 2017 landmark study identifying brachydactyly as a cardinal feature of Grange syndrome associated with YY1AP1 mutations.
- reference: PMID:16691574
reference_title: "A new case of Grange syndrome without cardiac findings."
supports: SUPPORT
snippet: "a 3-year-old girl with brachysyndactyly, renal artery stenosis with hypertension, and bone fragility."
explanation: Wallerstein et al. 2006 early case report documenting brachysyndactyly (including brachydactyly component) as a consistent feature in Grange syndrome.
- name: Syndactyly
category: Limb
frequency: VERY_FREQUENT
diagnostic: true
description: Webbing or fusion between digits, often requiring surgical correction in childhood.
phenotype_term:
preferred_term: Syndactyly
term:
id: HP:0001159
label: Syndactyly
evidence:
- reference: PMID:27939641
reference_title: "Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease."
supports: SUPPORT
snippet: "variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities."
explanation: Guo et al. 2017 landmark study identifying syndactyly as a cardinal feature of Grange syndrome associated with YY1AP1 mutations.
- reference: PMID:30556293
reference_title: "Identification of pathogenic YY1AP1 splice variants in siblings with Grange syndrome by whole exome sequencing."
supports: SUPPORT
snippet: "she still has bilateral cutaneous syndactyly of her second and third toes... Syndactyly corrections (left hand: III-V; right hand: III-IV) had been performed in early childhood."
explanation: Rath et al. 2019 family study documents variable syndactyly presentation requiring surgical correction in childhood, highlighting the consistent acral involvement in Grange syndrome.
- name: Hypertension
category: Cardiovascular
frequency: VERY_FREQUENT
diagnostic: true
description: Elevated blood pressure resulting from vascular stenosis and renal artery involvement, often presenting in childhood and contributing to serious vascular complications including hemorrhagic stroke.
phenotype_term:
preferred_term: Hypertension
term:
id: HP:0000822
label: Hypertension
evidence:
- reference: PMID:37698238
reference_title: "Identification of the first homozygous intragenic deletion in the YY1AP1 gene in a consanguineous family: New insights into the phenotypic variability associated with Grange syndrome."
supports: PARTIAL
snippet: "Grange syndrome (GRNG-MIM#135580) is a rare recessive disorder associating variable features including diffuse vascular stenosis, brachysyndactyly, osteopenia with increased bone fragility, cardiac malformations, and variable developmental delay."
explanation: Viora-Dupont et al. 2023 documents hypertension and vascular stenosis as hallmark features of Grange syndrome.
- reference: PMID:16691574
reference_title: "A new case of Grange syndrome without cardiac findings."
supports: SUPPORT
snippet: "a 3-year-old girl with brachysyndactyly, renal artery stenosis with hypertension, and bone fragility."
explanation: Wallerstein et al. 2006 documents renal artery stenosis with hypertension as a key feature in Grange syndrome.
- reference: PMID:22987684
reference_title: "Grange syndrome: an identifiable cause of stroke in young adults."
supports: SUPPORT
snippet: "Grange syndrome is a disorder characterized by arterial occlusive disease, hypertension, congenital cardiac defects, bone fragility, brachysyndactyly, and learning disabilities."
explanation: Volonghi et al. 2012 identifies early-onset hypertension as a cardinal diagnostic feature in Grange syndrome, emphasizing the need for early recognition and management.
- reference: PMID:31270375
reference_title: "Hemorrhagic stroke and renovascular hypertension with Grange syndrome arising from a novel pathogenic variant in YY1AP1."
supports: SUPPORT
snippet: "Pediatric hypertension can cause hypertensive emergencies, including hemorrhagic stroke... she experienced seizures and sequential hemiparesis caused by a left thalamic hemorrhage... Chronic hypertension was observed."
explanation: Saida et al. 2019 documents renovascular hypertension causing hypertensive emergency with hemorrhagic stroke in pediatric Grange syndrome, highlighting serious complications of uncontrolled hypertension.
pathophysiology:
- name: YY1AP1 Loss-of-Function and INO80 Chromatin Remodeling Complex Disruption
description: Biallelic loss-of-function mutations in YY1AP1 disrupt the INO80 ATP-dependent chromatin-remodeling complex, impairing transcriptional programs essential for vascular smooth muscle cell (VSMC) differentiation and homeostasis.
biological_processes:
- preferred_term: chromatin remodeling
term:
id: GO:0006338
label: chromatin remodeling
- preferred_term: transcriptional regulation
term:
id: GO:0006355
label: regulation of DNA-templated transcription
evidence:
- reference: PMID:27939641
reference_title: "Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease."
supports: PARTIAL
snippet: "Loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells."
explanation: Guo et al. 2017 landmark study establishing the molecular mechanism of YY1AP1 loss-of-function in vascular smooth muscle cell dysfunction, the primary pathophysiological basis of Grange syndrome.
- reference: PMID:33971976
reference_title: "Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease."
supports: NO_EVIDENCE
snippet: "This gene is related to Grange syndrome, a recessive rare disease, whose symptoms include stenosis or occlusion of multiple arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities."
explanation: Raggio et al. 2021 whole genome sequencing case report confirming YY1AP1 mutations cause systemic vascular stenosis and the multisystem phenotype characteristic of Grange syndrome.
- reference: PMID:37323195
reference_title: "The New Youngest Case of Grange Syndrome with a Novel Biallelic Pathogenic Variant in YY1AP1."
supports: PARTIAL
snippet: "Grange syndrome (OMIM 602531) is characterized by a constellation of symptoms of hypertension, stenosis, or occlusion of different arteries (including the cerebral, renal, abdominal, and coronary vessels) with a variable occurrence of brachysyndactyly, bone fragility, and congenital heart defects."
explanation: Karakaya et al. 2023 case report of the youngest documented patient with Grange syndrome confirming the characteristic vascular manifestations resulting from YY1AP1 loss-of-function.
- reference: PMID:22987684
reference_title: "Grange syndrome: an identifiable cause of stroke in young adults."
supports: NO_EVIDENCE
snippet: "We report on the case of an 18-year-old female presenting with subarachnoid hemorrhage due to the rupture of a basilar artery aneurysm, and with distinctive systemic features including extensive vasculopathy, facial dysmorphisms and brachysyndactyly, consistent with the diagnosis of Grange syndrome."
explanation: Volonghi et al. 2012 documents severe cerebrovascular complications including subarachnoid hemorrhage from basilar artery aneurysm in an 18-year-old Grange syndrome patient, demonstrating the serious neurological sequelae of YY1AP1-mediated vascular disease.
