_Med Genet 1994;31:927-932 Genetic heterogeneity in hereditary haemorrhagic telangiectasia: possible correlation with clinical phenotype Kimberly A McAllister, Felicia Lennon, Barbara Bowles-Biesecker, Wendy C McKinnon, Elizabeth A Helmbold, Dorene S Markel, Charles E Jackson, Alan E Guttmacher, Margaret A Pericak-Vance, Douglas A Marchuk Department of Genetics, Box 3175, Duke University Medical Center, Durham, NC 27710, USA K A McAllister D A Marchuk Division of Neurology, Box 2900, Duke University Medical Center, Durham, NC 27710, USA F Lennon M A Pericak-Vance Human Genome Center, Box 0674, University of Michigan Medical School, Ann Arbor, MI 48109, USA B Bowles-Biesecker E A Helmbold D S Markel C E Jackson Department of Pediatrics, University of Vermont College of Medicine, Burlington, VT 05401, USA W C McKinnon A E Guttmacher Division of Clinical and Molecular Genetics, Henry Ford Hospital, Detroit, MI 48202, USA C E Jackson Correspondence to Dr Marchuk. Received 13 June 1994 Revised version accepted for publication 9 August 1994 Abstract Hereditary haemorrhagic telangiectasia (HHT) or Osler-Weber-Rendu syndrome is an autosomal dominant vascular dys- plasia characterised by recurrent haem- orrhage. Our initial linkage studies found an HHT gene to be localised to 9q3 in two large kindreds. In the present study, we examine an additional five unrelated HHT families. Linkage analysis in this region resulted in a peak multipoint location score of 13-03, 10 cM proximal of D9S60. We found significant evidence for het- erogeneity of HHT. Multipoint analysis supports the family specific two point studies with odds of 3000000:1 showing linkage and heterogeneity over linkage and homogeneity. Four of the seven families give a posterior probability of >99% of being of the linked type, and three families appear unlinked to this region of 9q, and by multipoint analysis completely exclude the candidate region for HHT. Two new crossovers in affected persons in one of the linked families further define the proximal border of the candidate region on 9q3. A possible correlation in clinical pheno- type between the 9q3 linked families and unlinked families is described. Although six of the seven families clearly meet the clinical criteria for HHT diagnosis, a sig- nificant absence of pulmonary arterio- venous malformations is seen in all three 9q3 unlinked families. Genetic het- erogeneity of HHT and its potential cor- relation with a clinical phenotype may have a significant impact on the clinical management and treatment of HHT patients. (_JMed Genet 1994;31:927-932) Hereditary haemorrhagic telangiectasia or Osler-Rendu-Weber (HHT), the official GDB designation of the disease, is an autosomal dominant disorder of multisystemic vascular dysplasia with an estimated incidence of ap- proximately 1 in 50000. The three primary types of angiodysplasia exhibited are arterial venous malformations (AVMs, particularly pul- monary and cerebral), telangiectases (mucosal, dermal, and visceral), and aneurysms. Pene- trance is age dependent and is nearly complete by the age of 40. The most common clinical feature of HHT is recurrent epistaxis from vascular lesions in the nasal epithelium, which occurs in ap- proximately 90% of HHT patients and is often the first identifiable feature of the disease. Ga- strointestinal bleeding occurs in approximately 20% of HHT patients, but is often not seen until the fourth or fifth decade of life. Te- langiectases, which are seen in approximately 70% of affected persons, are vascular ab- normalities originating from capillaries and postcapillary venules that are most commonly seen on the face and lips and frequently on the trunk and limbs. Pulmonary arteriovenous malformations (PAVMs), occurring in approximately 20% of HHT patients, are often asymptomatic until the third or fourth decade of life and are often only identified when serious complications re- sult. Much of the estimated 10% mortality of HHT is associated with the two serious complications of undetected PAVMs: strokes and brain abscesses. Neurological manifestations from central nervous system angiodysplasia can also be seen in HHT. Approximately 10% of patients have cerebral AVMs and 7% have cerebral an- eurysms, which can result in cerebral haem- orrhage.1 Another common neurological manifestation is migraine headache, appearing in up to 50% of affected persons. These have been postulated to be the result of undiagnosed PAVMs.' The diffuse constellation of symptoms has been extensively studied and incidence rates have been calculated in a number of ret- rospective and prospective studies.2-5 Great variability of expression is seen with a wide disparity of clinical features even among mem- bers of the same family, indicating that factors other than the inherited germline mutation determine the individual phenotype. However, it is unclear whether all families present the entire spectrum of clinical features. Any differ- ences might be attributable to either allelic or non-allelic heterogeneity. Genetic linkage for some HHT families has recently been es- tablished to markers on 9q3.8 Genetic het- erogeneity has been suggested by a single family unlinked to this region.8 The extent of genetic heterogeneity and its relationship to the clinical heterogeneity of HHT has not been addressed. 927 group.bmj.com on July 15, 2011 - Published by jmg.bmj.com Downloaded from