14th International Congress
THE "NEW FRONTIERS"
OF ARRHYTHMIAS 2000

Jan. 29 - Feb. 5, 2000
Marilleva, Trento, Italy

RT-151

Genetic screening of different forms of congenital cardiomyopathies

Domenico A. Coviello.
Servizio di Genetica Medica, Policlinico Universitario di Modena, Modena, Italy

Genetic analysis

Advances in the Human Genome Project have been instrumental in clarifying the molecular defects in many genetic condition. Cloning and sequencing most of the human genome has made more efficient the “reverse genetics”, a method that allow to identify genes causing diseases without knowing the molecular mechanism that cause the disease.

In the last decade several cardiomyopathy causing genes have been identified, and chromosome loci were the mutated gene are located were identified (Tab. I). Two are the main strategies used: a) the linkage approach, i.e. the analysis of DNA polymorphic markers in all the subjects of a family where the condition has a mendelian transmission, to identify the chromosome locus responsible for the disease; b) the candidate gene approach, i.e. looking for mutations in already identified genes related to the structure or the function of the cardiac muscle.

The linkage analysis can be performed only on families with an adequate number of subjects, and with affected members at least on two generations. The analysis is informative when we can identify DNA markers that segregate with the affected phenotype; a dedicated computer program analyses the data and will tell us the probability of a casual segregation: when this probability is lower than 1/1000 we obtain a “lod score” value >3.0 indicating that the markers are quite near to the mutated gene that causes the disease. Additional work is required to identify the gene, or if a gene is already mapped in this region (chromosome locus) a mutation analysis in the affected members of the family is required to demonstrate that this is the gene causing the disease.

If we have only sporadic cases or small families it is possible to perform only the candidate gene approach. This study consist in the systematic analysis of all the candidate genes performed by direct sequencing or by more rapid but less reliable techniques.

TABLE I

Omim
Number

Gene/Locus description

Locus/Gene

name

map

Authors

160760

Myosin, cardiac, heavy chain, beta;

MYH7

192600

cardiomyopathy, familial hypertrophic, 1

CMH1

14q12

Geisterfer-Lowrance⁴

191045

Troponin T2, cardiac;

TNNT2

115195

cardiomyopathy, familial hypertrophic, 2

CMH2

1q32

Thierfelder⁵

191010

Tropomyosin 1;

TPM1

115196

cardiomyopathy, familial hypertrophic, 3

CMH3

15q22

Thierfelder⁵

600958

Myosin-binding protein C, cardiac;

MYBPC3

Watkins⁶, Carrier⁷,

115197

cardiomyopathy, familial hypertrophic, 4

CMH4

11p11.2

Numura⁸, Bonne⁹

115198

Cardiomyopathy, familial hypertrophic, 5 (families do not linked to any of the known loci)

CMH5

600858

Cardiomyopathy, familial hypertrophic, with Wolff-Parkinson-White syndrome

CMH6

7q3

MacRae¹⁰

191044

Troponin I, cardiac; cardiomyopathy, familial hypertrophic, 7;

TNNI3

CMH7

19q13.4

Kimura¹¹

160790

Myosin, light chain, alkali, ventricular and skeletal slow cardiomyopathy, hypertrophic, mid-left ventricular chamber type

MYL3

3p

Poetter¹²

160781

Myosin, light chain, regulatory ventricular;
cardiomyopathy, hypertrophic, mid-left
ventricular chamber type

MYL2

12q23-q24

Poetter¹², Flavigny¹³

188840

Titin cardiomyopathy, familial hypertrophic, 9

TTN

CMH9

2q24.3

Satoh¹⁴

102540

Actin, alpha, cardiac muscle cardiomyopathy, familial dilated and hypertrophic

ACTC

15q14

Mogensen¹⁵