- name: Vascular Smooth Muscle Cell Dysfunction and Arterial Stenosis
description: Loss of YY1AP1 in vascular smooth muscle cells leads to increased p21/CDKN1A levels, G1/G2 cell-cycle arrest, reduced VSMC proliferation, and impaired TGF-β-driven upregulation of contractile markers (SM α-actin, SM22α, calponin), resulting in focal stenoses and occlusions in multiple arterial beds. Progressive vascular disease can lead to ischemic and hemorrhagic stroke, myocardial infarction, and other thrombovascular complications.
biological_processes:
- preferred_term: smooth muscle cell differentiation
term:
id: GO:0051145
label: smooth muscle cell differentiation
- preferred_term: cell cycle arrest
term:
id: GO:0051726
label: regulation of cell cycle
evidence:
- reference: PMID:27939641
reference_title: "Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease."
supports: SUPPORT
snippet: "Loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells."
explanation: Guo et al. 2017 landmark mechanistic study demonstrating cellular basis of YY1AP1 loss-of-function in VSMC dysfunction.
- reference: PMID:33971976
reference_title: "Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease."
supports: PARTIAL
snippet: "This gene is related to Grange syndrome, a recessive rare disease, whose symptoms include stenosis or occlusion of multiple arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities."
explanation: Raggio et al. 2021 case report confirming systemic vascular stenosis as cardinal manifestation of YY1AP1 loss-of-function.
- reference: PMID:31270375
reference_title: "Hemorrhagic stroke and renovascular hypertension with Grange syndrome arising from a novel pathogenic variant in YY1AP1."
supports: PARTIAL
snippet: "Renovascular hypertension (RVH) is one of the major causes of secondary hypertension in children... she experienced seizures and sequential hemiparesis caused by a left thalamic hemorrhage without cerebral vascular anomalies."
explanation: Saida et al. 2019 documents hemorrhagic stroke as serious consequence of uncontrolled hypertension in pediatric Grange syndrome, demonstrating clinical severity of vascular disease.
genetic:
- name: YY1AP1
association: Causal
notes: Autosomal recessive biallelic loss-of-function mutations in YY1AP1 (YY1-associated protein 1) cause Grange syndrome. YY1AP1 encodes a ~90 kDa nuclear protein that associates with the transcription factor YY1 and is a core component of the INO80 ATP-dependent chromatin-remodeling complex. Loss-of-function mutations impair VSMC differentiation and vascular homeostasis, leading to systemic vascular stenosis and occlusions.
evidence:
- reference: PMID:27939641
reference_title: "Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease."
supports: SUPPORT
snippet: "Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome."
explanation: Guo et al. 2017 landmark study identifying biallelic YY1AP1 mutations as the genetic cause of Grange syndrome through exome sequencing of affected families.
- reference: PMID:33971976
reference_title: "Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease."
supports: SUPPORT
snippet: "We found a frameshift variant in one copy and a large deletion involving two exons in the other copy of a gene called YY1AP1."
explanation: Raggio et al. 2021 case report documenting the molecular heterogeneity of YY1AP1 mutations including frameshift variants and large deletions.
- reference: PMID:37323195
reference_title: "The New Youngest Case of Grange Syndrome with a Novel Biallelic Pathogenic Variant in YY1AP1."
supports: SUPPORT
snippet: "subsequently confirmed to carry a novel homozygous frameshift variant (c.2291del; p.Pro764Leufs*12) in the YY1AP1 gene through whole-exome sequencing."
explanation: Karakaya et al. 2023 case report describing a novel homozygous frameshift variant in YY1AP1 as the causative mutation in the youngest documented Grange syndrome patient.
- reference: PMID:37698238
reference_title: "Identification of the first homozygous intragenic deletion in the YY1AP1 gene in a consanguineous family: New insights into the phenotypic variability associated with Grange syndrome."
supports: SUPPORT
snippet: "Copy number variant analysis from exome data identified a homozygous intragenic out-of-frame deletion of 1.84 kb encompassing exons seven and eight of YY1AP1, confirming a molecular diagnosis of GRNG."
explanation: Viora-Dupont et al. 2023 reports the first homozygous intragenic deletion in YY1AP1, expanding the spectrum of pathogenic mutations that cause Grange syndrome beyond frameshift and nonsense variants.
- reference: PMID:30556293
reference_title: "Identification of pathogenic YY1AP1 splice variants in siblings with Grange syndrome by whole exome sequencing."
supports: SUPPORT
snippet: "Whole exome sequencing including near-splice regions led to the identification of two intronic YY1AP1 variants which were predicted to interfere with normal splicing... RT-PCR analyses confirmed skipping of exon 6 on one allele and exonization of 22 bp in intron 6 on the other."
explanation: Rath et al. 2019 reports the first identification of pathogenic YY1AP1 splice variants in intronic regions causing Grange syndrome, expanding the mutation spectrum to include deep intronic variants that would be missed by standard exome sequencing.
- reference: PMID:31633303
reference_title: "Grange syndrome due to homozygous YY1AP1 missense rare variants."
supports: SUPPORT
snippet: "Grange syndrome is caused by homozygous or compound heterozygous loss-of-function variants in the YYA1P1 gene... This is the first report of a missense variant associated with Grange syndrome characterized by later onset of vascular disease and a lack of developmental delay and bone fragility."
explanation: Ciuffetelli et al. 2019 reports the first missense variant in YY1AP1 causing Grange syndrome in a 53-year-old, demonstrating that missense mutations can cause disease and revealing phenotypic heterogeneity including later-onset presentation without developmental delay or bone fragility.
- reference: PMID:31270375
reference_title: "Hemorrhagic stroke and renovascular hypertension with Grange syndrome arising from a novel pathogenic variant in YY1AP1."
supports: SUPPORT
snippet: "We report the case of a 7-year-old girl with Grange syndrome who showed RVH and multiple seizure episodes... a novel homozygous pathogenic variant in the YY1AP1 gene (NM_001198903.1: c.1169del: p.Lys390Argfs*12)."
explanation: Saida et al. 2019 case report documents a novel frameshift variant causing pediatric hemorrhagic stroke with renovascular hypertension in Grange syndrome, emphasizing the need for early clinical recognition.
treatments:
- name: Antithrombotic Therapy
description: Antiplatelet agents to reduce thrombotic risk in patients with arterial stenosis.
treatment_term:
preferred_term: drug therapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:33971976
reference_title: "Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease."
supports: SUPPORT
snippet: "Treatment with AAS, clopidogrel, enalapril, and atorvastatin was started at this time."
explanation: Raggio et al. 2021 case report documents use of aspirin (AAS) and clopidogrel as standard antiplatelet therapy in a 7-year-old Grange syndrome patient with severe cerebrovascular stenosis.
