NHGRI uses new sequencing strategies to rapidly pinpoint causes of rare inherited illnesses

Strategy could benefit gene discovery for thousands of rare diseases

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BETHESDA, Md.—A team of researchers from theNational Human Genome Research Institute (NHGRI) has demonstrated a newtechnical strategy that promises to rapidly determine the genetic cause forvery rare inherited illnesses. In addition, the theory is that the knowledgegained from this work might lead to insights on more common illnesses and waysto diagnose or treat them.  
Relying on inexpensive, high-speed sequencing anda newly developed ability to capture pieces of the genome that encode genes,the team diagnosed an extremely rare X chromosome-linked cleft palate syndromeknown to affect just two families. The disorder, called TARP (talipesequinovarus, atrial septal defect, robin sequence, persistent left superiorvena cava), is caused by a mutation in a gene called RBM10.
This is the first example of uncovering a genedefect on the X chromosome by analyzing DNA samples from unaffected carriers.In this case, the DNA came from the mothers of the two affected families. DNAwas unavailable from any of the affected male infants because they died before,or soon after, birth. TARP syndrome is 100 percent lethal in males.
The findings were published in the May 14 issue ofthe American Journal of Human Genetics.
"This study demonstrates the feasibility of usingnew sequencing technologies to uncover causative genes for thousands of rarediseases, an effort that historically has been costly and arduous," says thepaper's senior author Dr. Leslie G. Biesecker, chief of NHGRI's Genetic DiseaseResearch Branch. "It is also gratifying to know that the two families known tobe affected by TARP syndrome finally have answers about what causes thedevastating disorder that has afflicted their families for decades."
"Studying the function of genes in rare diseases—boththose we already know something about and the one-third of genes in the humangenome we don't yet—can lead to a better understanding of their largerbiological function and role in other human diseases," notes Dr. James C.Mullikin, a co-author of the study and acting director of the NIH SequencingCenter in Rockville, Md., where the sequencing work was done. "For instance, furtherstudies of the RBM10 gene may give researchers further insight into more commonforms of cleft palate."
TARP syndrome was originally described in 1970. Itaffected a single family. Subsequently, it was mapped to the X chromosome by agroup that included NHGRI researchers in 2003. However, the mapping work onlynarrowed the search to a region containing 28 million base pairs, or letters ofDNA sequence, on the X chromosome that contained more than 200 genes.
At the time, sequencing all of those genes toidentify and validate variants was a daunting and costly task. So the sampleswere returned to the refrigerator until recently, when NHGRI researchersidentified a second family with TARP syndrome. Meanwhile, new sequencingtechnologies drove down the cost of sequencing DNA, and another technique wasdeveloped for capturing exons. Until recently, it was not possible to sequencethe exome on a single chromosome.
Several months ago, a kit specifically designed tocapture and sequence only the exons along the X chromosome prompted theresearchers to try again. NHGRI's researchers used the kit to sequence all ofthe exons on the X chromosomes of the mothers from the two families. Similarkits are currently available or being developed to target the exons on each ofthe other 22 chromosomes, as well as the Y sex chromosome.
In the original family, the researchers found aninsertion of single base pair, a mutation called a single frame-shift mutation,and in the second family the substitution of a single base pair, a mutationcalled a single nonsense mutation, both within the RBM10 gene, or the RNAbinding motif 10 gene. This gene is a member of the larger RBM gene family, butonly mutations in a few of its family member genes are known to cause humandisorders.
"There are about 2,500 of these rare, inheriteddisorders, and the cause of the great majority of them is unknown," says Biesecker."With the help of these new technologies, biomedical researchers canpotentially start making major inroads into finding the genes that cause suchdiseases."

CompleteNeanderthal Genome Sequenced
So, if use of sequencing technologies forstartling rare genetically inherited diseases doesn't seem esoteric enough,guess what else the NHGRI has been up to? Well, a few days before the abovestory was released, the institute reported that researchers have produced thefirst whole genome sequence of the 3 billion letters in the Neanderthal genome,and the initial analysis suggests that up to 2 percent of the DNA in the genomeof present-day humans outside of Africa originated in Neanderthals or inNeanderthals' ancestors.
"This sequencing project is a technological tourde force," says Dr. Eric D. Green, director of NHGRI. "You must appreciate thatthis international team has produced a draft sequence of a genome that existed400 centuries ago. Their analysis shows the power of comparative genomics andbrings new insights to our understanding of human evolution."
The Neanderthal DNA was removed from bonesdiscovered at Vindija Cave in Croatia and prepared in the clean room facilityof the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany,to prevent contamination with contemporary DNA.
To understand the genomic differences betweenpresent-day humans and Neanderthals, the researchers compared subtledifferences in the Neanderthal genome to the genomes found in DNA from the fivepeople, as well as to chimpanzee DNA. An analysis of the genetic variationshowed that Neanderthal DNA is 99.7 percent identical to present-day human DNA,and 98.8 percent identical to chimpanzee DNA. Present-day human DNA is also98.8 percent identical to chimpanzee.
The comparison between Neanderthal and present-dayhuman genomes has produced a catalog of genetic differences that allow theresearchers to identify features that are unique to present-day humans. Forexample, the catalog includes differences in genes that code for functionalelements, such as proteins, in which the Neanderthal versions are more likethose of the chimpanzee than present-day humans. Some evolutionary changes werefound in known genes involved in cognitive development, skull structure, energymetabolism, skin morphology and wound healing.

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