De novo mutation in COL2A1 leads to lethal foetal skeletal dysplasia

Skeletal dysplasia caused by genetic mutations places a heavy burden on families and society. This study was performed to precise diagnosis of variants of unknown significance and to expand the genotypic spectrum of lethal skeletal dysplasia.

According to the ultrasonic phenotype of the proband and whole-exome sequencing results, variation sites or genes that may be related to the disease were screened out. We verified the accuracy of the variation site through Sanger sequencing. Using bioinformatics, zebrafish models, and assisted reproduction technology (ART) combined with preimplantation genetic testing for monogenic diseases, the disease-causing mutation was verified.

A missense mutation (c.3944G>A, p.Cys1315Tyr) was found in the coding region of COL2A1. Although the mutation is a variant of unknown significance, it is highly conserved and was predicted to be harmful by the SIFT and PolyPhen-2 software. In contrast to the control group, col2a1a mutation-expressing zebrafish larvae showed significant spinal curvature. Through preimplantation genetic testing for monogenic diseases excluding the missense mutation, a child conceived by ART was birthed with normal bone development.

We identified a de novo mutation in human COL2A1 related to lethal skeletal dysplasia and expanded the mutation spectrum of type II collagenopathies. In addition, we provided a new strategy based on a zebrafish model and ART for patients who harbour variants of unknown significance to have a healthy baby without genetic disease similar to the proband.