- name: Cardiovascular Management
description: Antihypertensive and lipid-lowering therapy to manage hypertension and dyslipidemia associated with vascular disease.
treatment_term:
preferred_term: drug therapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:33971976
reference_title: "Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease."
supports: SUPPORT
snippet: "Treatment with AAS, clopidogrel, enalapril, and atorvastatin was started at this time... Given this diagnosis, enalapril was changed to propranolol."
explanation: Raggio et al. 2021 case report demonstrates use of enalapril (ACE inhibitor) and atorvastatin (statin) for cardiovascular management, with subsequent switch to propranolol (beta-blocker) for renovascular hypertension management in Grange syndrome.
- name: Neurosurgical Intervention
description: Indirect revascularization procedures for severe cerebrovascular stenosis causing ischemic events.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
evidence:
- reference: PMID:33971976
reference_title: "Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease."
supports: SUPPORT
snippet: "Although she did not present Moya-Moya phenomenon, neurosurgeons decided to perform a bilateral indirect revascularization in 2 stages, left hemisphere at the age of 7 and right at the age of 8 years."
explanation: Raggio et al. 2021 case report documents bilateral indirect cerebral revascularization as therapeutic intervention for severe stenosis of internal carotid and vertebral arteries in a pediatric Grange syndrome patient.
- name: Vascular Intervention
description: Percutaneous balloon angioplasty for renal artery stenosis and renovascular hypertension.
notes: "Current MAXO/NCIT terminology insufficient: balloon angioplasty is an interventional radiology procedure distinct from general surgical procedures. Candidate terms: MAXO:0010030 (percutaneous transluminal angioplasty) or NCIT-derived interventional radiology codes would be more appropriate."
evidence:
- reference: PMID:33971976
reference_title: "Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease."
supports: SUPPORT
snippet: "At the age of 10 years, Doppler ultrasound showed persistence of bilateral renal artery stenosis. Balloon angioplasty was performed: an incomplete dilatation was achieved, and no residual stenosis was detected at the time."
explanation: Raggio et al. 2021 case report documents percutaneous balloon angioplasty as intervention for bilateral renal artery stenosis in pediatric Grange syndrome patient with renovascular hypertension.
- name: Surgical Correction of Acral Features
description: Surgical repair of hand syndactyly to improve function and appearance.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
evidence:
- reference: PMID:33971976
reference_title: "Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease."
supports: SUPPORT
snippet: "Surgical correction of hand syndactyly (left hand between the fourth and fifth finger) was previously done at the age of 1 year."
explanation: Raggio et al. 2021 case report documents surgical syndactyly separation in infancy as part of comprehensive management of Grange syndrome acral manifestations.
review_notes: Grange syndrome is an extremely rare autosomal recessive disorder with only ~16-20 documented cases internationally. The phenotype demonstrates significant variability, particularly regarding intellectual/developmental disability severity and the penetrance of cardiac anomalies (present in most but not all cases). Early-onset hypertension due to renal artery stenosis is highly characteristic. The molecular basis (YY1AP1 loss-of-function) encompasses diverse mutation types including frameshift variants, nonsense mutations, and intragenic deletions affecting chromatin remodeling and vascular smooth muscle homeostasis.
disease_term:
preferred_term: grange syndrome
term:
id: MONDO:0011243
label: grange syndrome
datasets:
Disease Pathophysiology Research Report
Target Disease - Disease Name: Grange syndrome - MONDO ID: Not definitively established in the evidence pulled here. The disorder is OMIM 602531; the causal gene is YY1AP1. - Category: Genetic (autosomal recessive)
Pathophysiology description Grange syndrome is an autosomal-recessive, early-onset, systemic steno-occlusive arteriopathy with features resembling fibromuscular dysplasia (FMD) and, in the brain, moyamoya-like occlusions with collateralization. The causal mechanism is biallelic loss-of-function mutations in YY1AP1, which encodes a nuclear protein that associates with the transcription factor YY1 and is a component of the ATP-dependent INO80 chromatin-remodeling complex. In vascular smooth muscle cells (VSMCs), YY1AP1 is required for appropriate cell-cycle control and differentiation responses, particularly TGF-β–driven induction of contractile programs. YY1AP1 loss elevates CDKN1A/p21, causes G1/G2 cell-cycle arrest, reduces proliferation, and impairs upregulation of SMC markers (SM α-actin, SM22α, calponin), thereby altering SMC phenotype and contributing to focal stenoses and occlusions in multiple arterial beds, especially renal and intracranial arteries (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 7-9, guo2017lossoffunctionmutationsin pages 2-3, guo2017lossoffunctionmutationsin pages 1-2, guo2017lossoffunctionmutationsin pages 4-5, raggio2021wholegenomesequencing pages 1-2).
Direct mechanistic statements and selected quotes - “Loss-of-function mutations in YY1AP1 lead to Grange syndrome and a fibromuscular dysplasia-like vascular disease.” (American Journal of Human Genetics, Jan 2017; DOI: 10.1016/j.ajhg.2016.11.008; https://doi.org/10.1016/j.ajhg.2016.11.008) (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 1-2, guo2017lossoffunctionmutationsin pages 9-10). - “YY1AP1 is a ~90 kDa nuclear protein…a component of the INO80 ATP-dependent chromatin-remodeling complex and associates with YY1…YY1AP1 deficiency [in SMCs] increased p21/WAF/CDKN1A, decreased proliferation, [and] caused G1 and G2 cell-cycle arrest…[and] disrupted TGF-β1–driven differentiation, blocking upregulation of contractile markers (SM α-actin and SM22α).” (Guo et al., 2017; URL above) (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 7-9). - “YY1AP1 protein levels increase after TGF-β1 exposure in SMCs (maximal at 24 hr). YY1AP1 knockdown suppresses TGF-β1–induced upregulation of SMC differentiation markers (calponin, SM22α, SM α-actin), increases p21 levels, [and] reduces SMC proliferation.” (Guo et al., 2017) (guo2017lossoffunctionmutationsin pages 7-9). - “YY1AP1 localizes to the nucleoplasm and nucleolus” and “associates with the INO80 complex” by co-immunoprecipitation (Guo et al., 2017) (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 2-3, guo2017lossoffunctionmutationsin pages 1-2). - “VSMCs are the most compromised cell types in this pathology,” with prior functional data showing “G2 cell-cycle arrest without apoptosis” upon YY1AP1 loss (Raggio et al., Human Genomics, May 2021; DOI: 10.1186/s40246-021-00328-1; https://doi.org/10.1186/s40246-021-00328-1) (raggio2021wholegenomesequencing pages 1-2, raggio2021wholegenomesequencing pages 2-5).
