TY - JOUR T1 - <em>VHL</em> c.505 T&gt;C mutation confers a high age related penetrance but no increased overall mortality JF - Journal of Medical Genetics JO - J Med Genet SP - 508 LP - 514 DO - 10.1136/jmg.38.8.508 VL - 38 IS - 8 AU - Bernhard U Bender AU - Charis Eng AU - Manfred Olschewski AU - Dietmar P Berger AU - Jörg Laubenberger AU - Carsten Altehöfer AU - Günter Kirste AU - Miro Orszagh AU - Vera van Velthoven AU - Henning Miosczka AU - Dieter Schmidt AU - Hartmut P H Neumann Y1 - 2001/08/01 UR - http://jmg.bmj.com/content/38/8/508.abstract N2 - BACKGROUND Germline mutations of the VHL gene cause von Hippel-Lindau syndrome (VHL). In southern Germany, a specific mutation in this gene, c.505 T&gt;C, is one of the most frequent alterations owing to a founder effect. METHODS This study was conducted to evaluate morbidity, specific clinical risk profile, and mortality among a series of VHL c.505 T/C mutation carriers. A total of 125 eligible subjects carryingVHL c.505 T/C underwent ophthalmoscopy and gadolinium enhanced magnetic resonance imaging of the brain, the spinal cord, and the abdomen. Age related penetrance, morbidity, and mortality were assessed. RESULTS Frequently observed lesions were phaeochromocytoma (47%), retinal angiomas (36%), haemangioblastoma of the spine (36%), and haemangioblastoma of the brain (16%). Four patients developed renal cell carcinoma. VHL was symptomatic in 47% of subjects; 30% were asymptomatic despite the presence of at least one VHL related tumour and 23% of the carriers had no detectable VHL lesion. Of the 19 patients who had died (15%), 10 died of symptomatic VHL lesions. Overall penetrance by cumulative incidence functions is estimated at 48% by 35 years and 88% by 70 years. In contrast to the only existing published report based on patients with presumably unselected VHLgermline mutations, the mortality rate for c.505 T/C mutation carriers is comparable to that of the general population of Germany. CONCLUSIONS Our results are an important example that a specific genotype, at least in the case ofVHL c.505 T/C, can favourably impact on mortality despite a high age related penetrance. Our study also indirectly provides objective data which might be useful to the life and health insurance industry; it would appear that c.505 T&gt;C mutation positive subjects have similar disease specific mortality to that of the general population owing to a combination of phenotype and timely detection of mutation carrier status followed by aggressive clinical screening and, if necessary, treatment. ER -