From the Departments of Cardiological Sciences (A.S.C., E.W.A.N., R.K.M.,
W.J.M.), Dermatology (S.C.), Pathology (M.I.O.), and Medical Genetics
(V.A.M.), St George's Hospital Medical School, London, UK; Yannis
Protonotarios Medical Center, Hora Naxos, Naxos, Greece (N.P., A.T.); and
Genetics Team, Section of Epidemiology, Institute of Cancer Research, Royal
Marsden Hospital, Sutton, Surrey, UK (R.S.H.).
Correspondence to Dr A.S. Coonar, Department of Cardiological Sciences, St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK. E-mail a.coonar{at}sghms.ac.uk
Background—Arrhythmogenic right
ventricular cardiomyopathy (ARVC) is a
heart muscle disease of unknown etiology that causes
arrhythmias, heart failure, and sudden death. Diagnosis can be
difficult, and this hampers investigation of its molecular basis. Forms
of ARVC in which gene penetrance and disease expression are greater
should facilitate genetic study. We undertook a clinical and genetic
investigation of Naxos disease, originally described by Protonotarios
in 1986. This disease constitutes the triad of ARVC, diffuse
nonepidermolytic palmoplantar keratoderma, and woolly hair.
Methods and Results—We evaluated the population of Naxos, Greece,
to identify probands, which was followed by family screening.
Twenty-one affected persons from 9 families of 150 persons were
identified. Linkage analysis was performed with microsatellite
markers. The disease locus mapped to 17q21. A peak 2-point LOD score of
3.62 at
Conclusions—Hair and skin abnormalities were found to be reliable
markers of subsequent heart disease. This suggests the presence of a
single mutant gene with novel cardiac, skin, and hair function or two
or more tightly linked disease genes. Recessive inheritance of Naxos
disease and a founder effect were demonstrated. Identification of a
fully informative genetic marker linked to the disease and uncommon in
the background population may be of use as a test to identify disease
gene carriers.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Gene for Arrhythmogenic Right Ventricular Cardiomyopathy With Diffuse Nonepidermolytic Palmoplantar Keratoderma and Woolly Hair (Naxos Disease) Maps to 17q21
=0.0 was found with a marker within intron 4 of the keratin
9 gene, a member of the type I (acidic) keratin family. A preserved
homozygous disease haplotype was identified. Haplotype analysis
delimited the disease interval.
Key Words: genes • cardiomyopathy • Naxos disease
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