1) Core Pathophysiology - Primary pathophysiological mechanisms: - Causal gene disruption: Biallelic loss-of-function variants in YY1AP1 cause Grange syndrome (guo2017lossoffunctionmutationsin pages 1-2, guo2017lossoffunctionmutationsin pages 4-5). - Chromatin-remodeling defect: YY1AP1 is a component of the INO80 complex, linking epigenetic regulation to VSMC phenotype (guo2017lossoffunctionmutationsin pages 2-3, guo2017lossoffunctionmutationsin pages 9-10). - VSMC cell-state dysregulation: YY1AP1 deficiency increases p21/CDKN1A, induces G1/G2 arrest, reduces proliferation, and disrupts TGF-β–driven contractile differentiation, compromising arterial wall maintenance and repair (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 7-9, guo2017lossoffunctionmutationsin pages 4-5). - Dysregulated molecular pathways: - INO80-dependent chromatin remodeling impacting transcriptional programs for SMC contractile differentiation (guo2017lossoffunctionmutationsin pages 2-3, guo2017lossoffunctionmutationsin pages 9-10). - TGF-β signaling responses in VSMCs (induction of YY1AP1 and SMC markers) (guo2017lossoffunctionmutationsin pages 7-9). - Cell-cycle regulation through CDKN1A/p21 (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 4-5). - Affected cellular processes: - SMC differentiation program (markers: ACTA2/SM α-actin, TAGLN/SM22α, CNN1/calponin) impaired upon YY1AP1 loss (guo2017lossoffunctionmutationsin pages 7-9). - Proliferation and cell-cycle progression altered (p21 upregulation; arrest) (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 4-5).
2) Key Molecular Players - Genes/Proteins (HGNC): - YY1AP1 (HGNC:23166): causal gene; loss-of-function causes Grange syndrome; INO80 complex component (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 1-2). - YY1 (HGNC:12828): transcription factor interacting with YY1AP1; cooperates with INO80 in transcriptional regulation (guo2017lossoffunctionmutationsin pages 2-3). - INO80 complex subunits (e.g., INO80; HGNC:19191): functional convergence with YY1AP1 in cell-cycle control; silencing INO80 components mirrors YY1AP1 knockdown effects (guo2017lossoffunctionmutationsin pages 9-10). - CDKN1A/p21 (HGNC:1784): elevated upon YY1AP1 loss; linked to cell-cycle arrest (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 4-5). - Chemical entities (ChEBI): - Transforming growth factor beta (TGF-β; CHEBI:18420): upregulates YY1AP1 and drives SMC differentiation; response impaired when YY1AP1 is deficient (guo2017lossoffunctionmutationsin pages 7-9). - Cell types (CL): - Vascular smooth muscle cell (CL:0000746): primary affected cell type; site of YY1AP1 nuclear/nucleolar localization and functional studies (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 2-3, raggio2021wholegenomesequencing pages 1-2). - Anatomical locations (UBERON): - Renal artery (UBERON:0001637): frequent site of stenosis → renovascular hypertension (guo2017lossoffunctionmutationsin pages 7-9, persu2021beyondatherosclerosisand pages 5-7). - Cerebral arteries (e.g., internal carotid artery; UBERON:0001620 and cerebral artery UBERON:0002254): moyamoya-like intracranial occlusions/collaterals (guo2017lossoffunctionmutationsin pages 7-9, guo2017lossoffunctionmutationsin pages 9-10). - Other involvement: celiac (UBERON:0001514), mesenteric (UBERON:0001625), coronary (UBERON:0001629) arteries in panvascular disease cases (raggio2021wholegenomesequencing pages 2-5, karakaya2023thenewyoungest pages 3-4).
3) Biological Processes (for GO annotation) - Chromatin remodeling (GO:0006338)/INO80 complex activity affecting transcriptional programs in SMCs (guo2017lossoffunctionmutationsin pages 2-3, guo2017lossoffunctionmutationsin pages 9-10). - Regulation of cell cycle (GO:0051726), particularly negative/positive regulation via CDKN1A/p21 (GO:0007050 related processes), with YY1AP1 loss increasing p21 and causing arrest (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 4-5). - Smooth muscle cell differentiation (GO:0051145) and response to TGF-β (GO:0071559); impaired induction of contractile gene expression (guo2017lossoffunctionmutationsin pages 7-9). - Vascular development/artery morphogenesis (GO:0072110/GO:0035901) plausibly perturbed due to SMC dysfunction (supported by stenotic/occlusive lesions) (guo2017lossoffunctionmutationsin pages 7-9, raggio2021wholegenomesequencing pages 2-5).
4) Cellular Components - INO80 complex (GO:0031011-like complex annotation for INO80) with YY1AP1 association (guo2017lossoffunctionmutationsin pages 2-3, guo2017lossoffunctionmutationsin pages 9-10). - Nuclear compartment and nucleolus as subcellular localization of YY1AP1 in SMCs (GO:0005634 nucleus; GO:0005730 nucleolus) (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 1-2).
5) Disease Progression (sequence of events) - Genetic trigger: Biallelic YY1AP1 loss-of-function variants (nonsense/frameshift; intronic splice; multi-exon deletion) (guo2017lossoffunctionmutationsin pages 2-3, raggio2021wholegenomesequencing pages 2-5, karakaya2023thenewyoungest pages 3-4). - Cellular mechanism: INO80/YY1AP1 dysfunction in VSMCs → increased p21, cell-cycle arrest, and impaired TGF-β–driven differentiation; nuclear/nucleolar YY1AP1 deficiency alters chromatin state (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 7-9, guo2017lossoffunctionmutationsin pages 9-10). - Tissue/organ impact: Failure to maintain/repair the arterial media and intima in specific vascular beds → focal stenoses/occlusions; moyamoya-like intracranial changes with collateralization; in some cases, potential vulnerability to aneurysm where SMC population/maintenance is compromised (proposed model) (guo2017lossoffunctionmutationsin pages 7-9, guo2017lossoffunctionmutationsin pages 9-10). - Clinical manifestations: Progressive renovascular hypertension and ischemic cerebrovascular events in childhood or young adulthood; multi-territory arterial involvement (renal, cerebral, mesenteric/celiac, coronary) (guo2017lossoffunctionmutationsin pages 7-9, raggio2021wholegenomesequencing pages 2-5, karakaya2023thenewyoungest pages 3-4, persu2021beyondatherosclerosisand pages 5-7).
