Two New COL7A1 Mutations Identified in Boy With DEB
Two new mutations in the COL7A1 gene, one inherited from each parent, were identified as the cause of recessive dystrophic epidermolysis bullosa (DEB) in a 10-year-old boy, a case study reported.
Further functional analyses suggested that each mutation had only mild effects — supported by the fact that his parents had no signs of the disease — but their combination caused the condition.
These findings expand the genetic spectrum of DEB and support comprehensive genetic testing for those affected, as apparently harmless mutations that may be disregarded can lead to disease when combined with other mutations, the researchers noted.
The case study, “Whole exome sequencing identified a novel compound heterozygous variation in COL7A1 gene causing dystrophic epidermolysis bullosa,” was published in Molecular Genetics & Genomic Medicine.
DEB is one of the major forms of epidermolysis bullosa. It is caused by mutations in the COL7A1 gene, which provides instructions for making part of type VII collagen, a protein important for giving structure to the skin and other organs.
DEB can be inherited in a recessive or dominant pattern. In dominant DEB, inheriting only one copy of the mutated COL7A1 gene is sufficient to cause the disease. In recessive DEB, a more severe form, a child has to inherit two mutated copies (one from the mother and the other from the father) to develop full-blown disease.
To date, more than 800 mutations in COL7A1 have been associated with DEB. Most of them are associated with either recessive or dominant DEB, but some mutations are found in both forms, challenging genetic interpretation and counseling.
A research team in China now described the case of a 10-year-old boy with recessive DEB caused by two previously unknown COL7A1 mutations.
The boy’s case
The boy, born of healthy parents who were not related, had been diagnosed with DEB 10 days after birth. At 10 years of age, when he and his family were referred to the researchers’ center, the boy showed fragile, itchy skin, blistering, skin thickening, and raised scar tissue. He also had deformed, thickened, or discolored nails.
Genetic testing revealed that the boy carried two COL7A1 mutations — c.191T>C and c.5124G>A — one in each copy of the gene, which had never been identified before.
The mutation inherited from his father, c.191T>C, led to a modification in a single amino acid (protein’s building blocks) in a region of the protein that is evolutionarily conserved. This means that this particular region is identical across several species, a sign that it plays an important function in the protein’s function and that mutations in it could be damaging.
The mutation inherited from his mother, c.5124G>A, was also in an evolutionarily conserved region. This mutation did not result in an amino acid change (called a synonymous mutation), which could lead to a belief that it doesn’t cause disease, but further analyses demonstrated that it disrupted COL7A1’s normal splicing.
Splicing is a natural process through which a single gene gives rise to different protein products. Much like in a recipe, adding or removing certain key ingredients — in this case, pieces of genetic information called exons — can change the resulting protein.
The maternally inherited mutation favored the production of an intermediate molecule that lacked one exon, likely resulting in a shorter protein. It was, therefore, classified as likely disease-causing.
Together, the mutations were likely the DEB cause, the researchers noted, writing, “collectively, this variation measured up to be diagnostic.”
“To the best of our knowledge, only one case of DEB associated with a COL7A1 synonymous mutation has been reported,” the team wrote, adding that these rare reports emphasize the need to “be careful when filtering the variants.”
While the boy’s mother, who was pregnant, had undergone routine pregnancy screening that returned normal results, the team performed a prenatal diagnostic test to determine whether the fetus carried the same mutations. The boy’s sibling did not have either mutation, and a healthy girl was born several months later.
“Our findings expanded the mutation spectrum of COL7A1 gene, and provided solid evidence for the genetic counseling to the affected family,” the researchers wrote.
Since both parents carried a COL7A1 mutation, there was a 25% chance that DEB could develop in a future child, “so supporting diagnostic methods such as prenatal diagnosis are still recommended,” the team concluded.