Researchers Discover Tiny Gene Mutations that Cause Birth Abnormalities

By Jeffrey Norris, UCSF Today | October 10, 2006

The causes of developmental delay -- what used to be known as mental retardation -- are often unknown.

Environment often plays a role -- think of fetal alcohol syndrome. But genes are just as important a cause, notes UCSF pediatrician and scientist Katherine Rauen, MD, PhD. In fact, the best known cause of developmental delay -- Down syndrome -- is genetic.

Down syndrome is the result of an abnormal duplication of all or most of an entire chromosome. The genetic defect is so large that for decades it has been detectible, even as myriad other genetic syndromes remain untraceable to this day. To diagnose Down syndrome, gene-bearing chromosomes -- in a preparation known as a karyotype -- are viewed under a microscope.

But unlike Down syndrome, many instances of developmental delay are due to small mutations in DNA. These small mutations often consist of no more than a single missing or substituted letter within the string of DNA alphabet building blocks that make up long sequences of genetic code.

Until recently, it was too difficult to track down such small genetic errors that are behind so many cases of developmental delay.

By using the latest "microarray" laboratory techniques -- developed and refined by UCSF Comprehensive Cancer Center colleagues Donna Albertson and Daniel Pinkel -- Rauen and her fellow genetic sleuths are succeeding at last in their searches.

Many of the syndromes these researchers investigate are rare. But when their numbers are combined, these disorders account for many thousands of cases of developmental delay in the United States alone.

Modern Gene Sleuthing
Rauen and her research colleagues used blood samples of 23 affected children to identify tiny genetic mutations responsible for cranio-facio-cutaneous (CFC) syndrome.

Children born with CFC syndrome have curly, brittle hair, skin conditions, slow growth -- and most seriously -- heart defects and major cognitive disabilities.

The blood samples became available thanks to the establishment of a blood bank by patient advocates -- primarily parents. The advocates became aware of the scientific importance of tissue banks for tracking down the genetic causes of disease.

Rauen's driving research interest is to explore how certain genes play a role both in normal development and in the development of cancers. She became interested in CFC syndrome after studying a similar developmental disorder -- Costello syndrome -- during her medical training. Costello syndrome and a third cause of developmental delay -- Noonan syndrome -- are caused by small mutations in genes that also are known to be involved in cancer.

(Note that in November 2007 the UCSF Comprehensive Cancer Center was renamed the UCSF Helen Diller Family Comprehensive Cancer Center.)

Read more at Jeffrey Norris, UCSF Today