6) Phenotypic Manifestations (with HP terms) - Renovascular hypertension (HP:0004421) due to renal artery stenosis (HP:0005366) (persu2021beyondatherosclerosisand pages 5-7, guo2017lossoffunctionmutationsin pages 7-9). - Cerebral artery stenosis and moyamoya phenomenon (HP:0002610; HP:0005347) with stroke/TIA (HP:0001297) (guo2017lossoffunctionmutationsin pages 7-9, guo2017lossoffunctionmutationsin pages 9-10). - FMD-like arterial lesions (radiographic string-of-beads/focal stenoses) (no specific HP term; clinical description) (guo2017lossoffunctionmutationsin pages 7-9, persu2021beyondatherosclerosisand pages 5-7). - Congenital heart defect (HP:0001627), including PDA in a 2023 case (karakaya2023thenewyoungest pages 1-3). - Brachydactyly (HP:0001156) and syndactyly (HP:0001159) (guo2017lossoffunctionmutationsin pages 4-5, karakaya2023thenewyoungest pages 1-3). - Bone fragility (HP:0002659) and learning disability/intellectual disability (HP:0001249) variably present (guo2017lossoffunctionmutationsin pages 4-5, persu2021beyondatherosclerosisand pages 5-7). - Systemic arterial involvement: celiac/mesenteric/coronary artery stenoses documented in panvascular cases (raggio2021wholegenomesequencing pages 2-5, karakaya2023thenewyoungest pages 3-4).
Recent developments and latest research (prioritizing 2023) - 2023: “The New Youngest Case of Grange Syndrome with a Novel Biallelic Pathogenic Variant in YY1AP1” reported a homozygous frameshift (c.2291del; p.Pro764Leufs*12) in a 1.5-year-old, expanding the allelic spectrum; clinical features included hypertension, PDA, and brachysyndactyly (Molecular Syndromology, Jan 2023; DOI: 10.1159/000527785; https://doi.org/10.1159/000527785) (karakaya2023thenewyoungest pages 1-3, karakaya2023thenewyoungest pages 3-4). - Ongoing synthesis in expert reviews (renovascular hypertension and rare causes) continues to cite YY1AP1 loss-of-function in Grange syndrome and emphasize FMD-like pathology, consolidating the mechanistic axis of chromatin remodeling and SMC phenotypes (Hypertension, Oct 2021; DOI: 10.1161/HYPERTENSIONAHA.121.17004; https://doi.org/10.1161/hypertensionaha.121.17004) (persu2021beyondatherosclerosisand pages 5-7). - 2021 case with combined frameshift and large deletion provides structural-variant spectrum in YY1AP1 and highlights panvascular involvement (Human Genomics, May 2021; DOI: 10.1186/s40246-021-00328-1; https://doi.org/10.1186/s40246-021-00328-1) (raggio2021wholegenomesequencing pages 2-5). Note: Our evidence set did not retrieve 2024 regulatory-genomics or large-scale artery-specific datasets with citable IDs; thus, 2024 mechanistic extensions are not included here to maintain citation integrity.
Current applications and real-world implementations - Genetic diagnosis: Whole exome/genome sequencing reliably identifies biallelic YY1AP1 loss-of-function (nonsense, frameshift, splice, multi-exon deletion) enabling definitive diagnosis of Grange syndrome and guiding surveillance for systemic vascular involvement (guo2017lossoffunctionmutationsin pages 2-3, raggio2021wholegenomesequencing pages 2-5, karakaya2023thenewyoungest pages 3-4). - Clinical management implications: Recognition of bilateral renal artery stenosis risk and renovascular hypertension; procedural planning (e.g., hemodynamic risks during PDA closure noted in a 2023 case) and cautious use of renin-angiotensin system blockers if bilateral RAS is suspected (karakaya2023thenewyoungest pages 1-3, persu2021beyondatherosclerosisand pages 5-7). - Phenotype-directed vascular imaging: Screening cerebrovascular and renovascular beds for stenoses/occlusions with attention to FMD-like and moyamoya-like morphologies (guo2017lossoffunctionmutationsin pages 7-9, persu2021beyondatherosclerosisand pages 5-7).
Expert opinions and authoritative analyses - The AJHG 2017 report by Guo et al. provides foundational mechanistic evidence linking YY1AP1/INO80 to SMC biology and Grange syndrome, proposing that SMC de-differentiation/hyperplasia or failed SMC population/maintenance underlie occlusive versus aneurysmal phenotypes, respectively (guo2017lossoffunctionmutationsin pages 7-9, guo2017lossoffunctionmutationsin pages 9-10). - Hypertension (2021) review emphasizes Grange syndrome among rare causes of renovascular hypertension, reinforcing the clinical signature of focal, FMD-like lesions and the genetic etiology in YY1AP1 (persu2021beyondatherosclerosisand pages 5-7).
Relevant statistics and data from recent studies - 2023 case report notes that only 14 individuals (12 molecularly confirmed) had been reported up to that time, underscoring the ultra-rare nature of Grange syndrome (Molecular Syndromology, 2023) (karakaya2023thenewyoungest pages 1-3). - 2021 WGS case demonstrates compound heterozygosity (frameshift + large deletion) with parental segregation, illustrating the diagnostic utility of genome sequencing in suspected panvascular arteriopathy (Human Genomics, 2021) (raggio2021wholegenomesequencing pages 2-5).
Gene/protein annotations with ontology terms - YY1AP1 (HGNC:23166): nucleus/nucleolus; INO80 complex; positive regulation of SMC differentiation (context-dependent); cell-cycle progression; loss elevates CDKN1A/p21 (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 2-3, guo2017lossoffunctionmutationsin pages 1-2, guo2017lossoffunctionmutationsin pages 4-5). - YY1 (HGNC:12828): transcription factor partnering with YY1AP1/INO80 in transcriptional regulation (guo2017lossoffunctionmutationsin pages 2-3). - INO80 (HGNC:19191) and related subunits: chromatin remodeling; silencing induces p21 and cell-cycle arrest (guo2017lossoffunctionmutationsin pages 9-10). - CDKN1A/p21 (HGNC:1784): cell-cycle inhibitor elevated with YY1AP1 loss (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 4-5).
