Borjeson-Forssman-Lehmann syndrome

Mendelian MONDO:0010537 Pathograph 35 Show in embeddings browser hereditary disease syndromic intellectual disability

Borjeson-Forssman-Lehmann syndrome (BFLS) is an ultra-rare X-linked PHF6-related neurodevelopmental disorder. Core manifestations include developmental delay or intellectual disability, infantile hypotonia, characteristic craniofacial and digital findings, truncal obesity, and hypogonadism. Expression is sex- and variant-dependent: affected males often have inherited missense or small in-frame variants, whereas clinically affected females more often have de novo truncating variants or larger deletions or duplications and may show Blaschko-linear pigmentation, dental, retinal, or cortical abnormalities. PHF6-dependent transcriptional dysregulation is established, but specific downstream developmental pathways remain incompletely resolved and are supported mainly by cellular and mouse models.

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1
Mappings
1
Inheritance
7
Pathophys.
26
Phenotypes
4
Gaps
35
Pathograph
1
Genes
4
Medical Actions
3
Differentials
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Datasets
9
References
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Deep Research
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
🔗

Mappings

MONDO
MONDO:0010537 Borjeson-Forssman-Lehmann syndrome
skos:exactMatch MONDO
Primary MONDO identifier for Borjeson-Forssman-Lehmann syndrome.
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Inheritance

1
X-linked inheritance HP:0001417
BFLS is caused by pathogenic PHF6 variants on the X chromosome. Affected males and females are both reported, with inherited variants and mildly affected or unaffected carrier females in some families and de novo, often more disruptive variants in many clinically affected females.
X-linked inheritance
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene."
This directly supports X-linked PHF6-related inheritance.
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Discussions and Knowledge Gaps

4
Does PHF6 loss increase or decrease embryonic neural stem-cell self-renewal, and which experimental variable explains the opposite findings across recent BFLS mouse models?
CONTROVERSY OPEN bfls_neural_stem_cell_direction
Attached to
pathophysiology#Altered embryonic neural stem-cell regulation
One BFLS patient-variant and conditional-knockout study reports increased self-renewal with fewer neural progenitors, whereas another Phf6-deficient model reports reduced self-renewal with increased neuronal differentiation. The graph therefore records abnormal regulation without fixing its direction.
Show evidence (2 references)
DOI:10.1038/s44319-024-00082-0 SUPPORT Model Organism
"Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors."
This study reports increased self-renewal.
DOI:10.1371/journal.pgen.1011428 SUPPORT Model Organism
"Phf6 deficient neural precursor cells showed a reduced capacity for self-renewal and increased differentiation into neurons."
This study reports reduced self-renewal.
How do variant class, residual PHF6 activity, tissue-specific X-chromosome inactivation, and ascertainment combine to determine BFLS expression in affected females and males?
KNOWLEDGE GAP OPEN bfls_sex_variant_x_inactivation
Attached to
genetic#PHF6
Variant-class patterns differ strongly by sex, yet overlapping variants, affected and unaffected carrier females, and discordant X-inactivation observations prevent a simple deterministic genotype-phenotype model.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Therefore, a clear correlation between XCI and disease severity has not been demonstrated."
The cohort explicitly states that X-inactivation does not yet explain severity.
Is germline PHF6-related BFLS associated with a clinically meaningful age-specific cancer risk that warrants syndrome-specific surveillance?
KNOWLEDGE GAP OPEN bfls_cancer_risk
Somatic PHF6 variants occur in cancers and a few cancers have been reported in people with BFLS, but the denominator is very small and no risk estimate supports a syndrome-specific screening schedule. Cancer surveillance is therefore not represented as established BFLS management.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Therefore, at present, the cancer risk for BFLS patients remains uncertain due to lack of evidence."
The clinical-spectrum paper explicitly identifies cancer risk as unresolved.
Does the PHF6-Ephrin-receptor rescue pathway observed in mouse embryonic neural stem cells translate to human prenatal neurodevelopment or a safe therapeutic strategy?
HUMAN MODEL MISMATCH OPEN bfls_ephrin_translation
Attached to
pathophysiology#Ephrin receptor transcriptional dysregulation
EphA4 or EphA7 expression rescues a cell-level phenotype in mouse-derived embryonic neural stem cells, but this does not establish efficacy, safety, timing, or delivery in humans. The rescue is represented as mechanistic evidence and not as a treatment.
Show evidence (1 reference)
DOI:10.1038/s44319-024-00082-0 SUPPORT Model Organism
"EphR-A family of receptors rescues PHF6 loss-of-function defects in BFLS mice-derived eNSCs."
The rescue experiment is confined to mouse-derived embryonic neural stem cells.
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Pathophysiology

7
PHF6-dependent transcriptional dysregulation
PHF6 is a chromatin-associated transcriptional regulator. Pathogenic PHF6 variation disrupts broad transcriptional programs, including programs involved in chromatin regulation, axon development, neuronal development, and cortical neurogenesis. The causal gene-disease relationship is definitive, while the precise molecular consequence differs across variant classes and sex contexts.
PHF6 hgnc:18145 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves abnormal PHF6 (hgnc:18145). hgnc:18145 is a gene from the HUGO Gene Nomenclature Committee. ⚠ ABNORMAL
regulation of transcription by RNA polymerase II GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Ephrin receptor transcriptional dysregulation Mouse cortical binding, expression, knockdown, and rescue experiments identify Ephrin receptors as direct PHF6 transcriptional targets.
Abnormal neuronal morphogenesis PHF6 knockout directly impairs proliferation, neurite outgrowth, and migration in a differentiated human neuron-like cell model.
Human neurodevelopmental and neurologic manifestations Pathogenic PHF6 variants cause the human neurodevelopmental syndrome, but several developmental intermediates between broad transcriptional dysregulation and each clinical manifestation remain unknown.
Human endocrine and growth manifestations PHF6-related disease is associated with truncal obesity and gonadal and pubertal abnormalities, but the organ-level causal intermediates are not established.
Human craniofacial, ectodermal, and congenital manifestations The craniofacial, digital, skin, dental, retinal, and congenital findings form a reproducible PHF6-related phenotype cluster, although their tissue-specific developmental mechanisms are not yet resolved.
Show evidence (2 references)
CGGV:assertion_94ea5014-0a83-49ea-b001-fc2a8c24c0d9-2018-02-21T110000.000Z SUPPORT Other
"PHF6 | HGNC:18145 | Borjeson-Forssman-Lehmann syndrome | MONDO:0010537 | XL | Definitive"
ClinGen classifies the PHF6-BFLS gene-disease relationship as definitive.
DOI:10.1038/s41598-020-75999-2 SUPPORT In Vitro
"Transcriptome analysis revealed a broad deregulation of genes involved in chromatin and transcriptional regulation as well as in axon and neuron development."
The PHF6-knockout neuron-like cell model supports broad transcriptional dysregulation.
Ephrin receptor transcriptional dysregulation
PHF6 binds regulatory regions near Ephrin receptor genes and promotes their expression in developing mouse cortex. BFLS patient-variant mice and conditional Phf6-knockout mice show impaired Ephrin receptor regulation. This is a strong preclinical pathway, but direct confirmation in human prenatal neural tissue is unavailable.
EPHA4 hgnc:3388 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves decreased EPHA4 (hgnc:3388). hgnc:3388 is a gene from the HUGO Gene Nomenclature Committee. ↓ DECREASED EPHA7 hgnc:3390 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves decreased EPHA7 (hgnc:3390). hgnc:3390 is a gene from the HUGO Gene Nomenclature Committee. ↓ DECREASED
ephrin receptor signaling pathway GO:0048013 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal ephrin receptor signaling pathway (GO:0048013). GO:0048013 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Altered embryonic neural stem-cell regulation EphA-family knockdown phenocopies abnormal neural stem-cell self-renewal, and forced EphA4 or EphA7 expression rescues the mutant-cell phenotype in the mouse system.
Show evidence (1 reference)
DOI:10.1038/s44319-024-00082-0 SUPPORT Model Organism
"Our data indicate that PHF6 directly promotes Ephrin receptor expression to control eNSC behaviour in the developing brain, and that this pathway is impaired in BFLS."
This summarizes the model-supported PHF6-Ephrin-receptor pathway.
Altered embryonic neural stem-cell regulation
PHF6 loss or BFLS patient variants alter neural precursor self-renewal and progenitor output. Two recent mouse-model studies agree that precursor regulation is abnormal but report opposite directions for self-renewal, making the directional mechanism unresolved.
neural stem cell CL:0000047 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural stem cell (CL:0000047). CL:0000047 is a cell type from the Cell Ontology.
stem cell population maintenance GO:0019827 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal stem cell population maintenance (GO:0019827). GO:0019827 is a biological process from the Gene Ontology. ⚠ ABNORMAL neural precursor cell proliferation GO:0061351 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neural precursor cell proliferation (GO:0061351). GO:0061351 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Human neurodevelopmental and neurologic manifestations Disrupted prenatal precursor regulation is a plausible contributor to human BFLS neurodevelopment, but translation from the conflicting mouse cellular phenotypes to specific human manifestations is incomplete.
Show evidence (2 references)
DOI:10.1038/s44319-024-00082-0 SUPPORT Model Organism
"Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors."
One BFLS mouse-model study reports increased self-renewal and reduced progenitor output.
DOI:10.1371/journal.pgen.1011428 SUPPORT Model Organism
"Phf6 deficient neural precursor cells showed a reduced capacity for self-renewal and increased differentiation into neurons."
A separate mouse-model study supports abnormal precursor regulation but reports the opposite self-renewal direction.
Abnormal neuronal morphogenesis
CRISPR-mediated PHF6 knockout in human neuron-like cells perturbs proliferation, neurite extension, and migration. These observations provide direct cellular evidence, but the transformed-cell differentiation model does not reproduce human prenatal cortical development.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
neuron migration GO:0001764 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neuron migration (GO:0001764). GO:0001764 is a biological process from the Gene Ontology. ⚠ ABNORMAL axon development GO:0061564 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal axon development (GO:0061564). GO:0061564 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Human neurodevelopmental and neurologic manifestations Abnormal neuronal growth and migration plausibly contribute to cognitive and cortical findings, but the cell model does not directly demonstrate individual human clinical outcomes.
Show evidence (1 reference)
DOI:10.1038/s41598-020-75999-2 SUPPORT In Vitro
"Subsequently, we could demonstrate that PHF6 is indeed required for proper neuron proliferation, neurite outgrowth and migration."
This directly supports the cellular neuronal-development phenotype.
Human neurodevelopmental and neurologic manifestations
Neurodevelopmental and neurologic manifestations are an established clinical consequence cluster of pathogenic PHF6 variation. This node records the human genotype-phenotype relationship without asserting that one preclinical cellular pathway explains every manifestation.
Downstream
Intellectual disability Intellectual disability is the defining cognitive manifestation of PHF6-related BFLS.
Global developmental delay Delayed motor development is a universal early manifestation in the reported cohort.
Hypotonia Hypotonia is a common early neurologic manifestation.
Feeding difficulties in infancy Feeding difficulty is a frequent infantile manifestation with multifactorial developmental causes.
Delayed speech and language development Delayed or limited speech is a common neurodevelopmental manifestation.
Seizure Seizures occur in a minority of affected males and females.
Cortical brain anomalies Structural cortical abnormalities are particularly reported in affected females.
Peripheral neuropathy Peripheral neuropathy is an occasional neurologic complication.
Hearing impairment Conductive and sensorineural hearing impairment have both been reported.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Shared clinical features include early developmental delay, intellectual disability and obesity."
The cohort confirms the shared neurodevelopmental phenotype across sexes.
Human endocrine and growth manifestations
Truncal obesity, hypogonadism or small external genitalia, pubertal abnormalities, and gynecomastia are established clinical components of PHF6-related BFLS, although their tissue-specific molecular mechanisms are not established.
Downstream
Truncal obesity Truncal obesity is a classic and usually age-emergent BFLS manifestation.
Hypogonadism Gonadal or external-genital underdevelopment occurs in both affected males and females.
Gynecomastia Gynecomastia is concentrated in older affected males.
Short stature Short stature is variable and more characteristic of affected males.
Cryptorchidism Undescended testes are part of the male genital phenotype.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity."
The cohort confirms the characteristic endocrine and growth phenotype.
Human craniofacial, ectodermal, and congenital manifestations
Characteristic facial and digital morphology occurs in both sexes. Affected females with de novo PHF6 variants often have additional ectodermal, pigmentary, dental, retinal, and cortical features. This clinical cluster is established even though its tissue-specific molecular pathway is unknown.
Downstream
Large earlobe Large fleshy earlobes are a characteristic craniofacial finding.
Coarse facial features Facial coarsening develops with age and is a characteristic BFLS finding.
Linear skin hyperpigmentation Blaschko-linear hyperpigmentation is especially characteristic of affected females.
Dental anomalies Dental anomalies are particularly common in affected females.
Retinal anomalies Retinal and optic-nerve abnormalities are especially reported in affected females.
Keloid scarring Hypertrophic or keloid scarring is a reported skin complication.
Umbilical hernia Umbilical hernia is a reported congenital complication.
Talipes Talipes is a reported congenital limb anomaly.
Sparse hair Sparse or slow-growing hair is part of the ectodermal phenotype.
Tapered finger Short tapering fingers are characteristic in affected males and females.
Broad foot Broad feet are characteristic digital findings.
Short toe Short toes are characteristic digital findings.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"deep-set eyes, narrow palpebral fissures, large, fleshy ears, bulbous nasal tip, tapering fingers, and broad feet with short and/or flexed toes."
The cohort defines the craniofacial and digital phenotype shared across sexes.
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Pathograph

