Fetal anomalies
Gene: FGFR1

FGFR1 (fibroblast growth factor receptor 1)
EnsemblGeneIds (GRCh38): ENSG00000077782
EnsemblGeneIds (GRCh37): ENSG00000077782
OMIM: 136350, Gene2Phenotype
FGFR1 is in 20 panels

2 reviews

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on mode of inheritance: There are more than 3 individuals reported with biallelic FGFR1 variants and Hypogonadotropic hypogonadism. Individuals consistently presented with ectrodactyly, CC agenesis, and holoprosencephaly - disease features relevant to Fetal anomalies, as these would be detected on a prenatal scan. Hence, MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.
Created: 27 Mar 2026, 10:56 a.m. | Last Modified: 27 Mar 2026, 10:56 a.m.

Panel Version: 6.184

PMID: 27055092 Mazen et al., 2016
Male patient with congenital heart disease (CHD) and ambiguous genitalia, referred at 15 months. Consanguineous parents, positive family history for CHD. Trio WES revealed a homozygous FGFR1 c.1418G>A variant (hg38: c.1424G>A, p.Arg475Gln - rs747333248, 34 total alleles in gnomAD v4.1.0, no homozygotes). Patient also homozygous for a STARD3 p.Ala247Val mutation, no disease association reported for this gene. Ambiguous genitalia highlighted as unusual presentation in FGFR1-related disease.

PMID: 25394172 Villanueva et al., 2015
7 individuals with Congenital hypogonadotropic hypogonadism (CHH), 3/7 with anosmia, and 7/7 with split hand/foot malformation. The patients harboured FGFR1 variants - 6 heterozygous and 1 homozygous.
P1: male, homozygous for c.1286T>A, p.V429E. Heterozygous sister and parents. Sister has hyposmia, otherwise no phenotype reported in heterozygous family members.
In the 6 heterozygous pedigrees, CHH was an autosomal dominant trait with incomplete penetrance.

PMID: 23812909 Simonis et al., 2013
6 patients with Hartsfield syndrome and 1 female fetus with similar symptoms. FGFR1 variants were detected in the extracellular binding domain (two patients with homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Patients presented with holoprosencephaly 7/7 (lobar, alobar, or semilobar), corpus callosum agenesis 5/7 (full or partial), ectrodactyly 7/7 (hands and/or feet affected), growth retardation 6/6, genital anomalies 3/6 (micropenis, cryptorchidism), DD/ID 6/6 (mild to severe). Fetal case (patient 7) had no FGFR1 mutation detected.

PMID: 23154428 Jarzabek et al., 2012
5 Kallmann syndrome (KS) patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Patients 1-4 harboured de novo heterozygous FGFR1 mutations, while P5 was homozygous for the c.499G>T, p.Ala167Ser variant - his parents are sister are heterozygous and unaffected. All 5 patients had absent puberty, as well as hyposmia or anosmia. 3/5 patients presented with skeletal abnormalities and lip/palate malformations.
P5 (previously described in PMID: 12627230) had KS, cleft palate, corpus callosum agenesis, vertebral anomalies, unilateral fusion of fourth and fifth metacarpal bones, and bilateral oligodactyly of feet (four digits).

FGFR1 is associated with multiple dominant conditions in OMIM, including AD Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950 and AD Hartsfield syndrome, OMIM:615465 (accessed 27th Feb 2026).
Created: 27 Mar 2026, 10:43 a.m. | Last Modified: 27 Mar 2026, 10:52 a.m.

Panel Version: 6.183

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950; Hartsfield syndrome, OMIM:615465

Publications

Created: 27 Mar 2026, 10:43 a.m.
Last Modified: 27 Mar 2026, 10:52 a.m.
Panel version: 6.184

Rebecca Foulger (Genomics England curator)

Green List (high evidence)

This gene and phenotype were re-reviewed during meetings at Great Ormond Street hospital in March and April 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of re-review: Confirmed that phenotype is fetally-relevant: include on the Fetal anomalies panel as a Green gene. Additional notes from clinical re-review: Include on basis of Pfeiffer syndrome (MIM:101600).
Created: 29 Apr 2019, 12:28 p.m.

This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in March 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Confirmed that phenotype is fetally-relevant: keep on the Fetal anomalies panel as a Green gene.
Created: 24 Mar 2019, 4:30 p.m.

DDG2P rating in original PAGE list: Confirmed for OSTEOGLOPHONIC DYSPLASIA, Confirmed for KALLMANN SYNDROME TYPE 2, Confirmed for PFEIFFER SYNDROME, Confirmed for IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM, Confirmed for Encephalocraniocutaneous lipomatosis, and Confirmed for Hartsfield syndrome.
Created: 11 Dec 2018, 9:04 a.m.

Mosaicism tag added based on original PAGE file which records Mosaic MOI for Encephalocraniocutaneous lipomatosis.
Created: 8 Nov 2018, 4:52 p.m.

In the original PAGE file, listed as Mosaic for Encephalocraniocutaneous lipomatosis. In the original PAGE file, MOP listed as Dominant negative for Hartsfield syndrome, and listed as LOF for IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM, KALLMANN SYNDROME TYPE 2. MOP listed as Activating for OSTEOGLOPHONIC DYSPLASIA, Encephalocraniocutaneous lipomatosis and PFEIFFER SYNDROME
Created: 8 Nov 2018, 4:45 p.m.

Created: 8 Nov 2018, 4:45 p.m.

Panel version: 0.222

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

PAGE DD-Gene2Phenotype
Expert Review Green

Phenotypes

Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950
Hartsfield syndrome, OMIM:615465

Tags

mosaicism Q1_26_MOI

OMIM

136350

Clinvar variants

Variants in FGFR1

Penetrance

None

Panels with this gene

History Filter Activity

27 Mar 2026, Gel status: 3

Set Phenotypes

Ida Ertmanska (Genomics England Curator)

Phenotypes for gene: FGFR1 were changed from IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; OSTEOGLOPHONIC DYSPLASIA; PFEIFFER SYNDROME; KALLMANN SYNDROME TYPE 2; Hartsfield syndrome; Encephalocraniocutaneous lipomatosis to Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950; Hartsfield syndrome, OMIM:615465

27 Mar 2026, Gel status: 3

Added Tag

Ida Ertmanska (Genomics England Curator)

Tag Q1_26_MOI tag was added to gene: FGFR1.

8 Nov 2018, Gel status: 4