Cell type involvement (CL terms) - Vascular smooth muscle cell (CL:0000746): primary site of YY1AP1 function and dysfunction; altered proliferation/differentiation responses (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 7-9, raggio2021wholegenomesequencing pages 1-2).
Anatomical locations (UBERON terms) - Renal artery (UBERON:0001637) (persu2021beyondatherosclerosisand pages 5-7, guo2017lossoffunctionmutationsin pages 7-9). - Cerebral/internal carotid arteries (UBERON:0002254/UBERON:0001620) (guo2017lossoffunctionmutationsin pages 7-9, guo2017lossoffunctionmutationsin pages 9-10). - Celiac (UBERON:0001514), mesenteric (UBERON:0001625), coronary (UBERON:0001629) arteries (raggio2021wholegenomesequencing pages 2-5, karakaya2023thenewyoungest pages 3-4).
Chemical entities (CHEBI terms) - Transforming growth factor beta (TGF-β; CHEBI:18420) (guo2017lossoffunctionmutationsin pages 7-9).
Phenotype associations (HP terms) - Renovascular hypertension (HP:0004421); renal artery stenosis (HP:0005366) (persu2021beyondatherosclerosisand pages 5-7, guo2017lossoffunctionmutationsin pages 7-9). - Moyamoya phenomenon (HP:0005347); cerebral artery stenosis (HP:0002610); stroke/TIA (HP:0001297) (guo2017lossoffunctionmutationsin pages 7-9, guo2017lossoffunctionmutationsin pages 9-10). - Congenital heart defect (HP:0001627) including PDA (karakaya2023thenewyoungest pages 1-3). - Brachydactyly (HP:0001156), syndactyly (HP:0001159) (guo2017lossoffunctionmutationsin pages 4-5, karakaya2023thenewyoungest pages 1-3). - Bone fragility (HP:0002659), intellectual disability (HP:0001249) (guo2017lossoffunctionmutationsin pages 4-5, persu2021beyondatherosclerosisand pages 5-7).
Embedded artifact | Category | Item | Ontology ID | Evidence | Mechanistic/clinical note | |---|---|---|---|---| | Gene/Protein | YY1AP1 | | Guo et al. 2017; DOI:10.1016/j.ajhg.2016.11.008 (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 2-3) | Biallelic loss-of-function causes Grange syndrome; INO80 component; alters SMC differentiation | | Cellular Component (GO/CC) | INO80 chromatin-remodeling complex | | Guo et al. 2017; DOI:10.1016/j.ajhg.2016.11.008 (guo2017lossoffunctionmutationsin pages 2-3, guo2017lossoffunctionmutationsin pages 1-2) | YY1AP1 associates with INO80 in SMCs; chromatin remodeling linked to cell-cycle control | | Gene/Protein | YY1 | | Guo et al. 2017; DOI:10.1016/j.ajhg.2016.11.008 (guo2017lossoffunctionmutationsin pages 2-3) | Transcription factor interacting with YY1AP1/INO80 complex | | Biological Process (GO) | VSMC differentiation / TGF-β response | | Guo et al. 2017; Raggio et al. 2021 (guo2017lossoffunctionmutationsin pages 5-7, raggio2021wholegenomesequencing pages 1-2) | YY1AP1 required for TGF-β–driven induction of SMC contractile markers (SM α-actin, SM22α) | | Biological Process (GO) | Cell-cycle regulation / CDKN1A (p21) upregulation | | Guo et al. 2017; multiple functional assays (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 4-5) | YY1AP1 loss increases p21 (CDKN1A), causing G1/G2 arrest and reduced proliferation in SMCs | | Cellular Component (GO/CC) | Nuclear / nucleolar localization | | Guo et al. 2017 (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 1-2) | YY1AP1 localizes to nucleus and nucleolus in SMCs and cell models | | Cell Type (CL) | Vascular smooth muscle cell (VSMC) | | Guo et al. 2017; Raggio et al. 2021 (guo2017lossoffunctionmutationsin pages 5-7, raggio2021wholegenomesequencing pages 1-2) | Primary affected cell type; SMC dysfunction underlies stenotic/occlusive arteriopathy | | Anatomy (UBERON) | Renal artery | | Guo et al. 2017; Persu et al. 2021; case reports (guo2017lossoffunctionmutationsin pages 7-9, raggio2021wholegenomesequencing pages 2-5) | Frequent site of stenosis → renovascular hypertension in Grange syndrome | | Anatomy (UBERON) | Cerebral arteries (moyamoya-like) | | Guo et al. 2017; Guo et al. AJHG excerpts (guo2017lossoffunctionmutationsin pages 7-9, guo2017lossoffunctionmutationsin pages 9-10) | Intracranial stenoses/occlusions with collateral formation (moyamoya-like phenotype) | | Anatomy (UBERON) | Celiac / coronary / mesenteric arteries (panvascular) | | Raggio et al. 2021; Karakaya 2023 case (raggio2021wholegenomesequencing pages 2-5, karakaya2023thenewyoungest pages 1-3) | Multi-territory arterial involvement reported in molecularly confirmed cases | | Chemical/Drug (ChEBI) | Transforming growth factor beta (TGF-β) | | Guo et al. 2017 (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 7-9) | TGF-β upregulates YY1AP1 in SMCs and drives differentiation programs | | Biological Process (GO) | Fibromuscular dysplasia–like arteriopathy | | Guo et al. 2017; Persu et al. 2021 (guo2017lossoffunctionmutationsin pages 7-9, persu2021beyondatherosclerosisand pages 5-7) | Clinical pattern: focal stenoses/beaded appearance resembling FMD | | Anatomy (UBERON) | Hypertension (clinical consequence) | | Guo et al. 2017; clinical case reports (guo2017lossoffunctionmutationsin pages 7-9, karakaya2023thenewyoungest pages 1-3) | Result of renal artery stenosis and systemic vascular involvement | | Anatomy (UBERON) | Brachydactyly / syndactyly (skeletal) | | Guo et al. 2017; Karakaya 2023 (guo2017lossoffunctionmutationsin pages 4-5, karakaya2023thenewyoungest pages 1-3) | Recurrent skeletal anomalies in Grange syndrome alongside vascular disease |
Table: Compact table of key genes, processes, cell types, anatomical sites, and evidence linking YY1AP1/INO80 dysfunction to Grange syndrome; useful as a quick ontology-ready reference for knowledge-base entry.
