Scientists believe they have disproved a 30-year-old notion of what causes Down's syndrome.
The work challenges previous beliefs
A particular genetic region long assumed to be a critical factor in this condition is not as important as thought, says the Johns Hopkins team.
The US researchers studied mice engineered to have the 'culprit' genes believed to be responsible for causing Down's syndrome.
They told the journal Science that the cause was much more complicated.
They believe Down's syndrome arises from an interplay of complex genetic and developmental factors.
In Down's Syndrome, an extra copy of one chromosome is inherited, giving a person three copies of chromosome 21 instead of the usual two. This is known as trisomy 21.
Previous studies have supported the idea that extra genes within a critical region of chromosome 21 could be the root of the problem.
Rare cases of Down's syndrome occur when only a segment of chromosome 21, and the genes housed within it, is triplicated.
But Dr Roger Reeves and his colleagues say this notion can be disproved by measuring Down's syndrome-like characteristics in mice that are genetically engineered to possess the suspect genes.
Children and adults with Down's have a distinctive facial appearance as well as possessing three copies of chromosome 21 in their cells.
The researchers bred mice with one, two, or three copies of the critical region housed within chromosome 21, and compared them to other mice expressing both visible and genetic Down's syndrome-like characteristics.
The mice bred to have copies of only the critical region had facial and skeletal changes different to those seen in Down's syndrome.
Dr Reeves said: "These mice weren't normal but they weren't Down's syndrome mice either.
"Their faces were longer and narrower than normal, but Down's syndrome is characterised by shorter than normal facial bones.
"If anyone is going to try to treat the problems seen in Down's syndrome, we need to understand what is really happening and when in development it happens."
Peter Elliott, of the Down's Syndrome Research Foundation, said the idea that there was a Critical Down Syndrome Region was too simplistic.
"Our research is based upon an understanding of all the genes and how the extra 163 genes in Trisomy 21 affect the metabolism and so affect growth, development, health, and well being."
Mr Elliott said it was clear that the extra 163 genes produced extra chemical messengers which could disrupt the function of any of the 22,450 genes contained in the cells of people with Down's.
"Although the interaction of 163 extra genes affecting 22,287 other genes is very complex, we can look at the most serious outcomes, identify the particular gene at fault, then, develop a therapy to counteract the effect of that particular gene.
"But research to find treatment therapies and a cure for Down's syndrome is very complex. Millions will be needed to find the answers."
A spokesman from the Down's Syndrome Association said: "It is encouraging to see that research is continuing into the condition of Down's syndrome and producing results that help us understand the genetic make-up of chromosome 21 even further."
He said although the results disagreed with the findings of previous studies, they should be viewed as positive because they suggested that further research might lead to developments in treating specific health problems common to people with Down's syndrome.