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

26
Breast 1
Gynecomastia HP:0000771 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gynecomastia (HP:0000771). HP:0000771 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Gynaecomastia was reported in 5 males"
The cohort directly supports the sex- and age-specific phenotype.
Digestive 1
Feeding difficulties in infancy FREQUENT HP:0008872 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties in infancy (HP:0008872). HP:0008872 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/127 SUPPORT Other
""HPOId": "HP:0008872", "HPOTerm": "Feeding difficulties in infancy" }, "HPOFrequency": "Frequent (79-30%)""
Orphadata classifies infantile feeding difficulty as frequent.
Ear 1
Hearing impairment OCCASIONAL HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Nine individuals had a history of recurrent otitis media or conductive hearing loss or had required grommet insertion. Two had mild sensorineural hearing loss."
The cohort directly reports conductive and sensorineural hearing loss.
url:https://api.orphadata.com/rd-phenotypes/orphacodes/127 SUPPORT Other
""HPOId": "HP:0000365", "HPOTerm": "Hearing impairment" }, "HPOFrequency": "Occasional (29-5%)""
Orphadata classifies hearing impairment as occasional.
Endocrine 1
Hypogonadism VERY_FREQUENT HP:0000135 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogonadism (HP:0000135). HP:0000135 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/127 SUPPORT Other
""HPOId": "HP:0000135", "HPOTerm": "Hypogonadism" }, "HPOFrequency": "Very frequent (99-80%)""
Orphadata classifies hypogonadism as very frequent.
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Small external genitalia or features of hypogonadism were noted in six males and four females."
The recent cohort documents hypogonadal findings across both sexes.
Genitourinary 1
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Undescended testes were present in three."
The cohort directly reports cryptorchidism.
Head and Neck 2
Coarse facial features VERY_FREQUENT HP:0000280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarse facial features (HP:0000280). HP:0000280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Facial features tended to coarsen with age leading to a prominent brow and bulbous nose."
The cohort directly supports the age-dependent facial phenotype.
Dental anomalies Abnormality of the dentition HP:0000164 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dental anomalies, annotated with Abnormality of the dentition (HP:0000164). HP:0000164 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Affected females had a high rate of dental anomalies (6/8 in our series, 18/20 in previous patients"
The cohort and literature comparison directly support frequent female dental anomalies.
Integument 3
Linear skin hyperpigmentation Hyperpigmentation of the skin HP:0000953 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Linear skin hyperpigmentation, annotated with Hyperpigmentation of the skin (HP:0000953). HP:0000953 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies."
This directly supports linear pigmentation in the affected-female phenotype.
Keloid scarring HP:0010562 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Keloid scarring, annotated with Keloids (HP:0010562). HP:0010562 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes."
The human cohort directly reports keloid scarring.
Sparse hair HP:0008070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse hair (HP:0008070). HP:0008070 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Sparse, fine or slow growing hair was reported in four females and two males."
The cohort directly reports sparse hair in both sexes.
Musculoskeletal 1
Hypotonia VERY_FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/127 SUPPORT Other
""HPOId": "HP:0001252", "HPOTerm": "Hypotonia" }, "HPOFrequency": "Very frequent (99-80%)""
Orphadata classifies hypotonia as very frequent.
Nervous System 5
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Intellectual disability varied in severity from mild to severe."
The human cohort directly supports the core phenotype and its variable severity.
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"All the individuals had delayed motor milestones."
All 19 cohort participants had motor developmental delay.
Delayed speech and language development VERY_FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Limited or delayed speech was common (18/19)."
The cohort places delayed or limited speech in the very-frequent band.
Peripheral neuropathy OCCASIONAL HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes."
The cohort reports neuropathy, mapped here to the HPO peripheral-neuropathy term.
url:https://api.orphadata.com/rd-phenotypes/orphacodes/127 SUPPORT Other
""HPOId": "HP:0009830", "HPOTerm": "Peripheral neuropathy" }, "HPOFrequency": "Occasional (29-5%)""
Orphadata classifies peripheral neuropathy as occasional.
Seizure OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Two males and one female had a history of seizures."
Direct human evidence supports seizures in both sexes.
url:https://api.orphadata.com/rd-phenotypes/orphacodes/127 SUPPORT Other
""HPOId": "HP:0001250", "HPOTerm": "Seizure" }, "HPOFrequency": "Occasional (29-5%)""
Orphadata classifies seizures as occasional.
Growth 2
Truncal obesity VERY_FREQUENT HP:0001956 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Truncal obesity (HP:0001956). HP:0001956 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Many individuals were described as obese, had truncal obesity, or a BMI > 2 standard deviations (SD) above mean for age (9/10 males, 6/7 females)."
Fifteen of seventeen evaluable cohort participants met an obesity description or threshold.
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Short stature was common. Height was below average in 9/10 males"
The cohort directly documents reduced height among affected males.
Other 8
Large earlobe VERY_FREQUENT HP:0009748 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Large earlobe (HP:0009748). HP:0009748 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/127 SUPPORT Other
""HPOId": "HP:0009748", "HPOTerm": "Large earlobe" }, "HPOFrequency": "Very frequent (99-80%)""
Orphadata classifies large earlobes as very frequent.
Retinal anomalies Abnormal retinal morphology HP:0000479 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal anomalies, annotated with Abnormal retinal morphology (HP:0000479). HP:0000479 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies."
This directly supports retinal abnormalities in affected females.
Cortical brain anomalies Abnormal cerebral cortex morphology HP:0002538 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cortical brain anomalies, annotated with Abnormal cerebral cortex morphology (HP:0002538). HP:0002538 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies."
This directly supports cortical abnormalities in affected females.
Umbilical hernia HP:0001537 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Umbilical hernia (HP:0001537). HP:0001537 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes."
The cohort directly reports umbilical hernias.
Talipes HP:0001883 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes (HP:0001883). HP:0001883 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes."
The cohort directly reports talipes.
Tapered finger VERY_FREQUENT HP:0001182 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tapered finger (HP:0001182). HP:0001182 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/127 SUPPORT Other
""HPOId": "HP:0001182", "HPOTerm": "Tapered finger" }, "HPOFrequency": "Very frequent (99-80%)""
Orphadata classifies tapered fingers as very frequent.
Broad foot VERY_FREQUENT HP:0001769 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad foot (HP:0001769). HP:0001769 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/127 SUPPORT Other
""HPOId": "HP:0001769", "HPOTerm": "Broad foot" }, "HPOFrequency": "Very frequent (99-80%)""
Orphadata classifies broad feet as very frequent.
Short toe VERY_FREQUENT HP:0001831 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short toe (HP:0001831). HP:0001831 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/127 SUPPORT Other
""HPOId": "HP:0001831", "HPOTerm": "Short toe" }, "HPOFrequency": "Very frequent (99-80%)""
Orphadata classifies short toes as very frequent.
🧬

Genetic Associations

1
PHF6 (Pathogenic PHF6 variants)
Gene: PHF6 hgnc:18145 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PHF6 (hgnc:18145). hgnc:18145 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
CGGV:assertion_94ea5014-0a83-49ea-b001-fc2a8c24c0d9-2018-02-21T110000.000Z SUPPORT Other
"PHF6 | HGNC:18145 | Borjeson-Forssman-Lehmann syndrome | MONDO:0010537 | XL | Definitive"
ClinGen classifies the PHF6-BFLS relationship as definitive with X-linked inheritance.
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications."
The cohort supports the sex-associated variant-class pattern.
💊

Medical Actions

4
Neurodevelopmental follow-up and supportive intervention
Category: Monitoring Action: clinical assessmentNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is clinical assessment, annotated with Clinical Evaluation (NCIT:C124351). NCIT:C124351 is a clinical intervention from the NCI Thesaurus. Ontology label: Clinical Evaluation NCIT:C124351
Longitudinal developmental, neurologic, communication, behavioral, and educational assessment should guide individualized supportive therapies.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"A range of recommendations for the initial evaluation and management of BFLS patients are presented in Supplementary Tables S5 and S6."
The cohort authors explicitly recommend neurodevelopmental follow-up.
Endocrinology and pubertal review
Category: Monitoring Action: clinical assessmentNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is clinical assessment, annotated with Clinical Evaluation (NCIT:C124351). NCIT:C124351 is a clinical intervention from the NCI Thesaurus. Ontology label: Clinical Evaluation NCIT:C124351
Age-appropriate endocrinology assessment should evaluate growth, obesity, gonadal development, pubertal progression, and related endocrine concerns.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"endocrinology review, eye checks and skin care."
The cohort authors explicitly recommend endocrinology review.
Ophthalmologic surveillance
Category: Monitoring Action: eye examinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is eye examination (NCIT:C38060). NCIT:C38060 is a clinical intervention from the NCI Thesaurus. Ontology label: Eye Examination NCIT:C38060
Baseline and follow-up eye examinations should be individualized to detect refractive errors, strabismus, nystagmus, retinal disease, and optic-nerve abnormalities.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"endocrinology review, eye checks and skin care."
The cohort authors explicitly recommend eye checks.
Skin assessment and supportive care
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Skin care should address hypertrophic or keloid scarring, painful or recurrent digital fibromas, pigmentary changes, and wound-related concerns according to individual findings.
Target Phenotypes: Keloid scarring HP:0010562 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Keloid scarring, annotated with Keloids (HP:0010562). HP:0010562 is a phenotype from the Human Phenotype Ontology. Linear skin hyperpigmentation HP:0000953 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Linear skin hyperpigmentation, annotated with Hyperpigmentation of the skin (HP:0000953). HP:0000953 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"endocrinology review, eye checks and skin care."
The cohort authors explicitly recommend skin care.
🔬

Diagnosis

2
Clinical recognition of the BFLS pattern (A compatible syndromic neurodevelopmental phenotype prompts PHF6 testing.)
Clinical suspicion is raised by developmental delay or intellectual disability with characteristic facial and digital findings, infantile hypotonia, truncal obesity, and hypogonadism. Blaschko-linear pigmentation and dental, retinal, or cortical anomalies are particularly informative in affected females.
clinical assessment NCIT:C124351 NCI Thesaurus (NCIT)
Show evidence (1 reference)
url:https://api.orphadata.com/rd-cross-referencing/orphacodes/127 SUPPORT Other
"Borjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked obesity syndrome characterized by intellectual deficit, truncal obesity, characteristic facial features, hypogonadism, tapered fingers and short toes."
The Orphadata definition supplies the core recognizable clinical pattern.
PHF6 molecular genetic testing (Identification of a pathogenic or likely pathogenic PHF6 variant establishes the molecular diagnosis.)
Molecular confirmation requires identification and clinical interpretation of a pathogenic or likely pathogenic PHF6 variant. Testing should be able to detect both sequence variants and exon-level or whole-gene copy-number changes because the observed spectrum includes missense, splice, frameshift, nonsense, in-frame, deletion, and duplication variants.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (2 references)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females)."
The molecularly ascertained cohort supports PHF6 testing as the confirmatory approach.
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications."
The variant spectrum supports both sequence and copy-number analysis.
📈

Progression

3
Neonatal and infantile presentation
Age: Neonatal period through infancy
Onset is classified as neonatal. Hypotonia and feeding difficulty are common early findings, although recognition of the full syndromic pattern and molecular diagnosis may occur later.
Show evidence (2 references)
url:https://api.orphadata.com/rd-natural_history/orphacodes/127 SUPPORT Other
""AverageAgeOfOnset": [ "Neonatal" ]"
The structured natural-history record assigns neonatal onset.
url:https://api.orphadata.com/rd-phenotypes/orphacodes/127 SUPPORT Other
""HPOId": "HP:0001252", "HPOTerm": "Hypotonia" }, "HPOFrequency": "Very frequent (99-80%)""
Orphadata identifies hypotonia as a very frequent early feature.
Neurodevelopmental manifestations
Age: Infancy through childhood
Motor milestones and speech are delayed, and intellectual disability ranges from mild to severe. Behavioral problems are common and may add substantial care needs.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"All the individuals had delayed motor milestones. Intellectual disability varied in severity from mild to severe. Limited or delayed speech was common (18/19). Behavioural problems were also frequent (13/19, 6 males and 7 females)."
The 19-person PHF6 cohort documents the childhood neurodevelopmental course and its variable severity.
Evolving craniofacial, growth, and endocrine phenotype
Age: Late childhood through adulthood
Facial coarsening and truncal obesity often become more apparent from late childhood. Pubertal and gonadal manifestations require age-appropriate assessment; gynecomastia is particularly associated with older affected males.
Show evidence (2 references)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Facial features tend to coarsen with age beginning in late childhood in association with the onset of obesity"
This directly supports an age-dependent facial and growth phenotype.
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Gynaecomastia was reported in 5 males"
The cohort documents the age and sex concentration of gynecomastia.
📊