Evidence items (primary literature with PMIDs/DOIs/URLs) - Guo et al., 2017, The American Journal of Human Genetics. “Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease.” DOI: 10.1016/j.ajhg.2016.11.008. URL: https://doi.org/10.1016/j.ajhg.2016.11.008 (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 7-9, guo2017lossoffunctionmutationsin pages 2-3, guo2017lossoffunctionmutationsin pages 1-2, guo2017lossoffunctionmutationsin pages 9-10, guo2017lossoffunctionmutationsin pages 4-5, guo2017lossoffunctionmutationsin pages 10-10). - Raggio et al., 2021, Human Genomics. “Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease.” DOI: 10.1186/s40246-021-00328-1. URL: https://doi.org/10.1186/s40246-021-00328-1 (raggio2021wholegenomesequencing pages 1-2, raggio2021wholegenomesequencing pages 2-5). - Karakaya et al., 2023, Molecular Syndromology. “The New Youngest Case of Grange Syndrome with a Novel Biallelic Pathogenic Variant in YY1AP1.” DOI: 10.1159/000527785. URL: https://doi.org/10.1159/000527785 (karakaya2023thenewyoungest pages 1-3, karakaya2023thenewyoungest pages 3-4). - Persu et al., 2021, Hypertension. “Beyond Atherosclerosis and Fibromuscular Dysplasia: Rare Causes of Renovascular Hypertension.” DOI: 10.1161/HYPERTENSIONAHA.121.17004. URL: https://doi.org/10.1161/hypertensionaha.121.17004 (persu2021beyondatherosclerosisand pages 5-7).
Limitations and open questions - Lack of arterial tissue pathology in published cases limits direct histopathological correlation, as noted by Guo et al. (guo2017lossoffunctionmutationsin pages 7-9). - While SMC-autonomous mechanisms are well-supported, contributions from endothelial cells or adventitial fibroblasts remain to be defined. - The extent to which heterozygous YY1AP1 variation confers predisposition to adult FMD remains uncertain at the population level (guo2017lossoffunctionmutationsin pages 7-9).
Summary Grange syndrome is a chromatin-remodeling disorder of the arterial media driven by YY1AP1 loss-of-function within the INO80 complex. The consequence is dysregulated VSMC cell-cycle control and impaired TGF-β–dependent contractile differentiation, producing a systemic, FMD-like steno-occlusive arteriopathy with moyamoya-like intracranial involvement. Clinical recognition should prompt genomic testing and comprehensive vascular screening, with management focused on renovascular hypertension and ischemia risk (guo2017lossoffunctionmutationsin pages 5-7, guo2017lossoffunctionmutationsin pages 7-9, guo2017lossoffunctionmutationsin pages 2-3, guo2017lossoffunctionmutationsin pages 1-2, guo2017lossoffunctionmutationsin pages 9-10, guo2017lossoffunctionmutationsin pages 4-5, raggio2021wholegenomesequencing pages 1-2, karakaya2023thenewyoungest pages 1-3, karakaya2023thenewyoungest pages 3-4, raggio2021wholegenomesequencing pages 2-5, persu2021beyondatherosclerosisand pages 5-7).
References
(guo2017lossoffunctionmutationsin pages 5-7): Dong-chuan Guo, Xue-Yan Duan, Ellen S. Regalado, Lauren Mellor-Crummey, Callie S. Kwartler, Dong Kim, Kenneth Lieberman, Bert B.A. de Vries, Rolph Pfundt, Albert Schinzel, Dieter Kotzot, Xuetong Shen, Min-Lee Yang, Michael J. Bamshad, Deborah A. Nickerson, Heather L. Gornik, Santhi K. Ganesh, Alan C. Braverman, Dorothy K. Grange, and Dianna M. Milewicz. Loss-of-function mutations in yy1ap1 lead to grange syndrome and a fibromuscular dysplasia-like vascular disease. The American Journal of Human Genetics, 100:21-30, Jan 2017. URL: https://doi.org/10.1016/j.ajhg.2016.11.008, doi:10.1016/j.ajhg.2016.11.008. This article has 71 citations.
(guo2017lossoffunctionmutationsin pages 7-9): Dong-chuan Guo, Xue-Yan Duan, Ellen S. Regalado, Lauren Mellor-Crummey, Callie S. Kwartler, Dong Kim, Kenneth Lieberman, Bert B.A. de Vries, Rolph Pfundt, Albert Schinzel, Dieter Kotzot, Xuetong Shen, Min-Lee Yang, Michael J. Bamshad, Deborah A. Nickerson, Heather L. Gornik, Santhi K. Ganesh, Alan C. Braverman, Dorothy K. Grange, and Dianna M. Milewicz. Loss-of-function mutations in yy1ap1 lead to grange syndrome and a fibromuscular dysplasia-like vascular disease. The American Journal of Human Genetics, 100:21-30, Jan 2017. URL: https://doi.org/10.1016/j.ajhg.2016.11.008, doi:10.1016/j.ajhg.2016.11.008. This article has 71 citations.
(guo2017lossoffunctionmutationsin pages 2-3): Dong-chuan Guo, Xue-Yan Duan, Ellen S. Regalado, Lauren Mellor-Crummey, Callie S. Kwartler, Dong Kim, Kenneth Lieberman, Bert B.A. de Vries, Rolph Pfundt, Albert Schinzel, Dieter Kotzot, Xuetong Shen, Min-Lee Yang, Michael J. Bamshad, Deborah A. Nickerson, Heather L. Gornik, Santhi K. Ganesh, Alan C. Braverman, Dorothy K. Grange, and Dianna M. Milewicz. Loss-of-function mutations in yy1ap1 lead to grange syndrome and a fibromuscular dysplasia-like vascular disease. The American Journal of Human Genetics, 100:21-30, Jan 2017. URL: https://doi.org/10.1016/j.ajhg.2016.11.008, doi:10.1016/j.ajhg.2016.11.008. This article has 71 citations.
(guo2017lossoffunctionmutationsin pages 1-2): Dong-chuan Guo, Xue-Yan Duan, Ellen S. Regalado, Lauren Mellor-Crummey, Callie S. Kwartler, Dong Kim, Kenneth Lieberman, Bert B.A. de Vries, Rolph Pfundt, Albert Schinzel, Dieter Kotzot, Xuetong Shen, Min-Lee Yang, Michael J. Bamshad, Deborah A. Nickerson, Heather L. Gornik, Santhi K. Ganesh, Alan C. Braverman, Dorothy K. Grange, and Dianna M. Milewicz. Loss-of-function mutations in yy1ap1 lead to grange syndrome and a fibromuscular dysplasia-like vascular disease. The American Journal of Human Genetics, 100:21-30, Jan 2017. URL: https://doi.org/10.1016/j.ajhg.2016.11.008, doi:10.1016/j.ajhg.2016.11.008. This article has 71 citations.
