Borjeson-Forssman-Lehmann syndrome

Summary

Borjeson-Forssman-Lehmann syndrome (MONDO:0010537) is a disease caused by PHF6 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PHF6 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 148
• Phenotypes (HPO): 34

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000046	Small scrotum	Very frequent (80-99%)
HP:0000135	Hypogonadism	Very frequent (80-99%)
HP:0000280	Coarse facial features	Very frequent (80-99%)
HP:0000771	Gynecomastia	Very frequent (80-99%)
HP:0001182	Tapered finger	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001769	Broad foot	Very frequent (80-99%)
HP:0001831	Short toe	Very frequent (80-99%)
HP:0001836	Camptodactyly of toe	Very frequent (80-99%)
HP:0001956	Truncal obesity	Very frequent (80-99%)
HP:0008070	Sparse hair	Very frequent (80-99%)
HP:0008734	Decreased testicular size	Very frequent (80-99%)
HP:0008736	Hypoplasia of penis	Very frequent (80-99%)
HP:0009748	Large earlobe	Very frequent (80-99%)
HP:0000336	Prominent supraorbital ridges	Frequent (30-79%)
HP:0000490	Deeply set eye	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000574	Thick eyebrow	Frequent (30-79%)
HP:0000581	Blepharophimosis	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0000202	Orofacial cleft	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0003272	Abnormality of the hip bone	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Borjeson-Forssman-Lehmann syndrome
Mondo ID	MONDO:0010537
MeSH	C536575
OMIM	301900
Orphanet	127
DOID	DOID:0050681
SNOMED CT	21634003
UMLS	C0265339
MedGen	78557
GARD	0000936
NORD	866
Is cancer (heuristic)	no

Also known as: BFLS · BORJ · Borjeson syndrome · Borjeson-Forssman-Lehmann syndrome · Borjeson-Forssman-Lehmann syndrome, X-linked recessive · Börjeson-Forssman-Lehman Syndrome · intellectual disability, epilepsy, and endocrine disorder · intellectual disability-epilepsy-endocrine disorders syndrome · mental deficiency, epilepsy and endocrine disorders · mental retardation, epilepsy, and endocrine disorders · mental retardation, X-linked, syndromic, Borjeson-Forssman-Lehmann type · MRXSBFL · syndromic X-linked intellectual disability Borjeson-Forssman-Lehmann type

Data availability: 148 ClinVar variants · 6 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › X-linked syndromic intellectual disability › Borjeson-Forssman-Lehmann syndrome

Related subtypes (80): X-linked intellectual disability-psychosis-macroorchidism syndrome, X-linked intellectual disability-plagiocephaly syndrome, intellectual disability, X-linked 49, MEHMO syndrome, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability, Stocco dos Santos type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, X-linked intellectual disability-cerebellar hypoplasia syndrome, Allan-Herndon-Dudley syndrome, syndromic X-linked intellectual disability Claes-Jensen type, X-linked intellectual disability-retinitis pigmentosa syndrome, syndromic X-linked intellectual disability 14, syndromic X-linked intellectual disability 94, intellectual disability, X-linked syndromic, Turner type, syndromic X-linked intellectual disability Shrimpton type, X-linked intellectual disability-craniofacioskeletal syndrome, syndromic X-linked intellectual disability Raymond type, syndromic X-linked intellectual disability 17, syndromic X-linked intellectual disability Nascimento type, syndromic X-linked intellectual disability Chudley-Schwartz type, X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome, X-linked intellectual disability, Cantagrel type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, intellectual disability, X-linked 99, syndromic, female-restricted, intellectual disability, X-linked, syndromic, Bain type, Coffin-Lowry syndrome, syndromic X-linked intellectual disability 5, X-linked intellectual disability-seizures-psoriasis syndrome, Renpenning syndrome, Partington syndrome, syndromic X-linked intellectual disability 12, severe X-linked intellectual disability, Gustavson type, syndromic X-linked intellectual disability Snyder type, Wilson-Turner syndrome, Prieto syndrome, skeletal dysplasia-intellectual disability syndrome, X-linked intellectual disability-spastic quadriparesis syndrome, early-onset parkinsonism-intellectual disability syndrome, X-linked intellectual disability, Schimke type, X-linked intellectual disability, Cilliers type, X-linked intellectual disability, van Esch type, X-linked intellectual disability-epilepsy syndrome, ATR-X-related syndrome, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, X-linked intellectual disability, Schutz type, X-linked intellectual disability-hypotonia-movement disorder syndrome, X-linked intellectual disability with isolated growth hormone deficiency, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-precocious puberty-obesity syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability-macrocephaly-macroorchidism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Seemanova type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, X-linked intellectual disability-acromegaly-hyperactivity syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, fried syndrome, X-linked intellectual disability-ataxia-apraxia syndrome, intellectual developmental disorder, X-linked, syndromic, Pilorge type, Paganini-Miozzo syndrome, intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type, intellectual disability, X-linked, syndromic, 35, intellectual disability, X-linked, syndromic, Houge type, MED12-related intellectual disability syndrome, NAA10-related syndrome, ATP6AP2-related disorder, X-linked intellectual disability with hypopituitarism, SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder, intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, intellectual developmental disorder, X-linked, syndromic 37, CASK-related intellectual disability

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

148 retrieved; paginated sample, class counts are floors:

51 uncertain significance, 36 likely benign, 26 pathogenic, 15 benign, 10 likely pathogenic, 6 conflicting classifications of pathogenicity, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11063	NM_001015877.2(PHF6):c.1024C>T (p.Arg342Ter)	PHF6	Pathogenic	criteria provided, multiple submitters, no conflicts
11064	NM_001015877.2(PHF6):c.296G>T (p.Cys99Phe)	PHF6	Pathogenic	no assertion criteria provided
11065	NM_001015877.2(PHF6):c.700A>G (p.Lys234Glu)	PHF6	Pathogenic	no assertion criteria provided
11066	NM_001015877.2(PHF6):c.134G>A (p.Cys45Tyr)	PHF6	Pathogenic	criteria provided, multiple submitters, no conflicts
11067	NM_001015877.2(PHF6):c.686A>G (p.His229Arg)	PHF6	Pathogenic	no assertion criteria provided
11068	NM_001015877.2(PHF6):c.2T>C (p.Met1Thr)	PHF6	Pathogenic	criteria provided, multiple submitters, no conflicts
11069	NM_001015877.2(PHF6):c.769A>G (p.Arg257Gly)	PHF6	Pathogenic	criteria provided, single submitter
11070	NM_001015877.2(PHF6):c.22A>T (p.Lys8Ter)	PHF6	Pathogenic	no assertion criteria provided
11071	NM_001015877.2(PHF6):c.139-8A>G	PHF6	Pathogenic	no assertion criteria provided
11072	NM_001015877.2(PHF6):c.27dup (p.Gly10fs)	PHF6	Pathogenic	no assertion criteria provided
1320220	NM_001015877.2(PHF6):c.415G>T (p.Glu139Ter)	PHF6	Pathogenic	criteria provided, single submitter
139557	NM_001015877.2(PHF6):c.914G>T (p.Cys305Phe)	PHF6	Pathogenic	no assertion criteria provided
1710152	NM_001015877.2(PHF6):c.890G>T (p.Cys297Phe)	PHF6	Pathogenic	no assertion criteria provided
218375	NM_001015877.2(PHF6):c.418G>A (p.Ala140Thr)	PHF6	Pathogenic	criteria provided, single submitter
2427038	NC_000023.10:g.(?133511648)(133559360_?)del	PHF6	Pathogenic	criteria provided, single submitter
242879	NM_001015877.2(PHF6):c.255C>A (p.Cys85Ter)	PHF6	Pathogenic	no assertion criteria provided
2502441	NM_001015877.2(PHF6):c.743G>T (p.Gly248Val)	PHF6	Pathogenic	no assertion criteria provided
2769148	NM_001015877.2(PHF6):c.346C>T (p.Arg116Ter)	PHF6	Pathogenic	criteria provided, multiple submitters, no conflicts
2902140	NM_001015877.2(PHF6):c.385C>T (p.Arg129Ter)	PHF6	Pathogenic	criteria provided, single submitter
3242558	NM_001015877.2(PHF6):c.417A>T (p.Glu139Asp)	PHF6	Pathogenic	criteria provided, single submitter
4795937	NM_001015877.2(PHF6):c.181dup (p.Ser61fs)	PHF6	Pathogenic	criteria provided, single submitter
488410	NM_001015877.2(PHF6):c.673C>T (p.Arg225Ter)	PHF6	Pathogenic	criteria provided, multiple submitters, no conflicts
488575	NM_001015877.2(PHF6):c.29_30dup (p.Pro11fs)	PHF6	Pathogenic	criteria provided, single submitter
521446	NM_001015877.2(PHF6):c.820C>T (p.Arg274Ter)	PHF6	Pathogenic	criteria provided, multiple submitters, no conflicts
846281	NM_001015877.2(PHF6):c.829del (p.Arg277fs)	PHF6	Pathogenic	criteria provided, single submitter
976155	NM_001015877.2(PHF6):c.585+1G>A	PHF6	Pathogenic	criteria provided, single submitter
1324890	NM_001015877.2(PHF6):c.931_932del (p.Lys310_Ala311insTer)	PHF6	Likely pathogenic	criteria provided, single submitter
2432598	NM_001015877.2(PHF6):c.376delinsCC (p.Val126fs)	PHF6	Likely pathogenic	criteria provided, single submitter
2502440	NM_001015877.2(PHF6):c.146C>T (p.Ser49Leu)	PHF6	Likely pathogenic	no assertion criteria provided
3027441	NM_001015877.2(PHF6):c.729+2T>C	PHF6	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PHF6	Definitive	X-linked	Borjeson-Forssman-Lehmann syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PHF6	Orphanet:127	Borjeson-Forssman-Lehmann syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PHF6	HGNC:18145	ENSG00000156531	Q8IWS0	PHD finger protein 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PHF6	PHD finger protein 6	Transcriptional regulator that associates with ribosomal RNA promoters and suppresses ribosomal RNA (rRNA) transcription.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PHF6	Transcription factor	no		Znf_PHD, Znf_RING/FYVE/PHD, EPHD

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus epididymis	1
endothelial cell	1
oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PHF6	254	ubiquitous	marker	corpus epididymis, oocyte, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PHF6	2,999

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PHF6	Q8IWS0	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interaction of NuRD complexes with transcription factors	1	126.9×	0.008	PHF6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
blastocyst hatching	1	543.6×	0.004	PHF6
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	PHF6

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PHF6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PHF6	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PHF6

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PHF6	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.