Prevalence

1
Worldwide
Point Prevalence <1 per 1,000,000 <1 in 1,000,000
Orphadata reports a validated worldwide point-prevalence class below one per million, but supplies no measured numeric rate; this is therefore a class-only estimate.
Show evidence (1 reference)
url:https://api.orphadata.com/rd-epidemiology/orphacodes/127 SUPPORT Other
""PrevalenceClass": "<1 / 1 000 000", "PrevalenceGeographic": "Worldwide", "PrevalenceQualification": "Class only", "PrevalenceType": "Point prevalence""
The current Orphadata epidemiology record provides the worldwide point-prevalence class used here and explicitly identifies it as class-only.
⚖️

Clinical Burden

High
BFLS produces lifelong neurodevelopmental disability with variable speech limitation and behavior challenges, together with endocrine, visual, hearing, neurologic, skin, dental, and congenital complications that require multidisciplinary follow-up. Severity varies considerably, especially by sex and variant context, and the available cohorts are small; high burden does not imply uniformly severe expression in every affected person.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"All the individuals had delayed motor milestones. Intellectual disability varied in severity from mild to severe. Limited or delayed speech was common (18/19). Behavioural problems were also frequent (13/19, 6 males and 7 females)."
Universal motor delay, frequent speech limitation, and behavioral morbidity in the cohort support substantial lifelong care needs.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Borjeson-Forssman-Lehmann syndrome:

Coffin-Siris syndrome MONDO:0015452
Overlapping Features Coffin-Siris syndrome can overlap in young affected females through intellectual disability, sparse hair, and hypoplastic nails. PHF6 testing, Blaschko-linear pigmentation, and the broader BFLS sex- and variant-associated pattern help resolve the distinction.
Distinguishing Features
  • BFLS is molecularly defined by pathogenic PHF6 variation rather than a BAF/SWI-SNF complex gene defect.
  • Blaschko-linear pigmentation and the BFLS endocrine pattern favor PHF6-related disease.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"The phenotypic combination of ID, sparse hair and hypoplastic nails in younger affected females has been noted to overlap with Coffin-Siris syndrome (MIM# 135900)"
The cohort explicitly identifies Coffin-Siris syndrome as a clinical overlap.
Incontinentia pigmenti MONDO:0100162
Overlapping Features Incontinentia pigmenti is an important differential in affected females with Blaschko-linear pigmentation and ectodermal, dental, retinal, or neurologic findings. IKBKG testing distinguishes it from PHF6-related BFLS.
Distinguishing Features
  • Incontinentia pigmenti is caused by pathogenic IKBKG variants, whereas BFLS is caused by PHF6 variants.
  • The BFLS phenotype includes its characteristic facial, digital, obesity, and hypogonadism pattern.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"The streaky skin pigmentation in F1, F3 and F5 led to incontinentia pigmenti being considered and IKBKG gene testing being arranged."
The cohort documents real-world consideration and molecular exclusion of this differential.
Terminal osseous dysplasia-pigmentary defects syndrome MONDO:0010279
Overlapping Features Terminal osseous dysplasia with pigmentary defects overlaps in affected females through pigmentary abnormalities, digital anomalies, and recurrent digital fibromas. FLNA testing and the disorder-specific skeletal pattern distinguish it from PHF6-related BFLS.
Distinguishing Features
  • Terminal osseous dysplasia-pigmentary defects syndrome is caused by a recurrent FLNA splice-altering variant rather than PHF6 variation.
  • BFLS has a characteristic neurodevelopmental, obesity, hypogonadism, facial, and digital phenotype.
Show evidence (1 reference)
DOI:10.1038/s41431-023-01447-0 SUPPORT Human Clinical
"Similarly, a diagnosis of TODPD was considered for F2 due to her combination of pigmentary abnormalities, digital anomalies, and recurrent digital fibromas."
The cohort explicitly identifies TODPD as a differential in an affected female.
📊

Related Datasets

1
PHF6 regulation of developing mouse cortex and neural stem cells geo:GSE247838
Disease-mechanism dataset associated with the PHF6-Ephrin-receptor study, combining PHF6 cortical ChIP-seq with bulk RNA-seq after Phf6 knockdown in embryonic mouse cortical progenitors.
mouse MULTI OMICS PERTURBATION
cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this dataset samples this sample type This dataset samples cerebral cortex (UBERON:0000956). UBERON:0000956 is a sample type from the Uberon multi-species anatomy ontology. neural stem cell CL:0000047 Cell Ontology (CL) Relation: this dataset samples this sample type This dataset samples neural stem cell (CL:0000047). CL:0000047 is a sample type from the Cell Ontology.
Conditions: PHF6 cortical chromatin immunoprecipitation and IgG control Phf6 siRNA knockdown and non-targeting control in embryonic cortical progenitors
DOI:10.1038/s44319-024-00082-0
GSE153164 and BrainSpan are reused developmental atlases rather than BFLS-generated datasets and are not represented as disease datasets here.
Show evidence (1 reference)
DOI:10.1038/s44319-024-00082-0 SUPPORT Model Organism
"Gene Expression Omnibus (GEO GSE247838)."
The publication directly identifies GSE247838 as the repository accession.
{ }

