Clinical and genetic analysis of classical Ehlers-Danlos syndrome patient caused by synonymous mutation in COL5A2

Classical Ehlers-Danlos syndrome (cEDS) is a heterogeneous connective tissue disorder that mainly results from the germline mutation of COL5A1 and COL5A2. The majority of the COL5A2 mutations reported to date represent structural mutations, including missense or in-frame exon-skipping splice mutations. The only reported synonymous mutation was expected to affect on splicing of exon 29 by prediction programs which should be further confirmed.

Whole exome sequencing was performed to identify the genetic variants of a Chinese boy who was characterized by skin hyperextensibility, abnormal scarring, hypermobile joints and scoliosis. Sanger sequencing was used to validate the variants in his parents. Reverse transcription polymerase chain reaction (RT-PCR) was performed to analyze the functional effects of the variant.

A de novo heterozygous synonymous variant (NM_000393.5:c.1977 G>A) of COL5A2 gene was identified in the patient. The results of RT-PCR revealed that the synonymous variant led to skipping of exon 29 in the RNA transcript.

Our study supplies further supporting evidence that the synonymous COL5A2 mutation c.1977 G>A can cause skipping of exon 29 in the RNA transcript, thus resulting in the production of mutant α2(V)-chains and clinical phenotype of cEDS. This result highlights the need to include splicing-altering synonymous mutations into the screening for cEDS.