Disease Characterisation & Identification of a Novel Gene Locus for Arrhythmogenic Right Ventricular Cardiomyopathy

Abstract

Medical Research Society 19rin affected sibling pairs provided evidence for linkage with 12 markers in 5 distinct regions of chromosomes 2, 3, 7, 12 and 15 (p<O.OOl for an individual marker, or adjacent markers each with p4.01).In the second stage, a further 97 affected sibling pairs with IBD were genoty ed; linkage for the clustered markers on chromosomes 5, 7 and 12 was confirmed.Combinin data from the first and second stages provided striking eviience for linkage with 3 ad'acent markers on chromosome 12-Dl2S83 ( = 2.66 x lo-+, lod score 5.47). D12S92 (p = 2.14 x Idscore 4.59) and D12S368 (p = 5.03 x 10-5, lod score 3.29)and three adjacent markers on chromosome 7 -D7S519 (p = 1.33 x lo4, lod score 2.89). D7S669 (p = 8.20 x lO-5,1$ score 3.08) and D7S524 (p = 8.45 x 104, lod score 2.14).Individual markers ,on chromosome ,2. JD2S142) and chromosome 16 were linked with susceptibility to UC (p = 0.0071) and CD (p = 0.009), respective1 .These data not only sup ort the modYel of Crohn's disease and ulcerative colitis as relatexpolygenic disorders, but also provide compelling evidence for the chromosomal location of IBD susceptibility enes. Strong candidate genes are present in each of the re ions wkch have been implicated, and are currently being studie%. Y 5 Studies on Adenosine deaminase.(ADA) deficiency and hereditary haemovha ic telan ieetasia HHT). Claire L. Shovlin. diversitv oq EdinbureL. Adenosine deaminase (ADA) deficienc causes neonatesand voune children. in associalfon with ., immunodeficiency .in CD4+ Ivrnohooaenia. Adult onset c'ases Cere first 'described in two sisters whh k s 'iratory disease ]Shovlin CI al: h c c i 1993 341:14711. Analysis of the AJA oene demonstrated that the sisters were compound heterozygotes: f h a r paternal allelecontained a deletion between two ulu elements that flank the first exon, and is redicted to produce no ADA protein. The maternal allele was a C Po T missense mutation (Arg211Cys). Neither allelealone caused clinical disease in other.family members, and PEG-ADA re lacement therapy has resulted in immunological improvement in the a8ectedsisters IShovlin CI al: JImnunol 199453:2331 I. Heredita Haemorrhagic Telanpiectasia HHT, Rendu-Osler-Weber trait. At t e outset of this study the underlyin defect was nnknown, and comparison with other inhehed vascular Aseases did not silggest an aetiology 1Shovlin and Scoll: Annual Rcvicw of Physiology 1%,58:4K3-5071. Patients presenting with pulmona arteriovenous malformations (PAVMs) wqr? used to identify over 30%HT families. Clinical studies of these families revealed novel features of the disease IShovlin ct ill: syndromq is a vascular disordei inherite d as an autosomal dominant QUan J M d 1995.88%79-M1. Linkaoe analysis mapped an HHT disease locus to chromosome 9q and revgled genetic heterogeneit [Shwlin ct al: Naiurc Gcnclics I994,6:2(k209J. The disease interval was refmed usin oenomic libranes constructed in yeast artificial chromosomes EMS& grid PI bactenophage [Shovlin: BioTcchnrqucs I9S6,21:188-1')0]. candidate oenes ma ped im...