Source YAML

click to show 
name: Borjeson-Forssman-Lehmann syndrome
creation_date: "2026-04-15T15:45:03Z"
category: Mendelian
description: >-
  Borjeson-Forssman-Lehmann syndrome (BFLS) is an ultra-rare X-linked
  PHF6-related neurodevelopmental disorder. Core manifestations include
  developmental delay or intellectual disability, infantile hypotonia,
  characteristic craniofacial and digital findings, truncal obesity, and
  hypogonadism. Expression is sex- and variant-dependent: affected males often
  have inherited missense or small in-frame variants, whereas clinically
  affected females more often have de novo truncating variants or larger
  deletions or duplications and may show Blaschko-linear pigmentation, dental,
  retinal, or cortical abnormalities. PHF6-dependent transcriptional
  dysregulation is established, but specific downstream developmental pathways
  remain incompletely resolved and are supported mainly by cellular and mouse
  models.
disease_term:
  preferred_term: Borjeson-Forssman-Lehmann syndrome
  term:
    id: MONDO:0010537
    label: Borjeson-Forssman-Lehmann syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010537
      label: Borjeson-Forssman-Lehmann syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO identifier for Borjeson-Forssman-Lehmann syndrome.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: CGGV:assertion_94ea5014-0a83-49ea-b001-fc2a8c24c0d9-2018-02-21T110000.000Z
      reference_title: "PHF6 / Borjeson-Forssman-Lehmann syndrome (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "PHF6 | HGNC:18145 | Borjeson-Forssman-Lehmann syndrome | MONDO:0010537 | XL | Definitive"
      explanation: The definitive PHF6 gene-disease assertion supports classification as a genetic disease.
parents:
- hereditary disease
- syndromic intellectual disability
synonyms:
- BFLS
- Intellectual disability-epilepsy-endocrine disorders syndrome
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  percentage: "<1 per 1,000,000"
  notes: >-
    Orphadata reports a validated worldwide point-prevalence class below one
    per million, but supplies no measured numeric rate; this is therefore a
    class-only estimate.
  evidence:
  - reference: url:https://api.orphadata.com/rd-epidemiology/orphacodes/127
    reference_title: "https://api.orphadata.com/rd-epidemiology/orphacodes/127"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "PrevalenceClass": "<1 / 1 000 000", "PrevalenceGeographic": "Worldwide",
      "PrevalenceQualification": "Class only", "PrevalenceType": "Point prevalence"
    explanation: >-
      The current Orphadata epidemiology record provides the worldwide
      point-prevalence class used here and explicitly identifies it as
      class-only.
progression:
- phase: Neonatal and infantile presentation
  age_range: Neonatal period through infancy
  notes: >-
    Onset is classified as neonatal. Hypotonia and feeding difficulty are
    common early findings, although recognition of the full syndromic pattern
    and molecular diagnosis may occur later.
  evidence:
  - reference: url:https://api.orphadata.com/rd-natural_history/orphacodes/127
    reference_title: "https://api.orphadata.com/rd-natural_history/orphacodes/127"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "AverageAgeOfOnset": [ "Neonatal" ]
    explanation: The structured natural-history record assigns neonatal onset.
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0001252", "HPOTerm": "Hypotonia" },
      "HPOFrequency": "Very frequent (99-80%)"
    explanation: Orphadata identifies hypotonia as a very frequent early feature.
- phase: Neurodevelopmental manifestations
  age_range: Infancy through childhood
  notes: >-
    Motor milestones and speech are delayed, and intellectual disability ranges
    from mild to severe. Behavioral problems are common and may add substantial
    care needs.
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the individuals had delayed motor milestones. Intellectual
      disability varied in severity from mild to severe. Limited or delayed
      speech was common (18/19). Behavioural problems were also frequent
      (13/19, 6 males and 7 females).
    explanation: >-
      The 19-person PHF6 cohort documents the childhood neurodevelopmental
      course and its variable severity.
- phase: Evolving craniofacial, growth, and endocrine phenotype
  age_range: Late childhood through adulthood
  notes: >-
    Facial coarsening and truncal obesity often become more apparent from late
    childhood. Pubertal and gonadal manifestations require age-appropriate
    assessment; gynecomastia is particularly associated with older affected
    males.
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features tend to coarsen with age beginning in late childhood in
      association with the onset of obesity
    explanation: This directly supports an age-dependent facial and growth phenotype.
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gynaecomastia was reported in 5 males
    explanation: The cohort documents the age and sex concentration of gynecomastia.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    BFLS produces lifelong neurodevelopmental disability with variable speech
    limitation and behavior challenges, together with endocrine, visual,
    hearing, neurologic, skin, dental, and congenital complications that require
    multidisciplinary follow-up. Severity varies considerably, especially by
    sex and variant context, and the available cohorts are small; high burden
    does not imply uniformly severe expression in every affected person.
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the individuals had delayed motor milestones. Intellectual
      disability varied in severity from mild to severe. Limited or delayed
      speech was common (18/19). Behavioural problems were also frequent
      (13/19, 6 males and 7 females).
    explanation: >-
      Universal motor delay, frequent speech limitation, and behavioral
      morbidity in the cohort support substantial lifelong care needs.
inheritance:
- name: X-linked inheritance
  description: >-
    BFLS is caused by pathogenic PHF6 variants on the X chromosome. Affected
    males and females are both reported, with inherited variants and mildly
    affected or unaffected carrier females in some families and de novo,
    often more disruptive variants in many clinically affected females.
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual
      disability syndrome caused by variants in the PHF6 gene.
    explanation: This directly supports X-linked PHF6-related inheritance.
pathophysiology:
- name: PHF6-dependent transcriptional dysregulation
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Dysregulated Neurodevelopmental Transcriptional Program"
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    PHF6 is a chromatin-associated transcriptional regulator. Pathogenic PHF6
    variation disrupts broad transcriptional programs, including programs
    involved in chromatin regulation, axon development, neuronal development,
    and cortical neurogenesis. The causal gene-disease relationship is
    definitive, while the precise molecular consequence differs across variant
    classes and sex contexts.
  genes:
  - preferred_term: PHF6
    modifier: ABNORMAL
    term:
      id: hgnc:18145
      label: PHF6
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  downstream:
  - target: Ephrin receptor transcriptional dysregulation
    causal_link_type: DIRECT
    description: >-
      Mouse cortical binding, expression, knockdown, and rescue experiments
      identify Ephrin receptors as direct PHF6 transcriptional targets.
    evidence:
    - reference: DOI:10.1038/s44319-024-00082-0
      reference_title: PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We identify a panel of Ephrin receptors (EphRs) as direct
        transcriptional targets of PHF6.
      explanation: This directly supports the PHF6-to-Ephrin-receptor edge in the mouse cortical model.
  - target: Abnormal neuronal morphogenesis
    causal_link_type: DIRECT
    description: >-
      PHF6 knockout directly impairs proliferation, neurite outgrowth, and
      migration in a differentiated human neuron-like cell model.
    evidence:
    - reference: DOI:10.1038/s41598-020-75999-2
      reference_title: Loss of PHF6 leads to aberrant development of human neuron-like cells
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Subsequently, we could demonstrate that PHF6 is indeed required for
        proper neuron proliferation, neurite outgrowth and migration.
      explanation: The CRISPR cell model directly tests PHF6 loss and neuronal developmental readouts.
  - target: Human neurodevelopmental and neurologic manifestations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Pathogenic PHF6 variants cause the human neurodevelopmental syndrome, but
      several developmental intermediates between broad transcriptional
      dysregulation and each clinical manifestation remain unknown.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual
        disability syndrome caused by variants in the PHF6 gene.
      explanation: The human genotype-phenotype cohort establishes PHF6-related neurodevelopmental disease.
  - target: Human endocrine and growth manifestations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      PHF6-related disease is associated with truncal obesity and gonadal and
      pubertal abnormalities, but the organ-level causal intermediates are not
      established.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Affected males had classic features of BFLS including intellectual
        disability, distinctive facies, large ears, gynaecomastia, hypogonadism
        and truncal obesity.
      explanation: The clinical cohort directly links PHF6-related BFLS to its endocrine and growth phenotype cluster.
  - target: Human craniofacial, ectodermal, and congenital manifestations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The craniofacial, digital, skin, dental, retinal, and congenital findings
      form a reproducible PHF6-related phenotype cluster, although their
      tissue-specific developmental mechanisms are not yet resolved.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The phenotype of affected females with de novo variants overlapped with
        the males but included linear skin hyperpigmentation and a higher
        frequency of dental, retinal and cortical brain anomalies.
      explanation: The human cohort defines a recurrent multisystem phenotype, especially in affected females.
  evidence:
  - reference: CGGV:assertion_94ea5014-0a83-49ea-b001-fc2a8c24c0d9-2018-02-21T110000.000Z
    reference_title: "PHF6 / Borjeson-Forssman-Lehmann syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PHF6 | HGNC:18145 | Borjeson-Forssman-Lehmann syndrome | MONDO:0010537 | XL | Definitive"
    explanation: ClinGen classifies the PHF6-BFLS gene-disease relationship as definitive.
  - reference: DOI:10.1038/s41598-020-75999-2
    reference_title: Loss of PHF6 leads to aberrant development of human neuron-like cells
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Transcriptome analysis revealed a broad deregulation of genes involved in
      chromatin and transcriptional regulation as well as in axon and neuron
      development.
    explanation: The PHF6-knockout neuron-like cell model supports broad transcriptional dysregulation.
- name: Ephrin receptor transcriptional dysregulation
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    PHF6 binds regulatory regions near Ephrin receptor genes and promotes their
    expression in developing mouse cortex. BFLS patient-variant mice and
    conditional Phf6-knockout mice show impaired Ephrin receptor regulation.
    This is a strong preclinical pathway, but direct confirmation in human
    prenatal neural tissue is unavailable.
  genes:
  - preferred_term: EPHA4
    modifier: DECREASED
    term:
      id: hgnc:3388
      label: EPHA4
  - preferred_term: EPHA7
    modifier: DECREASED
    term:
      id: hgnc:3390
      label: EPHA7
  biological_processes:
  - preferred_term: ephrin receptor signaling pathway
    modifier: ABNORMAL
    term:
      id: GO:0048013
      label: ephrin receptor signaling pathway
  downstream:
  - target: Altered embryonic neural stem-cell regulation
    causal_link_type: DIRECT
    description: >-
      EphA-family knockdown phenocopies abnormal neural stem-cell self-renewal,
      and forced EphA4 or EphA7 expression rescues the mutant-cell phenotype in
      the mouse system.
    evidence:
    - reference: DOI:10.1038/s44319-024-00082-0
      reference_title: PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Knockdown of EphR-A phenocopies the PHF6 loss-of-function defects in
        altering eNSCs, and its forced expression rescues defects of BFLS
        mice-derived eNSCs.
      explanation: Knockdown and rescue experiments directly support this edge in embryonic mouse neural stem cells.
  evidence:
  - reference: DOI:10.1038/s44319-024-00082-0
    reference_title: PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our data indicate that PHF6 directly promotes Ephrin receptor expression
      to control eNSC behaviour in the developing brain, and that this pathway
      is impaired in BFLS.
    explanation: This summarizes the model-supported PHF6-Ephrin-receptor pathway.
- name: Altered embryonic neural stem-cell regulation
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    PHF6 loss or BFLS patient variants alter neural precursor self-renewal and
    progenitor output. Two recent mouse-model studies agree that precursor
    regulation is abnormal but report opposite directions for self-renewal,
    making the directional mechanism unresolved.
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  biological_processes:
  - preferred_term: stem cell population maintenance
    modifier: ABNORMAL
    term:
      id: GO:0019827
      label: stem cell population maintenance
  - preferred_term: neural precursor cell proliferation
    modifier: ABNORMAL
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
  downstream:
  - target: Human neurodevelopmental and neurologic manifestations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disrupted prenatal precursor regulation is a plausible contributor to
      human BFLS neurodevelopment, but translation from the conflicting mouse
      cellular phenotypes to specific human manifestations is incomplete.
    evidence:
    - reference: DOI:10.1038/s44319-024-00082-0
      reference_title: PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Characterization of BFLS mice harbouring PHF6 patient mutations reveals
        an increase in embryonic neural stem cell (eNSC) self-renewal and a
        reduction of neural progenitors.
      explanation: The mouse model supports a developmental link but cannot establish the full human clinical pathway.
  evidence:
  - reference: DOI:10.1038/s44319-024-00082-0
    reference_title: PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Characterization of BFLS mice harbouring PHF6 patient mutations reveals
      an increase in embryonic neural stem cell (eNSC) self-renewal and a
      reduction of neural progenitors.
    explanation: One BFLS mouse-model study reports increased self-renewal and reduced progenitor output.
  - reference: DOI:10.1371/journal.pgen.1011428
    reference_title: Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson–Forssman–Lehmann intellectual disability syndrome
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Phf6 deficient neural precursor cells showed a reduced capacity for
      self-renewal and increased differentiation into neurons.
    explanation: >-
      A separate mouse-model study supports abnormal precursor regulation but
      reports the opposite self-renewal direction.
- name: Abnormal neuronal morphogenesis
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Impaired Neuronal Maturation, Plasticity, and Postnatal Neurogenesis"
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    CRISPR-mediated PHF6 knockout in human neuron-like cells perturbs
    proliferation, neurite extension, and migration. These observations provide
    direct cellular evidence, but the transformed-cell differentiation model
    does not reproduce human prenatal cortical development.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neuron migration
    modifier: ABNORMAL
    term:
      id: GO:0001764
      label: neuron migration
  - preferred_term: axon development
    modifier: ABNORMAL
    term:
      id: GO:0061564
      label: axon development
  downstream:
  - target: Human neurodevelopmental and neurologic manifestations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal neuronal growth and migration plausibly contribute to cognitive
      and cortical findings, but the cell model does not directly demonstrate
      individual human clinical outcomes.
    evidence:
    - reference: DOI:10.1038/s41598-020-75999-2
      reference_title: Loss of PHF6 leads to aberrant development of human neuron-like cells
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Impairment of these processes might therefore contribute to the
        neurodevelopmental and cognitive dysfunction in BFLS.
      explanation: The authors explicitly frame translation from cell readouts to human dysfunction as contributory rather than definitive.
  evidence:
  - reference: DOI:10.1038/s41598-020-75999-2
    reference_title: Loss of PHF6 leads to aberrant development of human neuron-like cells
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Subsequently, we could demonstrate that PHF6 is indeed required for
      proper neuron proliferation, neurite outgrowth and migration.
    explanation: This directly supports the cellular neuronal-development phenotype.
- name: Human neurodevelopmental and neurologic manifestations
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Intellectual Disability with Growth and Craniofacial Dysmorphism"
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Neurodevelopmental and neurologic manifestations are an established
    clinical consequence cluster of pathogenic PHF6 variation. This node
    records the human genotype-phenotype relationship without asserting that
    one preclinical cellular pathway explains every manifestation.
  downstream:
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Intellectual disability is the defining cognitive manifestation of PHF6-related BFLS.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Intellectual disability varied in severity from mild to severe.
      explanation: The human cohort directly supports variable intellectual disability.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Delayed motor development is a universal early manifestation in the reported cohort.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: All the individuals had delayed motor milestones.
      explanation: This directly supports global developmental delay as a core manifestation.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypotonia is a common early neurologic manifestation.
    evidence:
    - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
      reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        "HPOId": "HP:0001252", "HPOTerm": "Hypotonia" },
        "HPOFrequency": "Very frequent (99-80%)"
      explanation: Orphadata classifies hypotonia as very frequent.
  - target: Feeding difficulties in infancy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Feeding difficulty is a frequent infantile manifestation with multifactorial developmental causes.
    evidence:
    - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
      reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        "HPOId": "HP:0008872", "HPOTerm": "Feeding difficulties in infancy" },
        "HPOFrequency": "Frequent (79-30%)"
      explanation: Orphadata classifies infantile feeding difficulty as frequent.
