Genomes of an entire family sequenced in world first

Sequencing the genomes of every family member gives researchers a powerful new tool for tracking down the defective genes that cause inherited diseases
3D representation of DNA strands
Family genome sequences can fast-track the identification of disease genes. Image: Kyu Oh/Getty Images

An American family has become the first to have the entire genome of each member mapped to identify the causes of rare diseases that affect the children.

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. Only a few families in the world have been formally diagnosed with the condition.

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. If we look at more and larger families we should be able to home in on the key genes linked to far more complex conditions, such as neurodegenerative diseases and autoimmune diseases," 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 big impact is going to be helping us understand diseases at the molecular level, but that is a longer play," Galas added.

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. Estimates based on comparisons between human and chimp genomes have previous led scientists to think the figure was higher, at around 75.

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.

Many patients who are referred to a clinical geneticist by their doctor are not diagnosed because scientists only know the genes involved in a fraction of the medical conditions they see.

"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.

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 three of 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 other family members and identified two mutant genes that cause the syndrome.

"This is the first time we have tried to identify a disease gene in this way," said Lupski. "We can [now] start to use this technology to interpret the clinical information in the context of the sequence, of the hand of cards you have been dealt."

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