Genetic Epilepsy

Gene: FGFR3

Green List (high evidence)

FGFR3 has many well-established gene-disease associations with various skeletal dysplasia phenotypes. Gain-of-function is the main mechanism of disease for these disorders, except camptodactyly-tall stature-scoliosis-hearing loss syndrome (CATSHL syndrome, see separate curation below). Specific monoallelic variants cause different phenotypes: >99% achondroplasia is caused by variants leading to the missense change p.Gly380Arg; Cysteine substitutions and stop-loss protein elongation variants are highly specific for Thanatophoric dysplasia (TD) type 1; p.Lys650Glu is associated with TD type 2; p.Ala391Glu causes Crouzon syndrome with acanthosis nigricans; and p.Pro250Arg causes Muenke syndrome.
Moderate evidence for CATSHL syndrome, AD & AR: PMID: 8630492, 17033969, 27139183, 24864036, 32641982 - 2 apparently unrelated families segregating the same missense, p.Arg621His. One consanguineous family with 2 affected brothers with homozygous p.Thr546Lys. Heterozygous individuals in the family were unaffected. No functional assays were conducted for either missense to demonstrate loss of function. Null mouse and zebrafish models are similar to the human CATSHL syndrome phenotype.

Created: 9 May 2022, 4:09 a.m. | Last Modified: 10 May 2022, 3:19 a.m.

Panel Version: 0.14020

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
achondroplasia MONDO:0007037; Thanatophoric dysplasia type 1 MONDO:0008546; Thanatophoric dysplasia type 2 MONDO:0008547; hypochondroplasia MONDO:0007793; Muenke syndrome MONDO:0011274; FGFR3-related chondrodysplasia MONDO:0019685; severe achondroplasia-developmental delay-acanthosis nigricans syndrome MONDO:0014658; Crouzon syndrome-acanthosis nigricans syndrome MONDO:0012833; camptodactyly-tall stature-scoliosis-hearing loss syndrome MONDO:0012504

Publications

• 8630492
• 32641982
• 27139183
• 24864036
• 17033969
• 20301331
• 20301540
• 20301650
• 20301628

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

There are reports of seizures in hypochondroplasia (likely related to temporal lobe abnormalities).

Created: 22 Jan 2020, 9:17 a.m. | Last Modified: 22 Jan 2020, 9:17 a.m.

Panel Version: 0.272

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hypochondroplasia, MIM#146000

Publications

• 24630288
• 27485793
• 23649205
• 12794698