  - target: Delayed speech and language development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Delayed or limited speech is a common neurodevelopmental manifestation.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Limited or delayed speech was common (18/19).
      explanation: The cohort directly quantifies delayed or limited speech.
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Seizures occur in a minority of affected males and females.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Two males and one female had a history of seizures.
      explanation: This replaces model-only support with direct human clinical evidence.
  - target: Cortical brain anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Structural cortical abnormalities are particularly reported in affected females.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The phenotype of affected females with de novo variants overlapped with
        the males but included linear skin hyperpigmentation and a higher
        frequency of dental, retinal and cortical brain anomalies.
      explanation: The cohort directly supports cortical abnormalities in the female de novo-variant phenotype.
  - target: Peripheral neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Peripheral neuropathy is an occasional neurologic complication.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Complications observed in our series included keloid scarring, digital
        fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and
        talipes.
      explanation: The cohort reports neuropathy as a BFLS complication.
  - target: Hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Conductive and sensorineural hearing impairment have both been reported.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Nine individuals had a history of recurrent otitis media or conductive
        hearing loss or had required grommet insertion. Two had mild
        sensorineural hearing loss.
      explanation: The cohort directly documents both conductive and sensorineural hearing loss.
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Shared clinical features include early developmental delay, intellectual
      disability and obesity.
    explanation: The cohort confirms the shared neurodevelopmental phenotype across sexes.
- name: Human endocrine and growth manifestations
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Truncal obesity, hypogonadism or small external genitalia, pubertal
    abnormalities, and gynecomastia are established clinical components of
    PHF6-related BFLS, although their tissue-specific molecular mechanisms are
    not established.
  downstream:
  - target: Truncal obesity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Truncal obesity is a classic and usually age-emergent BFLS manifestation.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Many individuals were described as obese, had truncal obesity, or a BMI
        > 2 standard deviations (SD) above mean for age (9/10 males, 6/7 females).
      explanation: The cohort directly quantifies obesity across affected males and females.
  - target: Hypogonadism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Gonadal or external-genital underdevelopment occurs in both affected males and females.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Small external genitalia or features of hypogonadism were noted in six
        males and four females.
      explanation: The cohort documents hypogonadal features in both sexes.
  - target: Gynecomastia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Gynecomastia is concentrated in older affected males.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Gynaecomastia was reported in 5 males
      explanation: The cohort directly supports the sex- and age-specific manifestation.
  - target: Short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Short stature is variable and more characteristic of affected males.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Short stature was common. Height was below average in 9/10 males
      explanation: The cohort documents reduced height particularly among affected males.
  - target: Cryptorchidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Undescended testes are part of the male genital phenotype.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Undescended testes were present in three.
      explanation: The cohort directly reports cryptorchidism in affected males.
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected males had classic features of BFLS including intellectual
      disability, distinctive facies, large ears, gynaecomastia, hypogonadism
      and truncal obesity.
    explanation: The cohort confirms the characteristic endocrine and growth phenotype.
- name: Human craniofacial, ectodermal, and congenital manifestations
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Characteristic facial and digital morphology occurs in both sexes. Affected
    females with de novo PHF6 variants often have additional ectodermal,
    pigmentary, dental, retinal, and cortical features. This clinical cluster is
    established even though its tissue-specific molecular pathway is unknown.
  downstream:
  - target: Large earlobe
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Large fleshy earlobes are a characteristic craniofacial finding.
    evidence:
    - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
      reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        "HPOId": "HP:0009748", "HPOTerm": "Large earlobe" },
        "HPOFrequency": "Very frequent (99-80%)"
      explanation: Orphadata classifies large earlobes as very frequent.
  - target: Coarse facial features
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Facial coarsening develops with age and is a characteristic BFLS finding.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Facial features tended to coarsen with age leading to a prominent brow
        and bulbous nose.
      explanation: The cohort directly supports age-dependent facial coarsening.
  - target: Linear skin hyperpigmentation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Blaschko-linear hyperpigmentation is especially characteristic of affected females.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The phenotype of affected females with de novo variants overlapped with
        the males but included linear skin hyperpigmentation and a higher
        frequency of dental, retinal and cortical brain anomalies.
      explanation: The cohort directly supports the female-predominant pigmentary phenotype.
  - target: Dental anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Dental anomalies are particularly common in affected females.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Affected females had a high rate of dental anomalies (6/8 in our series,
        18/20 in previous patients
      explanation: The cohort and literature comparison directly support frequent dental anomalies in affected females.
  - target: Retinal anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Retinal and optic-nerve abnormalities are especially reported in affected females.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The phenotype of affected females with de novo variants overlapped with
        the males but included linear skin hyperpigmentation and a higher
        frequency of dental, retinal and cortical brain anomalies.
      explanation: This directly supports retinal abnormalities in the affected-female phenotype.
  - target: Keloid scarring
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypertrophic or keloid scarring is a reported skin complication.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Complications observed in our series included keloid scarring, digital
        fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and
        talipes.
      explanation: The cohort directly reports keloid scarring.
  - target: Umbilical hernia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Umbilical hernia is a reported congenital complication.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Complications observed in our series included keloid scarring, digital
        fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and
        talipes.
      explanation: The cohort directly reports umbilical hernias.
  - target: Talipes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Talipes is a reported congenital limb anomaly.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Complications observed in our series included keloid scarring, digital
        fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and
        talipes.
      explanation: The cohort directly reports talipes.
  - target: Sparse hair
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Sparse or slow-growing hair is part of the ectodermal phenotype.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Sparse, fine or slow growing hair was reported in four females and two males.
      explanation: The cohort directly supports sparse hair in both sexes.
  - target: Tapered finger
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Short tapering fingers are characteristic in affected males and females.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Males and females had short, tapering fingers often with 5th finger
        clinodactyly and broad feet with short toes
      explanation: The cohort directly supports tapering fingers.
  - target: Broad foot
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Broad feet are characteristic digital findings.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Males and females had short, tapering fingers often with 5th finger
        clinodactyly and broad feet with short toes
      explanation: The cohort directly supports broad feet.
  - target: Short toe
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Short toes are characteristic digital findings.
    evidence:
    - reference: DOI:10.1038/s41431-023-01447-0
      reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Males and females had short, tapering fingers often with 5th finger
        clinodactyly and broad feet with short toes
      explanation: The cohort directly supports short toes.
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      deep-set eyes, narrow palpebral fissures, large, fleshy ears, bulbous nasal
      tip, tapering fingers, and broad feet with short and/or flexed toes.
    explanation: The cohort defines the craniofacial and digital phenotype shared across sexes.
phenotypes:
- name: Intellectual disability
  category: Neurologic
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Intellectual disability is a defining feature and ranges from mild to
    severe in reported affected individuals.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Intellectual disability varied in severity from mild to severe.
    explanation: The human cohort directly supports the core phenotype and its variable severity.
- name: Global developmental delay
  category: Neurologic
  frequency: VERY_FREQUENT
  diagnostic: true
  description: Delayed motor milestones are a core early manifestation.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All the individuals had delayed motor milestones.
    explanation: All 19 cohort participants had motor developmental delay.
- name: Hypotonia
  category: Neurologic
  frequency: VERY_FREQUENT
  description: Hypotonia is a characteristic infantile feature.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0001252", "HPOTerm": "Hypotonia" },
      "HPOFrequency": "Very frequent (99-80%)"
    explanation: Orphadata classifies hypotonia as very frequent.
- name: Feeding difficulties in infancy
  category: Gastrointestinal
  frequency: FREQUENT
  description: Feeding difficulty is a common early-life manifestation.
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0008872", "HPOTerm": "Feeding difficulties in infancy" },
      "HPOFrequency": "Frequent (79-30%)"
    explanation: Orphadata classifies infantile feeding difficulty as frequent.
- name: Delayed speech and language development
  category: Neurologic
  frequency: VERY_FREQUENT
  description: Speech is commonly delayed or limited.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Limited or delayed speech was common (18/19).
    explanation: The cohort places delayed or limited speech in the very-frequent band.
- name: Truncal obesity
  category: Metabolic
  frequency: VERY_FREQUENT
  description: >-
    Truncal obesity is a classic manifestation that often becomes more apparent
    from late childhood.
  phenotype_term:
    preferred_term: Truncal obesity
    term:
      id: HP:0001956
      label: Truncal obesity
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many individuals were described as obese, had truncal obesity, or a BMI
      > 2 standard deviations (SD) above mean for age (9/10 males, 6/7 females).
    explanation: Fifteen of seventeen evaluable cohort participants met an obesity description or threshold.
- name: Hypogonadism
  category: Endocrine
  frequency: VERY_FREQUENT
  description: >-
    Hypogonadism or small external genitalia occurs in affected males and
    females; ascertainment depends on age and pubertal status.
  phenotype_term:
    preferred_term: Hypogonadism
    term:
      id: HP:0000135
      label: Hypogonadism
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0000135", "HPOTerm": "Hypogonadism" },
      "HPOFrequency": "Very frequent (99-80%)"
    explanation: Orphadata classifies hypogonadism as very frequent.
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Small external genitalia or features of hypogonadism were noted in six
      males and four females.
    explanation: The recent cohort documents hypogonadal findings across both sexes.
- name: Large earlobe
  category: Morphological
  frequency: VERY_FREQUENT
  description: Large fleshy earlobes are part of the characteristic facial phenotype.
  phenotype_term:
    preferred_term: Large earlobe
    term:
      id: HP:0009748
      label: Large earlobe
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0009748", "HPOTerm": "Large earlobe" },
      "HPOFrequency": "Very frequent (99-80%)"
    explanation: Orphadata classifies large earlobes as very frequent.
- name: Gynecomastia
  category: Endocrine
  description: Gynecomastia is particularly reported in older affected males.
  phenotype_term:
    preferred_term: Gynecomastia
    term:
      id: HP:0000771
      label: Gynecomastia
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gynaecomastia was reported in 5 males
    explanation: The cohort directly supports the sex- and age-specific phenotype.
- name: Coarse facial features
  category: Morphological
  frequency: VERY_FREQUENT
  diagnostic: true
  description: Facial features coarsen with age, with a prominent brow and bulbous nose.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features tended to coarsen with age leading to a prominent brow
      and bulbous nose.
    explanation: The cohort directly supports the age-dependent facial phenotype.
- name: Linear skin hyperpigmentation
  category: Dermatologic
  description: >-
    Blaschko-linear or streaky hyperpigmentation is a distinctive finding in
    affected females with de novo PHF6 variants.
  phenotype_term:
    preferred_term: Linear skin hyperpigmentation
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotype of affected females with de novo variants overlapped with
      the males but included linear skin hyperpigmentation and a higher
      frequency of dental, retinal and cortical brain anomalies.
    explanation: This directly supports linear pigmentation in the affected-female phenotype.
- name: Dental anomalies
  category: Dental
  description: Dental abnormalities are especially common in affected females.
  phenotype_term:
    preferred_term: Dental anomalies
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected females had a high rate of dental anomalies (6/8 in our series,
      18/20 in previous patients
    explanation: The cohort and literature comparison directly support frequent female dental anomalies.
- name: Retinal anomalies
  category: Ophthalmologic
  description: Retinal and optic-nerve abnormalities are especially reported in affected females.
  phenotype_term:
    preferred_term: Retinal anomalies
    term:
      id: HP:0000479
      label: Abnormal retinal morphology
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotype of affected females with de novo variants overlapped with
      the males but included linear skin hyperpigmentation and a higher
      frequency of dental, retinal and cortical brain anomalies.
    explanation: This directly supports retinal abnormalities in affected females.
- name: Cortical brain anomalies
  category: Neurologic
  description: Malformations of cortical development occur particularly in affected females.
  phenotype_term:
    preferred_term: Cortical brain anomalies
    term:
      id: HP:0002538
      label: Abnormal cerebral cortex morphology
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotype of affected females with de novo variants overlapped with
      the males but included linear skin hyperpigmentation and a higher
      frequency of dental, retinal and cortical brain anomalies.
    explanation: This directly supports cortical abnormalities in affected females.
- name: Keloid scarring
  category: Dermatologic
  description: Hypertrophic or keloid scarring is a reported complication.
  phenotype_term:
    preferred_term: Keloid scarring
    term:
      id: HP:0010562
      label: Keloids
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complications observed in our series included keloid scarring, digital
      fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and
      talipes.
    explanation: The human cohort directly reports keloid scarring.
- name: Peripheral neuropathy
  category: Neurologic
  frequency: OCCASIONAL
  description: Peripheral neuropathy is an occasional neurologic complication.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complications observed in our series included keloid scarring, digital
      fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and
      talipes.
    explanation: The cohort reports neuropathy, mapped here to the HPO peripheral-neuropathy term.
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0009830", "HPOTerm": "Peripheral neuropathy" },
      "HPOFrequency": "Occasional (29-5%)"
    explanation: Orphadata classifies peripheral neuropathy as occasional.
- name: Umbilical hernia
  category: Morphological
  description: Umbilical hernia is a reported congenital complication.
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complications observed in our series included keloid scarring, digital
      fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and
      talipes.
    explanation: The cohort directly reports umbilical hernias.
- name: Talipes
  category: Morphological
  description: Talipes is a reported congenital limb anomaly.
  phenotype_term:
    preferred_term: Talipes
    term:
      id: HP:0001883
      label: Talipes
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complications observed in our series included keloid scarring, digital
      fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and
      talipes.
    explanation: The cohort directly reports talipes.
- name: Seizure
  category: Neurologic
  frequency: OCCASIONAL
  description: Seizures occur in a minority of affected males and females.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Two males and one female had a history of seizures.
    explanation: Direct human evidence supports seizures in both sexes.
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0001250", "HPOTerm": "Seizure" },
      "HPOFrequency": "Occasional (29-5%)"
    explanation: Orphadata classifies seizures as occasional.
- name: Hearing impairment
  category: Audiologic
  frequency: OCCASIONAL
  description: Conductive hearing loss and mild sensorineural hearing loss have both been reported.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nine individuals had a history of recurrent otitis media or conductive
