The family of four is unusual because the parents are healthy but both son and daughter have two rare inherited medical conditions that cause facial and limb malformations and lung problems.
Mutations in “recessive” genes are responsible for these conditions, meaning that in each case the children must have inherited a defective copy from both their mother and their father to get the disease.
One of the conditions, Miller’s syndrome, causes facial and limb abnormalities and affects only around one in a million people. The second disease, called primary ciliary dyskinesia, makes the hair-like structures that sweep mucus from the lungs and airways stop working, and affects around one in 10,000 people globally. The chances of one person having both conditions are less than one in a billion.
Scientists at the Institute for Systems Biology in Seattle sequenced the entire genomes of all four family members and used the information to pinpoint four genes that might be responsible for the diseases. Mutations in two of the genes were later confirmed to be the cause of the diseases. The breakthrough, reported in the journal “Science”, gives researchers a powerful new tool to track down quickly the defective genes behind almost any disease that is caused to a significant extent by genetic glitches.
“It remains to be seen how far we can push it, but I really don’t see any limitation to this,” said David Galas, professor of genetics and a senior author on the study. With many diseases, identifying the defective gene can help doctors make a diagnosis and arrange for appropriate counselling for the patient and other family members.
The researchers also report the first measurement of how many new, spontaneous mutations parents pass on to their children. They identified 30 from each parent, meaning that each child inherited 60 new mutations in total.
Writing in the journal, the scientists explain that in future, everyone is likely to have a full genome sequence in their medical records, making such familial genetic comparisons easier.
“What this group has shown is that with one family, you can get almost directly to the important mutation itself. It’s a big deal, because if we can collect families affected by a condition, we might be able to get much more rapidly towards understanding their genetic causes,” said Matthew Hurles, a geneticist at the Wellcome Trust Sanger Institute in Cambridge, UK.
Rare disorder
In a separate study, a researcher at Baylor College of Medicine in Houston, Texas, helped discover genetic mutations that cause his own rare medical condition. James Lupski inherited Charcot-Marie-Tooth syndrome, a rare disorder that leads to a loss of sensitivity and muscle in the hands and feet. Neither of his parents have the disease, but his siblings do.
Writing in “The New England Journal of Medicine”, Lupski and his colleagues describe how they compared his genome with those of his family members and identified two mutant genes that cause the syndrome. “We can [now] start to use this technology to interpret the clinical information in the context of the sequence,” Lupski said.