Preclinical Diagnosis of Familial Hypertrophic Cardiomyopathy by Genetic Analysis of Blood Lymphocytes

Abstract

Transcripts of beta cardiac myosin heavy-chain gene can be detected in blood lymphocytes and used to screen for mutations that cause familial hypertrophic cardiomyopathy. This approach makes practical the identification of mutations responsible for this disorder and may be applicable to other diseases in which direct analysis is difficult because the mutated gene is expressed only in certain tissues. Preclinical or prenatal screening in an affected family will make it possible to study the disease longitudinally and to develop preventive interventions.

Whole blood RNA offers a rapid, comprehensive approach to genetic diagnosis of cardiovascular diseases

“…An obvious example is ARVD, a rare but lethal cardiomyopathy associated with mutations in one of the largest genes in the genome, the cardiac ryanodine receptor (ARVD2) (RYR2, 105 exons), 33 and with plakophilin 2 (ARVD9) (PKP2, 14 exons). 34 Using RNA from purified or transformed lymphocytes, others have successfully amplified mRNA encoding beta-myosin heavy chain (MYH7), one of the proteins mutated in HCM, 14 as well as genes involved in cystic fibrosis (CFTR), 35 Duchenne muscular dystrophy (DMD), 36 and malignant hyperthermia (RYR1). 37 Differences in gene expression patterns between purified or transformed lymphocytes and unfractionated whole blood cells 38 may actually favor the detection of certain transcripts.…”

“…37 Differences in gene expression patterns between purified or transformed lymphocytes and unfractionated whole blood cells 38 may actually favor the detection of certain transcripts. 14,15 On the other hand, using whole blood RNA, we have successfully amplified mRNA from multiple genes not previously accessible to RNA sequencing, including those linked to LQTS/Brugada syndrome (SCN5A), ARVD (PKP2), dilated cardiomyopathy (lamin A/C, LMNA) and Barth Syndrome (tafazzin, TAZ; our unpublished data). These findings represent a useful starting observation for future technical improvements.…”

“…This can be a particular problem for cardiac-restricted genes, since myocardial tissue from the proband is usually unavailable. Ectopic transcription has been noted for a number of genes 13 and "leaky" expression of the HCM-linked genes beta myosin heavy chain (MYH7), cardiac troponin T (TNNT2), and MYBPC3 in lymphocytes 14,15,16 has not proven robust enough to serve as a source of genetic testing material.…”

Detection of a new mutation in the beta-myosin heavy chain gene in an individual with hypertrophic cardiomyopathy.

“…A missense mutation in exon 13 of fMHC gene has been found in all affected members of another family with FHCM (8). Similarly, another missense mutation in exon 9 of the ,BMHC gene has been described in a family with FHCM (9). We have examined DNA from the probands of 59 families with FHCM and have detected the exon 13 missense mutation in a single family, but did not detect the a/l hybrid gene in any family.…”

On not listening to patients.

“…'6 17 Nevertheless, they seem to be sensitive enough to detect most heavy carriers. [8][9][10][11][12][13][14][15][16][17][18][19][20] In a retrospective analysis a latex agglutination test gave positive results in all mothers who delivered infants with group B streptococcal infections, and no neonatal deaths due to group B streptococcal infection occurred in the group testing negative. The sensitivity of such kits may also improve.…”