      hearing loss or had required grommet insertion. Two had mild
      sensorineural hearing loss.
    explanation: The cohort directly reports conductive and sensorineural hearing loss.
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0000365", "HPOTerm": "Hearing impairment" },
      "HPOFrequency": "Occasional (29-5%)"
    explanation: Orphadata classifies hearing impairment as occasional.
- name: Short stature
  category: Growth
  description: Reduced height is variable and more characteristic of affected males.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Short stature was common. Height was below average in 9/10 males
    explanation: The cohort directly documents reduced height among affected males.
- name: Cryptorchidism
  category: Genitourinary
  description: Undescended testes are part of the male genital phenotype.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Undescended testes were present in three.
    explanation: The cohort directly reports cryptorchidism.
- name: Sparse hair
  category: Dermatologic
  description: Sparse, fine, or slow-growing hair occurs in affected males and females.
  phenotype_term:
    preferred_term: Sparse hair
    term:
      id: HP:0008070
      label: Sparse hair
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sparse, fine or slow growing hair was reported in four females and two males.
    explanation: The cohort directly reports sparse hair in both sexes.
- name: Tapered finger
  category: Morphological
  frequency: VERY_FREQUENT
  description: Short tapering fingers are characteristic in affected males and females.
  phenotype_term:
    preferred_term: Tapered finger
    term:
      id: HP:0001182
      label: Tapered finger
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0001182", "HPOTerm": "Tapered finger" },
      "HPOFrequency": "Very frequent (99-80%)"
    explanation: Orphadata classifies tapered fingers as very frequent.
- name: Broad foot
  category: Morphological
  frequency: VERY_FREQUENT
  description: Broad feet are characteristic digital findings.
  phenotype_term:
    preferred_term: Broad foot
    term:
      id: HP:0001769
      label: Broad foot
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0001769", "HPOTerm": "Broad foot" },
      "HPOFrequency": "Very frequent (99-80%)"
    explanation: Orphadata classifies broad feet as very frequent.
- name: Short toe
  category: Morphological
  frequency: VERY_FREQUENT
  description: Short toes are characteristic digital findings.
  phenotype_term:
    preferred_term: Short toe
    term:
      id: HP:0001831
      label: Short toe
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0001831", "HPOTerm": "Short toe" },
      "HPOFrequency": "Very frequent (99-80%)"
    explanation: Orphadata classifies short toes as very frequent.
biochemical: []
genetic:
- name: PHF6
  association: Pathogenic PHF6 variants
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: PHF6
    term:
      id: hgnc:18145
      label: PHF6
  notes: >-
    The PHF6-BFLS relationship is definitive. Affected males often have
    inherited missense variants or small in-frame deletions, while affected
    females more often have de novo truncating variants or large
    deletions/duplications. This is a cohort-level pattern rather than an
    absolute genotype-phenotype rule; missense variants also occur in affected
    females and X-inactivation does not fully explain severity.
  evidence:
  - reference: CGGV:assertion_94ea5014-0a83-49ea-b001-fc2a8c24c0d9-2018-02-21T110000.000Z
    reference_title: "PHF6 / Borjeson-Forssman-Lehmann syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PHF6 | HGNC:18145 | Borjeson-Forssman-Lehmann syndrome | MONDO:0010537 | XL | Definitive"
    explanation: ClinGen classifies the PHF6-BFLS relationship as definitive with X-linked inheritance.
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected males often have missense variants or small in-frame deletions
      while affected females tend to have truncating variants or large
      deletions/duplications.
    explanation: The cohort supports the sex-associated variant-class pattern.
environmental: []
diagnosis:
- name: Clinical recognition of the BFLS pattern
  description: >-
    Clinical suspicion is raised by developmental delay or intellectual
    disability with characteristic facial and digital findings, infantile
    hypotonia, truncal obesity, and hypogonadism. Blaschko-linear pigmentation
    and dental, retinal, or cortical anomalies are particularly informative in
    affected females.
  presence: A compatible syndromic neurodevelopmental phenotype prompts PHF6 testing.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: url:https://api.orphadata.com/rd-cross-referencing/orphacodes/127
    reference_title: "https://api.orphadata.com/rd-cross-referencing/orphacodes/127"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Borjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked obesity
      syndrome characterized by intellectual deficit, truncal obesity,
      characteristic facial features, hypogonadism, tapered fingers and short
      toes.
    explanation: The Orphadata definition supplies the core recognizable clinical pattern.
- name: PHF6 molecular genetic testing
  description: >-
    Molecular confirmation requires identification and clinical interpretation
    of a pathogenic or likely pathogenic PHF6 variant. Testing should be able to
    detect both sequence variants and exon-level or whole-gene copy-number
    changes because the observed spectrum includes missense, splice, frameshift,
    nonsense, in-frame, deletion, and duplication variants.
  presence: Identification of a pathogenic or likely pathogenic PHF6 variant establishes the molecular diagnosis.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: PHF6
        term:
          id: hgnc:18145
          label: PHF6
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We ascertained 19 individuals from 15 families with likely pathogenic or
      pathogenic PHF6 variants (11 males and 8 females).
    explanation: The molecularly ascertained cohort supports PHF6 testing as the confirmatory approach.
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected males often have missense variants or small in-frame deletions
      while affected females tend to have truncating variants or large
      deletions/duplications.
    explanation: The variant spectrum supports both sequence and copy-number analysis.
differential_diagnoses:
- name: Coffin-Siris syndrome
  description: >-
    Coffin-Siris syndrome can overlap in young affected females through
    intellectual disability, sparse hair, and hypoplastic nails. PHF6 testing,
    Blaschko-linear pigmentation, and the broader BFLS sex- and
    variant-associated pattern help resolve the distinction.
  disease_term:
    preferred_term: Coffin-Siris syndrome
    term:
      id: MONDO:0015452
      label: Coffin-Siris syndrome
  distinguishing_features:
  - BFLS is molecularly defined by pathogenic PHF6 variation rather than a BAF/SWI-SNF complex gene defect.
  - Blaschko-linear pigmentation and the BFLS endocrine pattern favor PHF6-related disease.
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotypic combination of ID, sparse hair and hypoplastic nails in
      younger affected females has been noted to overlap with Coffin-Siris
      syndrome (MIM# 135900)
    explanation: The cohort explicitly identifies Coffin-Siris syndrome as a clinical overlap.
- name: Incontinentia pigmenti
  description: >-
    Incontinentia pigmenti is an important differential in affected females
    with Blaschko-linear pigmentation and ectodermal, dental, retinal, or
    neurologic findings. IKBKG testing distinguishes it from PHF6-related BFLS.
  disease_term:
    preferred_term: IKBKG-related immunodeficiency with or without ectodermal dysplasia
    term:
      id: MONDO:0100162
      label: IKBKG-related immunodeficiency with or without ectodermal dysplasia
  distinguishing_features:
  - Incontinentia pigmenti is caused by pathogenic IKBKG variants, whereas BFLS is caused by PHF6 variants.
  - The BFLS phenotype includes its characteristic facial, digital, obesity, and hypogonadism pattern.
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The streaky skin pigmentation in F1, F3 and F5 led to incontinentia
      pigmenti being considered and IKBKG gene testing being arranged.
    explanation: The cohort documents real-world consideration and molecular exclusion of this differential.
- name: Terminal osseous dysplasia-pigmentary defects syndrome
  description: >-
    Terminal osseous dysplasia with pigmentary defects overlaps in affected
    females through pigmentary abnormalities, digital anomalies, and recurrent
    digital fibromas. FLNA testing and the disorder-specific skeletal pattern
    distinguish it from PHF6-related BFLS.
  disease_term:
    preferred_term: terminal osseous dysplasia-pigmentary defects syndrome
    term:
      id: MONDO:0010279
      label: terminal osseous dysplasia-pigmentary defects syndrome
  distinguishing_features:
  - Terminal osseous dysplasia-pigmentary defects syndrome is caused by a recurrent FLNA splice-altering variant rather than PHF6 variation.
  - BFLS has a characteristic neurodevelopmental, obesity, hypogonadism, facial, and digital phenotype.
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similarly, a diagnosis of TODPD was considered for F2 due to her
      combination of pigmentary abnormalities, digital anomalies, and recurrent
      digital fibromas.
    explanation: The cohort explicitly identifies TODPD as a differential in an affected female.
datasets:
- accession: geo:GSE247838
  title: PHF6 regulation of developing mouse cortex and neural stem cells
  description: >-
    Disease-mechanism dataset associated with the PHF6-Ephrin-receptor study,
    combining PHF6 cortical ChIP-seq with bulk RNA-seq after Phf6 knockdown in
    embryonic mouse cortical progenitors.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: MULTI_OMICS_PERTURBATION
  sample_types:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
    tissue_term:
      preferred_term: cerebral cortex
      term:
        id: UBERON:0000956
        label: cerebral cortex
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
    cell_type_term:
      preferred_term: neural stem cell
      term:
        id: CL:0000047
        label: neural stem cell
  conditions:
  - PHF6 cortical chromatin immunoprecipitation and IgG control
  - Phf6 siRNA knockdown and non-targeting control in embryonic cortical progenitors
  publication: DOI:10.1038/s44319-024-00082-0
  evidence:
  - reference: DOI:10.1038/s44319-024-00082-0
    reference_title: PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Gene Expression Omnibus (GEO GSE247838).
    explanation: The publication directly identifies GSE247838 as the repository accession.
  notes: >-
    GSE153164 and BrainSpan are reused developmental atlases rather than
    BFLS-generated datasets and are not represented as disease datasets here.
clinical_trials: []
treatments:
- name: Neurodevelopmental follow-up and supportive intervention
  action_category: MONITORING
  description: >-
    Longitudinal developmental, neurologic, communication, behavioral, and
    educational assessment should guide individualized supportive therapies.
  treatment_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A range of recommendations for the initial evaluation and management of
      BFLS patients are presented in Supplementary Tables S5 and S6.
    explanation: The cohort authors explicitly recommend neurodevelopmental follow-up.
- name: Endocrinology and pubertal review
  action_category: MONITORING
  description: >-
    Age-appropriate endocrinology assessment should evaluate growth, obesity,
    gonadal development, pubertal progression, and related endocrine concerns.
  treatment_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      endocrinology review, eye checks and skin care.
    explanation: The cohort authors explicitly recommend endocrinology review.
- name: Ophthalmologic surveillance
  action_category: MONITORING
  description: >-
    Baseline and follow-up eye examinations should be individualized to detect
    refractive errors, strabismus, nystagmus, retinal disease, and optic-nerve
    abnormalities.
  treatment_term:
    preferred_term: eye examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      endocrinology review, eye checks and skin care.
    explanation: The cohort authors explicitly recommend eye checks.
- name: Skin assessment and supportive care
  action_category: THERAPEUTIC
  description: >-
    Skin care should address hypertrophic or keloid scarring, painful or
    recurrent digital fibromas, pigmentary changes, and wound-related concerns
    according to individual findings.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Keloid scarring
    term:
      id: HP:0010562
      label: Keloids
  - preferred_term: Linear skin hyperpigmentation
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      endocrinology review, eye checks and skin care.
    explanation: The cohort authors explicitly recommend skin care.
discussions:
- discussion_id: bfls_neural_stem_cell_direction
  prompt: >-
    Does PHF6 loss increase or decrease embryonic neural stem-cell self-renewal,
    and which experimental variable explains the opposite findings across
    recent BFLS mouse models?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Altered embryonic neural stem-cell regulation
  rationale: >-
    One BFLS patient-variant and conditional-knockout study reports increased
    self-renewal with fewer neural progenitors, whereas another Phf6-deficient
    model reports reduced self-renewal with increased neuronal differentiation.
    The graph therefore records abnormal regulation without fixing its
    direction.
  evidence:
  - reference: DOI:10.1038/s44319-024-00082-0
    reference_title: PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Characterization of BFLS mice harbouring PHF6 patient mutations reveals
      an increase in embryonic neural stem cell (eNSC) self-renewal and a
      reduction of neural progenitors.
    explanation: This study reports increased self-renewal.
  - reference: DOI:10.1371/journal.pgen.1011428
    reference_title: Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson–Forssman–Lehmann intellectual disability syndrome
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Phf6 deficient neural precursor cells showed a reduced capacity for
      self-renewal and increased differentiation into neurons.
    explanation: This study reports reduced self-renewal.
- discussion_id: bfls_sex_variant_x_inactivation
  prompt: >-
    How do variant class, residual PHF6 activity, tissue-specific
    X-chromosome inactivation, and ascertainment combine to determine BFLS
    expression in affected females and males?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#PHF6
  rationale: >-
    Variant-class patterns differ strongly by sex, yet overlapping variants,
    affected and unaffected carrier females, and discordant X-inactivation
    observations prevent a simple deterministic genotype-phenotype model.
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, a clear correlation between XCI and disease severity has not
      been demonstrated.
    explanation: The cohort explicitly states that X-inactivation does not yet explain severity.
- discussion_id: bfls_cancer_risk
  prompt: >-
    Is germline PHF6-related BFLS associated with a clinically meaningful
    age-specific cancer risk that warrants syndrome-specific surveillance?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    Somatic PHF6 variants occur in cancers and a few cancers have been reported
    in people with BFLS, but the denominator is very small and no risk estimate
    supports a syndrome-specific screening schedule. Cancer surveillance is
    therefore not represented as established BFLS management.
  evidence:
  - reference: DOI:10.1038/s41431-023-01447-0
    reference_title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, at present, the cancer risk for BFLS patients remains
      uncertain due to lack of evidence.
    explanation: The clinical-spectrum paper explicitly identifies cancer risk as unresolved.
- discussion_id: bfls_ephrin_translation
  prompt: >-
    Does the PHF6-Ephrin-receptor rescue pathway observed in mouse embryonic
    neural stem cells translate to human prenatal neurodevelopment or a safe
    therapeutic strategy?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Ephrin receptor transcriptional dysregulation
  rationale: >-
    EphA4 or EphA7 expression rescues a cell-level phenotype in mouse-derived
    embryonic neural stem cells, but this does not establish efficacy, safety,
    timing, or delivery in humans. The rescue is represented as mechanistic
    evidence and not as a treatment.
  evidence:
  - reference: DOI:10.1038/s44319-024-00082-0
    reference_title: PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      EphR-A family of receptors rescues PHF6 loss-of-function defects in BFLS
      mice-derived eNSCs.
    explanation: The rescue experiment is confined to mouse-derived embryonic neural stem cells.
review_notes: >-
  The 2026 re-review replaced the original narrow phenotype list with a
  sex-aware clinical profile grounded in the 19-person PHF6 cohort and current
  Orphadata records, added neonatal onset, progression, ultra-rare prevalence,
  high but variable clinical burden, diagnostic strategy, explicit
  differentials, monitoring and supportive management, and GSE247838, the
  disease-mechanism GEO dataset. Every pathograph edge now states
  mechanistic directness and carries evidence; preclinical cellular mechanisms
  remain provisional, while human phenotype-cluster nodes avoid pretending
  that one mouse pathway explains all multisystem findings. The contradictory
  neural-stem-cell self-renewal results, unresolved sex/variant/X-inactivation
  model, uncertain cancer risk, and preclinical status of Ephrin-receptor rescue
  are explicitly retained as open discussions. ClinicalTrials.gov API queries
  for "Borjeson-Forssman-Lehmann syndrome" and "PHF6 syndrome" were checked on
  2026-07-24 and returned no disease-specific studies, so clinical_trials
  remains empty. No disease-modifying treatment is established. The D2P audit
  identified many externally asserted granular features; central
  source-backed findings were added, but rows lacking precise cached human
  support were not bulk-imported. The bundled Asta report was used only for
  source discovery; all curated assertions were checked against direct
  reference caches.
references:
- reference: DOI:10.1038/s41431-023-01447-0
  title: "Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families"
  findings: []
- reference: DOI:10.1038/s41598-020-75999-2
  title: Loss of PHF6 leads to aberrant development of human neuron-like cells
  findings: []
- reference: DOI:10.1038/s44319-024-00082-0
  title: PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS
  findings: []
- reference: DOI:10.1371/journal.pgen.1011428
  title: Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson–Forssman–Lehmann intellectual disability syndrome
  findings: []
- reference: CGGV:assertion_94ea5014-0a83-49ea-b001-fc2a8c24c0d9-2018-02-21T110000.000Z
  title: "PHF6 / Borjeson-Forssman-Lehmann syndrome (Definitive)"
  findings: []
- reference: url:https://api.orphadata.com/rd-cross-referencing/orphacodes/127
  title: "https://api.orphadata.com/rd-cross-referencing/orphacodes/127"
  findings: []
- reference: url:https://api.orphadata.com/rd-epidemiology/orphacodes/127
  title: "https://api.orphadata.com/rd-epidemiology/orphacodes/127"
  findings: []
- reference: url:https://api.orphadata.com/rd-natural_history/orphacodes/127
  title: "https://api.orphadata.com/rd-natural_history/orphacodes/127"
  findings: []
- reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
  title: "https://api.orphadata.com/rd-phenotypes/orphacodes/127"
  findings: []
📚

