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Fetal anomalies v6.184 FGFR1 Ida Ertmanska commented on gene: FGFR1: 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.
Fetal anomalies v6.184 FGFR1 Ida Ertmanska 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
Fetal anomalies v6.183 FGFR1 Ida Ertmanska Tag Q1_26_MOI tag was added to gene: FGFR1.
Fetal anomalies v6.183 FGFR1 Ida Ertmanska changed review comment from: 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). P1 was homozygous for L165S, heterozygous parents unaffected. P2 was homozygous for L191S, parents not available for testing.

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).; to: 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).
Fetal anomalies v6.183 FGFR1 Ida Ertmanska reviewed gene: FGFR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23154428, 23812909, 25394172, 27055092; Phenotypes: Hypogonadotropic hypogonadism 2 with or without anosmia, OMIM:147950, Hartsfield syndrome, OMIM:615465; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.222 FGFR1 Rebecca Foulger commented on gene: FGFR1: 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).
Fetal anomalies v0.222 FGF8 Rebecca Foulger edited their review of gene: FGF8: Added comment: 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: Structural features from birth. PMID:20463092 report 2 families; 1 affected indiv also had cleft lip and palate. PMID:24280688 report a singleton with micropenis, cleft lip and palate, craniofacial anomalies and ventricular septal defect (VSD) at birth. PMID:18596921 report 6 families with missense variants; one also had variant in FGFR1; in one family 2 sibs had cleft lip/palate but reduced penetrance. Overall include on Fetal panel based on cleft lip/palate phenotype. ; Changed publications: 20463092, 24280688, 18596921
Fetal anomalies v0.134 FGFR1 Rebecca Foulger edited their review of gene: FGFR1: Added comment: 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.; Changed rating: GREEN
Fetal anomalies v0.9 FGFR1 Rebecca Foulger commented on gene: FGFR1: 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.
Fetal anomalies v0.3 FGFR1 Rebecca Foulger Tag mosaicism tag was added to gene: FGFR1.
Fetal anomalies v0.3 FGFR1 Rebecca Foulger commented on gene: FGFR1: Mosaicism tag added based on original PAGE file which records Mosaic MOI for Encephalocraniocutaneous lipomatosis.
Fetal anomalies v0.3 FGFR1 Rebecca Foulger reviewed gene: FGFR1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v0.1 FGFR1 Rebecca Foulger Added phenotypes Hartsfield syndrome for gene: FGFR1
Fetal anomalies v0.1 FGFR1 Rebecca Foulger Added phenotypes Encephalocraniocutaneous lipomatosis for gene: FGFR1
Fetal anomalies v0.1 FGFR1 Rebecca Foulger Added phenotypes IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM for gene: FGFR1
Fetal anomalies v0.1 FGFR1 Rebecca Foulger Added phenotypes PFEIFFER SYNDROME for gene: FGFR1
Fetal anomalies v0.1 FGFR1 Rebecca Foulger Added phenotypes KALLMANN SYNDROME TYPE 2 for gene: FGFR1
Fetal anomalies v0.1 FGFR1 Rebecca Foulger gene: FGFR1 was added
gene: FGFR1 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: FGFR1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: FGFR1 were set to OSTEOGLOPHONIC DYSPLASIA