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The International Registry of Werner syndrome (www.wernersyndrome.org) has been providing molecular diagnosis of the Werner syndrome (WS) for the past decade. The present communication summarizes, from among 99 WS subjects, the spectrum of 50 distinct mutations discovered by our group and by others since the WRN gene (also called RECQL2 or REQ3) was first cloned in 1996; 25 of these have not previously been published. All WRN mutations reported thus far have resulted in the elimination of the nuclear localization signal at the C-terminus of the protein, precluding functional interactions in the nucleus; thus, all could be classified as null mutations. We now report two new mutations in the N-terminus that result in instability of the WRN protein. Clinical data confirm that the most penetrant phenotype is bilateral ocular cataracts. Other cardinal signs were seen in more than 95% of the cases. The median age of death, previously reported to be in the range of 46-48 years, is 54 years. Lymphoblastoid cell lines (LCLs) have been cryopreserved from the majority of our index cases, including material from nuclear pedigrees. These, as well as inducible and complemented hTERT (catalytic subunit of human telomerase) immortalized skin fibroblast cell lines are available to qualified investigators.

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The development and usage of two companion NIH-funded genetic testing information databases, GeneTests (www.genetests.org) and GeneClinics (www.geneclinics.org), now merged into one web site, reflect the steadily increasing use of genetic testing and the expanding audience for genetic testing information. Established in 1993 as Helix, a genetics laboratory directory of approximately 110 listings, GeneTests has grown into a database of over 900 tests for inherited diseases, a directory of over 500 international laboratories, a directory of over 1,000 U.S. and international genetics clinics, and a resource for educational/teaching materials and reports of summary genetic test data. GeneClinics, founded in 1997 as an expert-authored, peer-reviewed, disease-specific knowledge base relating genetic testing to patient care, has grown steadily, now containing over 130 expert-authored, peer-reviewed full-text entries relating genetic testing information to diagnosis, management, and genetic counseling of specific inherited diseases. In spring 2001 the two databases were merged and in October 2001 the two web sites were merged for the purpose of seamless navigation into the GeneTests-GeneClinics site (www.genetests.org or www.geneclinics.org); the GeneClinics knowledge base was renamed "GeneReviews" to avoid confusion with the U.S. and international clinic directories. As genetic testing has moved steadily out of research venues and into routine medical practice, the user audience for these databases has become international and expansive and includes healthcare providers, patients, educators, policy makers, and the media. The use of these combined resources has grown to approximately 3,200 visits/day.

No abstract