Holoprosencephaly - NOT chromosomal

Gene: FGFR1

Green List (high evidence)

Comment on mode of inheritance: There are 4 individuals reported in literature with biallelic FGFR1 variants and spectrum of holoprosencephaly: lobar, alobar, corpus callosum agenesis, and absent septum pellucidum with a hypoplastic anterior corpus callosum. Based on available evidence, the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next update.

Created: 27 Feb 2026, 1:11 p.m. | Last Modified: 27 Feb 2026, 1:11 p.m.

Panel Version: 5.7

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. Presented with absent puberty, severe split hand/foot malformation (both hands and feet), cryptorchidism, absent septum pellucidum, hypoplastic anterior corpus callosum. Heterozygous sister and parents. Sister has hyposmia, otherwise no phenotype reported in carrier family members.

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. P1 had alobar HPE, P2 - lobar.

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 Feb 2026, 1:05 p.m. | Last Modified: 27 Feb 2026, 1:09 p.m.

Panel Version: 5.7

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

• 23154428
• 23812909
• 25394172

As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: The Specialist Test Group all agreed that there is enough evidence to rate this gene Green

Created: 29 Jul 2019, 2:13 p.m. | Last Modified: 29 Jul 2019, 2:13 p.m.

Panel Version: 1.20

Comment when marking as ready: Sufficient cases for causation.

Created: 30 May 2017, 3:44 p.m.

Comment on list classification: 6 cases (5 missense, 1 splicing) in PMID 27363716

Created: 30 May 2017, 3:43 p.m.

I don't know

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
615465

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
615465

Publications

• 19504604