Ehlers‐Danlos/myopathy overlap syndrome caused by a large de novo deletion in COL12A1

Autosomal dominant and recessive mutations in COL12A1 cause the Ehlers-Danlos/myopathy overlap syndrome. Here, we describe a boy with fetal hypokinesia, severe neonatal weakness, striking hyperlaxity, high arched palate, retrognathia, club feet, and pectus excavatum. His motor development was initially delayed but muscle strength improved with time while hyperlaxity remained very severe causing recurrent joint dislocations. Using trio exome sequencing and a copy number variation (CNV) analysis tool, we identified an in-frame de novo heterozygous deletion of the exons 45 to 54 in the COL12A1 gene. Collagen XII immunostaining on cultured skin fibroblasts demonstrated intracellular retention of collagen XII, supporting the pathogenicity of the deletion. The phenotype of our patient is slightly more severe than other cases with dominantly acting mutations, notably with the presence of fetal hypokinesia. This case highlights the importance of CNVs analysis in the COL12A1 gene in patients with a phenotype suggesting Ehlers-Danlos/myopathy overlap syndrome.