References & Deep Research

References

9
DOI:10.1038/s41431-023-01447-0
Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families
No top-level findings curated for this source.
DOI:10.1038/s41598-020-75999-2
Loss of PHF6 leads to aberrant development of human neuron-like cells
No top-level findings curated for this source.
DOI:10.1038/s44319-024-00082-0
PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS
No top-level findings curated for this source.
DOI:10.1371/journal.pgen.1011428
Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson–Forssman–Lehmann intellectual disability syndrome
No top-level findings curated for this source.
CGGV:assertion_94ea5014-0a83-49ea-b001-fc2a8c24c0d9-2018-02-21T110000.000Z
PHF6 / Borjeson-Forssman-Lehmann syndrome (Definitive)
No top-level findings curated for this source.
url:https://api.orphadata.com/rd-cross-referencing/orphacodes/127
https://api.orphadata.com/rd-cross-referencing/orphacodes/127
No top-level findings curated for this source.
url:https://api.orphadata.com/rd-epidemiology/orphacodes/127
https://api.orphadata.com/rd-epidemiology/orphacodes/127
No top-level findings curated for this source.
url:https://api.orphadata.com/rd-natural_history/orphacodes/127
https://api.orphadata.com/rd-natural_history/orphacodes/127
No top-level findings curated for this source.
url:https://api.orphadata.com/rd-phenotypes/orphacodes/127
https://api.orphadata.com/rd-phenotypes/orphacodes/127
No top-level findings curated for this source.

Deep Research

1
Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Borjeson-Forssman-Lehmann syndrome. Core disease mechanisms, molecular and...
Asta Scientific Corpus Retrieval 20 citations 2026-04-15T11:45:31.142880

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Borjeson-Forssman-Lehmann syndrome. Core disease mechanisms, molecular and...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

  • Authors: M. M. Wong, L. Watson, Esther B. E. Becker
  • Year: 2017
  • Venue: Journal of neurology & neuromedicine
  • URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
  • DOI: 10.29245/2572.942X/2017/7.1134
  • PMID: 28825058
  • PMCID: 5558869
  • Citations: 9
  • Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
  • Evidence snippets:
  • Snippet 1 (score: 0.411) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[2] Loss of PHF6 leads to aberrant development of human neuron-like cells

  • Authors: Anna Fliedner, A. Gregor, F. Ferrazzi, A. Ekici, H. Sticht et al.
  • Year: 2020
  • Venue: Scientific Reports
  • URL: https://www.semanticscholar.org/paper/f2f43b6e6d05720f643288cc9ed9ce2900597142
  • DOI: 10.1038/s41598-020-75999-2
  • PMID: 33149206
  • PMCID: 7642390
  • Citations: 10
  • Summary: It is demonstrated that PHF6 is indeed required for proper neuron proliferation, neurite outgrowth and migration and might therefore contribute to the neurodevelopmental and cognitive dysfunction in BFLS.
  • Evidence snippets:
  • Snippet 1 (score: 0.401) > Pathogenic variants in PHD finger protein 6 (PHF6) cause Borjeson–Forssman–Lehmann syndrome (BFLS), a rare X-linked neurodevelopmental disorder, which manifests variably in both males and females. To investigate the mechanisms behind overlapping but distinct clinical aspects between genders, we assessed the consequences of individual variants with structural modelling and molecular techniques. We found evidence that de novo variants occurring in females are more severe and result in loss of PHF6, while inherited variants identified in males might be hypomorph or have weaker effects on protein stability. This might contribute to the different phenotypes in male versus female individuals with BFLS. Furthermore, we used CRISPR/Cas9 to induce knockout of PHF6 in SK-N-BE (2) cells which were then differentiated to neuron-like cells in order to model nervous system related consequences of PHF6 loss. Transcriptome analysis revealed a broad deregulation of genes involved in chromatin and transcriptional regulation as well as in axon and neuron development. Subsequently, we could demonstrate that PHF6 is indeed required for proper neuron proliferation, neurite outgrowth and migration. Impairment of these processes might therefore contribute to the neurodevelopmental and cognitive dysfunction in BFLS.

[3] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 37
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.400) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[4] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

  • Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
  • Year: 2026
  • Venue: Nucleus
  • URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
  • DOI: 10.1080/19491034.2025.2611484
  • PMID: 41489464
  • PMCID: 12773485
  • Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
  • Evidence snippets:
  • Snippet 1 (score: 0.397) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[5] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

  • Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
  • Year: 2023
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
  • DOI: 10.3389/fphar.2023.1290253
  • PMID: 38026943
  • PMCID: 10662320
  • Citations: 3
  • Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[6] Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson–Forssman–Lehmann intellectual disability syndrome

  • Authors: Helen M. McRae, Melody Pui-Yee Leong, Maria I. Bergamasco, A. Garnham, Yifang Hu et al.
  • Year: 2024
  • Venue: PLOS Genetics
  • URL: https://www.semanticscholar.org/paper/8d31365b1878a146f68e332161beb9033e27d35a
  • DOI: 10.1371/journal.pgen.1011428
  • PMID: 39405291
  • PMCID: 11478892
  • Citations: 1
  • Influential citations: 1
  • Summary: It is shown that PHF6 protein levels are greatly reduced in cells derived from a subset of patients with BFLS, providing insight into the molecular effects of loss of PHF6 in the developing brain.
  • Evidence snippets:
  • Snippet 1 (score: 0.392) > Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability and endocrine disorder caused by pathogenic variants of plant homeodomain finger gene 6 (PHF6). An understanding of the role of PHF6 in vivo in the development of the mammalian nervous system is required to advance our knowledge of how PHF6 mutations cause BFLS. Here, we show that PHF6 protein levels are greatly reduced in cells derived from a subset of patients with BFLS. We report the phenotypic, anatomical, cellular and molecular characterization of the brain in males and females in two mouse models of BFLS, namely loss of Phf6 in the germline and nervous system-specific deletion of Phf6. We show that loss of PHF6 resulted in spontaneous seizures occurring via a neural intrinsic mechanism. Histological and morphological analysis revealed a significant enlargement of the lateral ventricles in adult Phf6-deficient mice, while other brain structures and cortical lamination were normal. Phf6 deficient neural precursor cells showed a reduced capacity for self-renewal and increased differentiation into neurons. Phf6 deficient cortical neurons commenced spontaneous neuronal activity prematurely suggesting precocious neuronal maturation. We show that loss of PHF6 in the foetal cortex and isolated cortical neurons predominantly caused upregulation of genes, including Reln, Nr4a2, Slc12a5, Phip and ZIC family transcription factor genes, involved in neural development and function, providing insight into the molecular effects of loss of PHF6 in the developing brain.

[7] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

  • Authors: Kyung-Yil Lee
  • Year: 2022
  • Venue: Cell & Bioscience
  • URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
  • DOI: 10.1186/s13578-022-00920-5
  • PMID: 36384812
  • PMCID: 9668226
  • Citations: 9
  • Influential citations: 1
  • Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
  • Evidence snippets:
  • Snippet 1 (score: 0.392) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[8] Therapies for Mitochondrial Disease: Past, Present, and Future

  • Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R Thorburn, S. Rahman et al.
  • Year: 2025
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
  • DOI: 10.1002/jimd.70065
  • PMID: 40714961
  • PMCID: 12301291
  • Citations: 3
  • Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.388) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[9] Recent Evidences of Epigenetic Alterations in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

  • Authors: R. Ragusa, Pasquale Bufano, A. Tognetti, M. Laurino, Chiara Caselli
  • Year: 2025
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/2660cdbbe1f205c631fe890e5c6a3c8d9b81ce5f
  • DOI: 10.3390/ijms26062571
  • PMID: 40141213
  • PMCID: 11942187
  • Citations: 4
  • Summary: A systematic review of the latest knowledge on epigenetic modifications that characterize COPD, summarizing epigenetic factors that could serve as potential novel biomarkers and therapeutic targets for the treatment of COPD patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.386) > The papers included were clustered according to epigenetic mechanisms involved in COPD (molecular and cellular processes, as biomarker or therapeutic target). Tables 4-9 describe the extracted information, including the following: Study = name of first author et al., year; Country (Region) = where the study took place; Number of participants = sample size; Type of sample = biological sample employed; Gene affected = gene or group of genes whose expression can be "regulated" by epigenetic mechanisms; Epigenetic alteration = type of epigenetic alteration observed in the presence of disease; Activity in COPD = involvement of epigenetic elements in different molecular and cellular mechanisms associated with COPD; and Role of epigenetic mechanisms = epigenetic modifications that can be used to explain the pathophysiology of COPD or as biomarkers and therapeutic targets.

[10] Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia

  • Authors: Esmeralda Alonso-Barroso, B. Pérez, L. Desviat, E. Richard
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/da649a0f04477c53b448c5ac5f873f8762235290
  • DOI: 10.3390/ijms22031161
  • PMID: 33503868
  • PMCID: 7865492
  • Citations: 16
  • Influential citations: 1
  • Summary: The novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.
  • Evidence snippets:
  • Snippet 1 (score: 0.385) > The study of the mechanisms involved in disease physiopathology has been mainly performed using the hypomorphic PA mouse model that mimics the biochemical and clinical phenotype [5]. Using this model, bioenergetic failure, oxidative damage and deregulation of miRNAs induced by accumulating propionyl-CoA have been described as potential mechanisms contributing to PA physiopathology [6][7][8]. The limitations of animal models for the study of cardiac energy metabolism [9] and of the commonly available cellular human models such as fibroblasts, underline the importance of generating new relevant cell models to provide deeper insight into the underlying mechanisms of disease. The use of in vitro models with human cellular context is highly recommended and, in this sense, induced pluripotent stem cells (iPSCs) have certain advantages since they provide the genetic background of the patient and represent an unlimited source of biological material for the study of pathophysiology and treatment effectiveness [10]. We have previously generated an iPSC line from a PA patient with defects in the PCCA gene that showed full pluripotency, differentiation capacity and genetic stability [11]. > In the present study, we aimed to establish a platform that served as a disease model to study the cellular and molecular alterations operating in cardiac tissue affected by PA disease. We described the characterization of cardiomyocytes derived from the PCCA iPSC line (PCCA iPSC-CMs) and the analysis of specific pathways potentially involved in cardiac PA physiopathology.

[11] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

  • Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
  • Year: 2025
  • Venue: Pathophysiology
  • URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
  • DOI: 10.3390/pathophysiology32010009
  • PMID: 39982365
  • PMCID: 12077258
  • Citations: 25
  • Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
  • Evidence snippets:
  • Snippet 1 (score: 0.383) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[12] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.382) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[13] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

  • Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
  • Year: 2016
  • Venue: Molecular Psychiatry
  • URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
  • DOI: 10.1038/mp.2016.89
  • PMID: 27240529
  • PMCID: 4995546
  • Citations: 77
  • Influential citations: 2
  • Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.378) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[14] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

  • Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
  • Year: 2025
  • Venue: Journal of Veterinary Internal Medicine
  • URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
  • DOI: 10.1111/jvim.70139
  • PMID: 40492724
  • PMCID: 12150350
  • Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.377) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[15] Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery

  • Authors: Xiao-lei Wu, Zhang-zhong Yang, Jinjun Zou, Huile Gao, Zhenhua Shao et al.
  • Year: 2025
  • Venue: Signal Transduction and Targeted Therapy
  • URL: https://www.semanticscholar.org/paper/57c532f807605e5181ca30a675ad0d79e3625453
  • DOI: 10.1038/s41392-025-02179-x
  • PMID: 40328798
  • PMCID: 12056177
  • Citations: 33
  • Influential citations: 1
  • Summary: The role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases are discussed, and the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies for effective prevention and early intervention are illustrated.
  • Evidence snippets:
  • Snippet 1 (score: 0.376) > Neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s, Huntington’s disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.

