COL11A1 – Fibrochondrogenesis

Fibrochondrogenesis is a rare autosomal recessive skeletal dysplasia characterized by short-limbed growth failure, neonatally lethal skeletal abnormalities, and variable extra-skeletal features including developmental delay and ocular defects. The α1 chain of type XI collagen, encoded by COL11A1, is essential for cartilage fibrillogenesis and normal skeletal development. Biallelic loss-of-function variants in COL11A1 disrupt collagen XI formation, leading to the classic fibrochondrogenesis phenotype.

Two unrelated consanguineous Emirati families presented with children surviving beyond the neonatal period, manifesting short-limb skeletal dysplasia, global developmental delay, profound sensorineural deafness, and high myopia. Homozygosity mapping linked the disorder to chromosome 1 and identified homozygous null variants c.4084C>T (p.Arg1362Ter) and c.3708+437T>G in COL11A1 in the two probands ([PMID:21668896]). Segregation in both pedigrees and absence of these alleles in population databases support pathogenicity.

A clinical whole-exome sequencing study of an 18-week Iranian aborted fetus from consanguineous parents revealed a novel homozygous missense variant c.3440G>A (p.Gly1147Asp), affecting a highly conserved glycine residue in exon 45 and predicted to disrupt the collagen triple helix ([PMID:36397853]). This single additional proband confirms autosomal recessive inheritance and expands the variant spectrum of COL11A1 in fibrochondrogenesis.

Functional analyses demonstrate that the intronic c.3708+437T>G variant activates a pseudoexon between exons 48 and 49, introducing a frameshift and premature termination codon, consistent with a null allele ([PMID:21668896]). In silico tools predict that the p.Gly1147Asp substitution destabilizes the triple helical domain, further supporting a loss-of-function mechanism.

The pathogenic mechanism involves absence or severe reduction of α1(XI) collagen, impairing cartilage matrix assembly and leading to lethal skeletal dysplasia. The survival of some homozygous null individuals suggests phenotypic variability potentially influenced by modifier alleles or residual low-level expression of alternative splice isoforms.

In summary, biallelic COL11A1 variants have moderate clinical validity for fibrochondrogenesis, with consistent autosomal recessive transmission, a clear loss-of-function mechanism, and phenotype concordance across three probands. COL11A1 should be included in diagnostic gene panels for prenatal and neonatal skeletal dysplasias.

Key Take-home: Autosomal recessive COL11A1 loss-of-function variants cause fibrochondrogenesis and warrant targeted genetic testing in perinatal skeletal dysplasia.

References

• Clinical genetics • 2012 • Clinical and molecular analysis of UAE fibrochondrogenesis patients expands the phenotype and reveals two COL11A1 homozygous null mutations. PMID:21668896
• Clinical Case Reports • 2022 • Clinical whole-exome sequencing analysis reveals a novel missense COL11A1 mutation resulting in an 18-week Iranian male aborted fetus with Fibrochondrogenesis 1: A case report. PMID:36397853

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