(guo2017lossoffunctionmutationsin pages 9-10): Dong-chuan Guo, Xue-Yan Duan, Ellen S. Regalado, Lauren Mellor-Crummey, Callie S. Kwartler, Dong Kim, Kenneth Lieberman, Bert B.A. de Vries, Rolph Pfundt, Albert Schinzel, Dieter Kotzot, Xuetong Shen, Min-Lee Yang, Michael J. Bamshad, Deborah A. Nickerson, Heather L. Gornik, Santhi K. Ganesh, Alan C. Braverman, Dorothy K. Grange, and Dianna M. Milewicz. Loss-of-function mutations in yy1ap1 lead to grange syndrome and a fibromuscular dysplasia-like vascular disease. The American Journal of Human Genetics, 100:21-30, Jan 2017. URL: https://doi.org/10.1016/j.ajhg.2016.11.008, doi:10.1016/j.ajhg.2016.11.008. This article has 71 citations.
(guo2017lossoffunctionmutationsin pages 4-5): Dong-chuan Guo, Xue-Yan Duan, Ellen S. Regalado, Lauren Mellor-Crummey, Callie S. Kwartler, Dong Kim, Kenneth Lieberman, Bert B.A. de Vries, Rolph Pfundt, Albert Schinzel, Dieter Kotzot, Xuetong Shen, Min-Lee Yang, Michael J. Bamshad, Deborah A. Nickerson, Heather L. Gornik, Santhi K. Ganesh, Alan C. Braverman, Dorothy K. Grange, and Dianna M. Milewicz. Loss-of-function mutations in yy1ap1 lead to grange syndrome and a fibromuscular dysplasia-like vascular disease. The American Journal of Human Genetics, 100:21-30, Jan 2017. URL: https://doi.org/10.1016/j.ajhg.2016.11.008, doi:10.1016/j.ajhg.2016.11.008. This article has 71 citations.
(raggio2021wholegenomesequencing pages 1-2): Víctor Raggio, Nicolas Dell’Oca, Camila Simoes, Alejandra Tapié, Conrado Medici, Gonzalo Costa, Soledad Rodriguez, Gonzalo Greif, Estefania Garrone, María Laura Rovella, Virgina Gonzalez, Margarita Halty, Gabriel González, Jong-Yeon Shin, Sang-Yoon Shin, Changhoon Kim, Jeong-Sun Seo, Martin Graña, Hugo Naya, and Lucia Spangenberg. Whole genome sequencing reveals a frameshift mutation and a large deletion in yy1ap1 in a girl with a panvascular artery disease. Human Genomics, May 2021. URL: https://doi.org/10.1186/s40246-021-00328-1, doi:10.1186/s40246-021-00328-1. This article has 11 citations and is from a peer-reviewed journal.
(raggio2021wholegenomesequencing pages 2-5): Víctor Raggio, Nicolas Dell’Oca, Camila Simoes, Alejandra Tapié, Conrado Medici, Gonzalo Costa, Soledad Rodriguez, Gonzalo Greif, Estefania Garrone, María Laura Rovella, Virgina Gonzalez, Margarita Halty, Gabriel González, Jong-Yeon Shin, Sang-Yoon Shin, Changhoon Kim, Jeong-Sun Seo, Martin Graña, Hugo Naya, and Lucia Spangenberg. Whole genome sequencing reveals a frameshift mutation and a large deletion in yy1ap1 in a girl with a panvascular artery disease. Human Genomics, May 2021. URL: https://doi.org/10.1186/s40246-021-00328-1, doi:10.1186/s40246-021-00328-1. This article has 11 citations and is from a peer-reviewed journal.
(persu2021beyondatherosclerosisand pages 5-7): Alexandre Persu, Caitriona Canning, Aleksander Prejbisz, Piotr Dobrowolski, Laurence Amar, Constantina Chrysochou, Jacek Kądziela, Mieczysław Litwin, Daan van Twist, Patricia Van der Niepen, Gregoire Wuerzner, Peter de Leeuw, Michel Azizi, Magda Januszewicz, and Andrzej Januszewicz. Beyond atherosclerosis and fibromuscular dysplasia: rare causes of renovascular hypertension. Hypertension, 78:898-911, Oct 2021. URL: https://doi.org/10.1161/hypertensionaha.121.17004, doi:10.1161/hypertensionaha.121.17004. This article has 38 citations and is from a domain leading peer-reviewed journal.
(karakaya2023thenewyoungest pages 3-4): Taner Karakaya, Ayberk Turkyilmaz, Deniz Eris, Mehtap Kaya, Kupra Oksuz, Meltem Aygul Eryigit, and Gizem Gönen. The new youngest case of grange syndrome with a novel biallelic pathogenic variant in yy1ap1. Molecular Syndromology, 14:239-245, Jan 2023. URL: https://doi.org/10.1159/000527785, doi:10.1159/000527785. This article has 1 citations and is from a peer-reviewed journal.
(karakaya2023thenewyoungest pages 1-3): Taner Karakaya, Ayberk Turkyilmaz, Deniz Eris, Mehtap Kaya, Kupra Oksuz, Meltem Aygul Eryigit, and Gizem Gönen. The new youngest case of grange syndrome with a novel biallelic pathogenic variant in yy1ap1. Molecular Syndromology, 14:239-245, Jan 2023. URL: https://doi.org/10.1159/000527785, doi:10.1159/000527785. This article has 1 citations and is from a peer-reviewed journal.
(guo2017lossoffunctionmutationsin pages 10-10): Dong-chuan Guo, Xue-Yan Duan, Ellen S. Regalado, Lauren Mellor-Crummey, Callie S. Kwartler, Dong Kim, Kenneth Lieberman, Bert B.A. de Vries, Rolph Pfundt, Albert Schinzel, Dieter Kotzot, Xuetong Shen, Min-Lee Yang, Michael J. Bamshad, Deborah A. Nickerson, Heather L. Gornik, Santhi K. Ganesh, Alan C. Braverman, Dorothy K. Grange, and Dianna M. Milewicz. Loss-of-function mutations in yy1ap1 lead to grange syndrome and a fibromuscular dysplasia-like vascular disease. The American Journal of Human Genetics, 100:21-30, Jan 2017. URL: https://doi.org/10.1016/j.ajhg.2016.11.008, doi:10.1016/j.ajhg.2016.11.008. This article has 71 citations.