[16] Mitochondrial Biomarkers in the Omics Era: A Clinical-Pathophysiological Perspective

  • Authors: J. Gervasoni, A. Primiano, M. Cicchinelli, L. Santucci, Serenella Servidei et al.
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/07c164ce4ffbef88bb87a0761bc653dfb74eeeb0
  • DOI: 10.3390/ijms25094855
  • PMID: 38732076
  • PMCID: 11084339
  • Citations: 4
  • Summary: Omics technologies such as proteomics and metabolomics considered in this review, can support unresolved mitochondrial questions, helping to improve outcomes for patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > Mitochondrial diseases represent a large collection of rare neurometabolic syndromes characterized by extremely difficult clinical management, both chronically and during acute events. This condition is due to a lack of complete understanding of the metabolic and molecular mechanisms involved in the pathogenesis, and also to the absence of reliable diagnostic and prognostic biomarkers that are able to identify the disease in its multiple clinical manifestations and monitor its progression. Although genetic testing provides secure diagnoses, heteroplasmy, and gaps in knowledge of pathological mechanisms limit genomics in offering a comprehensive spectrum of diseases and their variations in severity and progression. Additionally, the absence of validated biomarkers has made identifying new therapies a challenge [24,25]. > Several techniques have developed to interrogate this complex process in multiple dimensions (DNA, RNA, proteins, and metabolites), known as "omics". These disciplines allow to investigate the different classes of biological components (genes-genomic, proteinsproteomic, and metabolites-metabolomic) that determine the phenotype of an organism. Different analytical techniques (Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) are used to identify either the metabolite patterns that are significant for the determination of the metabolic phenotype of the system under investigation, or the proteins used to determine of the alteration in the proteomic asset that can be identified as a possible marker of disease. Metabolomics and proteomic studies can be conducted with targeted, semi-targeted, and untargeted analytical approaches. Analysis is usually performed on multiple biological fluids: urine, saliva, plasma or serum, cerebrospinal fluid, cell cultures, tissue extracts, or biopsies. Through metabolic analysis, we can measure the metabolic profile, obtaining a fingerprint determined by the perturbation that is characteristic of the pathogenetic process [26].

[17] The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force

  • Authors: M. Beaudin, A. Matilla-Dueñas, B. Soong, J. Pedroso, O. Barsottini et al.
  • Year: 2019
  • Venue: Cerebellum (London, England)
  • URL: https://www.semanticscholar.org/paper/8be333265c4faffaeb605213aa48cb23b33981c1
  • DOI: 10.1007/s12311-019-01052-2
  • PMID: 31267374
  • PMCID: 6867988
  • Citations: 49
  • Summary: A consensus is built on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > The importance of a proper recessive ataxia classification goes beyond the clinical diagnosis perspective. Autosomal recessive ataxias can be regrouped according to the deficient cellular and metabolic pathways involved, which provide a better understanding of cerebellar physiology and of its selective vulnerability to certain metabolic defects. This is also essential from a therapeutic perspective, as disorders that belong to the same metabolic pathway may to the same treatment options, indicating potential for drug repurposing. Figure 3 presents a pathophysiological classification of autosomal recessive ataxias. Certain genes are presented more than once since some proteins are involved in several metabolic pathways or may interfere with other cellular processes as they accumulate in neurons or glial cells. Table 3 presents a more detailed listing of the pathogenic pathways involved along with relevant references. Certain pathways are predominantly involved, notably mitochondrial dysfunction, which may result from abnormal mitochondrial DNA maintenance with progressive mutagenesis, defective mitochondrial protein synthesis and quality control, increased levels of reactive oxygen species and oxidative stress, deficient coenzyme Q10 metabolism, altered mitochondrial dynamics, defective mitochondrial chain assembly, or abnormal mitochondrial RNA maturation and processing (Table 3). Interestingly, many of the disorders caused by mitochondrial dysfunction also present with a mitochondrial clinical syndrome as shown in Fig. 1. Disorders of DNA repair mechanisms are also common, with double-strand break repair pathway or single-strand break repair complexes predominantly involved. Pathogenic mutations in these genes are also associated with a susceptibility to ionizing radiations and predisposition for cancers, but the neurological syndrome is characterized by cerebellar involvement and extrapyramidal movement disorders. It remains debated whether defective DNA repair is the main pathogenic mechanism causing the neurological phenotype [230], but the fact that several interacting genes in this pathway are involved in degenerative cerebellar ataxias suggests that the cerebellum has a peculiar susceptibility to DNA damage for which the underlying mechanism is not understood. Finally, altered synaptic morphology or synaptic dysfunction of Purkinje cells (PC) is frequently involved in recessive ataxias and is associated with aberrant Fig. 1 Clinical classification of autosomal recessive ataxias.

[18] Clinical Phenotypes of Cardiovascular and Heart Failure Diseases Can Be Reversed? The Holistic Principle of Systems Biology in Multifaceted Heart Diseases

  • Authors: K. Lourida, G. Louridas
  • Year: 2022
  • Venue: Cardiogenetics
  • URL: https://www.semanticscholar.org/paper/3960806730c4c1115f527e22d6d0a76536570ec5
  • DOI: 10.3390/cardiogenetics12020015
  • Citations: 4
  • Influential citations: 1
  • Summary: Only by understanding the complexity of chronic heart diseases and explaining the interrelationship between different interconnected biological networks can the probability for clinical phenotypes reversal be increased.
  • Evidence snippets:
  • Snippet 1 (score: 0.371) > Treatment with ACEIs, ARBs, and β-blockers impedes deterioration of myocardial function as well as clinical deterioration caused by the deleterious impact of the compensatory systems [58,59]. Therefore, the therapy with ACEIs, ARBs, and β-blockers is the appropriate therapy to block LV remodeling and HF progression and reduce symptoms and/or mortality [55]. > In general, the HF syndrome demonstrates a modular construction with predictable behavior of functional clinical phenotypes having a strong impact on biological networks from epigenetic, cellular to regulatory systems [18]. The importance of individual genes for the pathogenesis and clinical progression of the HF syndrome is restricted to the hypertrophic and dilated cardiomyopathies. It seems that some HF patients have a complex multigenic inheritance, but the importance of individual genes is limited. In contrast, the significant role of epigenetics, proteomics, and metabolomics is increased; but, the complete genetic network system and the interactions between multiomics systems are still uncertain [60]. Multimodal systems that include genetic networks, multiomics, metabolic pathways, environmental factors, and sophisticated disease-related clinical networks are required to be integrated and provide a new holistic and realistic picture. > Significant breakthroughs have been made to understand many of the pathophysiological mechanisms of HFrEF but the natural pathophysiological history and clinical progression of HFpEF still remains inadequately defined [39]. The subclinical progression of pre-clinical diastolic dysfunction (PDD) of LV "to clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement . . . continue to be poorly understood" [40]. Prospective studies are expected to clarify the natural history and clinical progression of HFpEF and define the LV remodeling mechanisms involved. The pathophysiology of LV systolic dysfunction is different to the diastolic dysfunction, as systolic dysfunction is considered a disease of calcium handling and diastolic dysfunction is regarded as a disease of increased myofilament sensitivity to calcium [61][62][63].

[19] Insights Into Cockayne Syndrome Type B: What Underlies Its Pathogenesis?

  • Authors: Ricardo Afonso-Reis, Cristiana R Madeira, D. Brito, C. Nóbrega
  • Year: 2025
  • Venue: Aging Cell
  • URL: https://www.semanticscholar.org/paper/1b86ba09359d5e2f0ff083dd037d872b4faec812
  • DOI: 10.1111/acel.70136
  • PMID: 40536083
  • PMCID: 12266758
  • Citations: 3
  • Summary: It is proposed that CS‐B pathogenesis arises from a combination of DNA damage accumulation, transcriptional dysregulation, and mitochondrial dysfunction, and it is argued that these molecular features influence each other, rather than acting as isolated mechanisms.
  • Evidence snippets:
  • Snippet 1 (score: 0.370) > Cockayne Syndrome complementation group B is a complex disorder with diverse underlying molecular mechanisms that contribute for its highly debilitating and multisystemic phenotype. Years of research focusing on the physiological role of ERCC6 have provided extensive knowledge regarding different processes and cellular pathways dependent on ERCC6. Most accumulated knowledge regarding ERCC6 function is related to its crucial role in TC-NER. Nevertheless, significant advances have been made associating ERCC6 with several other mechanisms that are essential for proper cell functioning. This has helped bridge the gap in the knowledge in the pathological context of Cockayne Syndrome. Currently, ERCC6 has been identified to play an important role in distinct DNA repair mechanism, responsible for tackling different type of DNA damage. These mechanisms include TC-NER, BER, and DSB repair where ERCC6 is essential for the recruitment of repair machinery, and ICL repair where ERCC6 modulates effector repair factors. Notably, ERCC6 function is not limited to DNA repair. In fact, ERCC6 is implicated in transcription by remodeling chromatin of relevant regions, modulating RNAP I and II and cooperating with transcription factors and co-factors. Additionally, mitochondrial processes such as mtDNA maintenance, mitochondrial transcription and structural organization also rely on ERCC6. The key role ERCC6 plays in all these cellular processes, highlights the importance of ERCC6 for proper cell functioning. Ultimately, ERCC6 dysfunction leads to extremely deleterious consequences to the cell, which culminates in cellular malfunction and cell death. > Premature aging is a hallmark of progeroid syndromes, such as Cockayne Syndrome. Therefore, a relation between normal aging and Cockayne syndrome pathophysiology may be established to explore the potential mechanisms driving CS progression. Considering the cellular processes ERCC6 is involved in a physiological context, in this review we have organized CS-B pathophysiology into main three molecular features. These features include DNA damage accumulation, transcriptional dysregulation and mitochondrial dysfunction. Importantly, we consider that these features do not act as isolated pathways but rather influence one another, through a mechanism interplay. This interplay has the potential to exacerbate dysfunction of affected features or induce dysfunction of an otherwise functional feature.

[20] “Betwixt Mine Eye and Heart a League Is Took”: The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy

  • Authors: D. Rovina, Elisa Castiglioni, Francesco Niro, Sara Mallia, G. Pompilio et al.
  • Year: 2020
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/9303acc2a5c14adba1c342a87f27f2ae2a57195d
  • DOI: 10.3390/ijms21196997
  • PMID: 32977524
  • PMCID: 7582534
  • Citations: 3
  • Summary: Cardiovascular cells derived from muscular dystrophy patients’ induced pluripotent stem cells are well suited to mimic dystrophin-associated cardiomyopathy and hold great promise for the development of future fully effective therapies.
  • Evidence snippets:
  • Snippet 1 (score: 0.370) > Since inception, iPSC technology has shown enormous potential to model disease, solving many challenges associated with traditional approaches such as animal and primary cell/tissue models. On the basis of their characteristics, patient-specific iPSCs can provide disease-related cells which may have been previously inaccessible, e.g., neurons and cardiomyocytes. Taking advantage of these intrinsic properties, iPSCs carrying patient-specific mutations can be used to model the molecular mechanisms underlying the disease pathophysiology and screen responses to various types of therapeutics. The phenotype ranges that can be investigated by iPSC models involve a broad range of molecular, metabolic, electrophysiological, and cellular analytic techniques. iPSC disease models have been widely applied to study monogenic disorders that are caused by a single gene mutation [130] and sporadic complex disorders involving multiple or unknown genes [131]. The use of iPSC-based models for the latter disease type is more problematic with respect to monogenic diseases, since the phenotype is often the result of multiple small-effect genetic variants in combination with environmental factors. However, this approach was used to model many different complex diseases including Alzheimer's disease, Parkinson's disease, schizophrenia, and cardiac arrhythmias [132][133][134][135]. Without knowing the detailed underlying genetics, differentiated patient-specific iPSCs could provide disease-relevant cells that carry all the genetic elements implicated in the development of the disease and can be useful to analyze the common mechanisms of disease development. Indeed, patient-specific iPSCs obtained from multiple affected individuals that show similar phenotypes could be comparatively investigated in order to find common altered mechanistic pathways or functional activities. > One of the major issues concerning disease modeling using iPSCs is the relative immaturity of the cells differentiated from iPSCs. On the basis of this observation, iPSC-based models are considered more suitable for disorders with an early onset rather than late onset, for which cellular aging could play a role in the disease phenotype. However, despite their fetal phenotype, iPSC-derived cells have highlighted different phenotypes, suggesting that the pathology starts before the appearance of clinical symptoms, potentially allowing the discovery of novel mechanisms involved in the development of pathology [52,136]. > Recently, in

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