Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Achondroplasia (ACH)

Dipl.-Biol. Christina Sofeso, Dr. rer. nat. Christoph Marschall

Scientific Background

Achondroplasia is an autosomal dominant inherited, disproportionate dwarfism syndrome, which is characterized by a rhizomelic shortening of the limbs. The disease prevalence 1 in 26,000-28,000 live births. The disorder is caused by gain of function variants in the fibroblast growth factor receptor 3 (FGFR3 gene) that lead to changes in the FGF-dependent calcium signal transduction. Up to 20% of the cases are inherited but the majority of cases are caused by new mutations in the FGFR3 gene (probably germline mosaicisms in paternal germ cells, or spontaneous mutations in early fetal development).

The classic cases of achondroplasia have mutations in codon 380 of the FGFR3 gene, which lead to a substitution of glycine by arginine. The resulting dysregulation of endochondral ossification eventually leads to disproportionately short stature. The mutation rate of the nucleic acid at position 1,138, localized in codon 380, is elevated by a factor of 1,000 compared to the average mutation rate in the human genome and thus, belongs to the regions with the highest mutation rates. The spontaneous mutation rate in this region is strongly affected by the age of the father, and is 10 times higher at a paternal age of 50 than at 20 (paternal age effect).

Since mild cases of achondroplasia caused by Gly380Arg and severe cases of hypochondroplasia caused by Asn540Lys are clinically very similar and therefore easily confused, both changes are investigated in the first step of diagnosis.

FGFR3 domains and mutations

Schematic representation of the domains of the FGFR3 protein and the location of the mutations in the protein (modified from Hilbert et al. 1998, Monatsschr Kinderheilkd 146:687)

Literature

Pereira 2019, Pediatr Rev 40:316 / Daugherty 2017, Neonatal Netw 36:337 / Klag et Horton 2015, Hum Mol Genet pii:ddv419 / Laederich et al. 2012, Expert Rev Mol Med 14:e11 / Wright et Irving 2011, Arch Dis Child 97:129 / Baujat et al. 2008, Best Pract Res Clin Rheumatol 22:3 / Vajo et al. 2000, Endocr Rev 21:23 / Witkowski et al. 1999, Lexikon der Syndrome und Fehlbildungen, 6. Auflage / Shiang et al. 1994, Cell 78:335 / Rousseau et al. 1994, Nature 371:252