GeneBe

FGF8

protein-coding

fibroblast growth factor 8, the group of Receptor ligands|Fibroblast growth factor family

Gene summary

The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein is known to be a factor that supports androgen and anchorage independent growth of mammary tumor cells. Overexpression of this gene has been shown to increase tumor growth and angiogensis. The adult expression of this gene is restricted to testes and ovaries. Temporal and spatial pattern of this gene expression suggests its function as an embryonic epithelial factor. Studies of the mouse and chick homologs revealed roles in midbrain and limb development, organogenesis, embryo gastrulation and left-right axis determination. The alternative splicing of this gene results in four transcript variants. [provided by RefSeq, Jul 2008]

MANE transcript

NM_033163.5

Inheritance

AD, Digenic

ClinVar variants

P:22U:70B:27

Top phenotype

Hypogonadotropic hypogonadism 6, with or without anosmia

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr10:101,770,109-101,780,371

External References & Databases

Ensembl (ENSG00000107831)NCBI Gene (2253)OMIM (600483)HGNC:3686GenCCUniProt (P55075)AlphaFoldClinVar (FGF8)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~10.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

femoral agenesis/hypoplasiaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0016032

Submitter: PanelApp Australia

hypogonadotropic hypogonadism 6 with or without anosmiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012988

Submitter: PanelApp Australia

hypogonadotropic hypogonadismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018555

Submitter: Orphanet

Kallmann syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018800

Submitter: Orphanet

congenital heart diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: PanelApp Australia

hypogonadotropic hypogonadism 6 with or without anosmiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012988

Submitter: Labcorp Genetics (formerly Invitae)

hypogonadotropic hypogonadism 6 with or without anosmiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012988

Submitter: Ambry Genetics

congenital heart diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*FGF8* was first reported in relation to autosomal dominant congenital heart disease in 2020 (Zhou et al., PMID 32664970). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. Therefore, these disease entities have been lumped into one disease entity, autosomal dominant congenital heart disease. Evidence for association with hypogonadotrophic hypogonadism was not included in the curation. At least two rare missense variants have been reported in two probands in one publication (PMID: 32664970) and are included in this curation using an allele frequency threshold of 1x10-5. This gene disease relationship is supported by expression studies, protein interaction studies and animal models (PMIDs 7768185, 32664970, 10603341, 19509466, 9462741, 10603341, 12223415). There was additional experimental evidence that was not scored due to reaching the maximum experimental points. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 5/7/2024 (SOP version 10).

Clinical Genomic Database (CGD)

Hypogonadotropic hypogonadism 6, with or without anosmiaAD/Digenic

Manifestation: Craniofacial; Dental; Endocrine; Musculoskeletal; Neurologic

Intervention: Endocrine

Rationale: In Hypogonadotropic hypogonadism, surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease; In order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required

Comments: Relatively complex patterns of inheritance (eg, involving variants in FGFR1) have been described; Hypoplastic femurs and pelvis is caused by a genomic rearrangement that causes a regulatory position effect on FGF8

Refs: 18596921; 21045958; 21832120; 20301509; 21976454; 22319038Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FGF8 variants in ClinVar

15 Conditions Cataloged
not providedTotal: 80
Inborn genetic diseasesTotal: 27
Hypogonadotropic hypogonadism 6 with or without anosmiaTotal: 24
not specifiedTotal: 19
FGF8-related disorderTotal: 14
Holoprosencephaly sequenceTotal: 12
Semilobar holoprosencephalyTotal: 2
Holoprosencephaly 1Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033163.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
3
clinvar
22
clinvar
 25
missense
4
clinvar
9
clinvar
64
clinvar
5
clinvar
 82
nonsense
1
clinvar
2
clinvar
 3
start loss
0
frameshift
3
clinvar
2
clinvar
 5
splice donor/acceptor (+/-2bp)
3
clinvar
1
clinvar
 4
Total51770270119

Highest pathogenic variant AF is 0.000005472458

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_033163.5RefSeqNP_149353.16MANE Select
ENST00000320185.7EnsemblENSP00000321797.26MANE Select
NM_001206389.2RefSeqNP_001193318.13Standard
NM_006119.6RefSeqNP_006110.15Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
fgf8aDanio rerio

Structure: midbrain hindbrain boundary neural rod

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • PI3K-Akt signaling pathway - Homo sapiens (human)
  • Gastric cancer - Homo sapiens (human)
  • Melanoma - Homo sapiens (human)
  • Breast cancer - Homo sapiens (human)
  • Regulation of actin cytoskeleton - Homo sapiens (human)

Biological Process

  • MAPK cascade
  • branching involved in blood vessel morphogenesis
  • metanephros development
  • branching involved in ureteric bud morphogenesis
  • organ induction

Molecular Function

  • protein tyrosine kinase activity
  • Ras guanyl-nucleotide exchange factor activity
  • fibroblast growth factor receptor binding
  • growth factor activity
  • 1-phosphatidylinositol-3-kinase activity

Cellular Component

  • extracellular region
  • external side of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000320185
Coding exons
6
Length
5956
Individuals with no LoFs
125739
Homozygous LoFs
0
Heterozygous LoFs
1
Defined
125740
p
0.00000398
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.57991540.6440.00001021546
Missense (PolyPhen)2542.2620.59155381
Synonymous0.06876666.70.9890.00000433500
Loss of Function2.73212.40.1626.83e-7128

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration. Required for normal brain, eye, ear and limb development during embryogenesis. Required for normal development of the gonadotropin-releasing hormone (GnRH) neuronal system (PubMed:16384934, PubMed:16597617, PubMed:8663044). Plays a role in neurite outgrowth in hippocampal cells (PubMed:21576111). {ECO:0000269|PubMed:16384934, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:21576111, ECO:0000269|PubMed:8663044}.;
Disease
DISEASE: Hypogonadotropic hypogonadism 6 with or without anosmia (HH6) [MIM:612702]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:18596921, ECO:0000269|PubMed:23643382}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in FGF8 as well as in other HH- associated genes including FGFR1 (PubMed:23643382). {ECO:0000269|PubMed:23643382}.;

Recessive Scores

pRec
0.586

Intolerance Scores

RVIS EVS
-0.32
RVIS percentile EVS
31.46

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.720

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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