Clinical genetic testing in cardiomyopathies

The completion of the Human Genome Project was a landmark achievement that revealed the reference DNA sequence for our own genome. Almost immediately it became clear that there was no single reference DNA sequence, as even the approximately half-dozen human DNA samples used by the Human Genome Project contained tens of thousands of variations [1]. As clinical genetic testing becomes more mainstream, and various projects underway perform full DNA genome sequencing in thousands of individuals, the extent of this genetic variation is increasingly being appreciated. It is widely recognized that most of this variation is probably not relevant for determining health or risk of disease and it has been collectively referred to as genetic noise. As in much of biology, separation of the signal from the noise can be challenging, and as molecular genetic sequencing expands in use and in the total length of DNA that can be sequenced in a single assay, problems in distinguishing a diagnostic genetic change from background genetic variation will remain a difficult task for researchers and clinicians to fulfill. Newer DNA sequencing technology can now complete the sequencing of an entire human genome several times in a matter of days, which is orders of magnitude faster than the nearly 13 years required for the initial first-pass done by the Human Genome Project consortium [2]. This technology, which will shortly be widely used in clinical genetic testing, will undoubtedly add new challenges to the difficulty of distinguishing signal from noise

Variants in the 3&#39; untranslated region of the <em>KCNQ1</em>-encoded K_v7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner.

Aims Heterozygous mutations in KCNQ1 cause type 1 long QT syndrome (LQT1), a disease characterized by prolonged heart rate-corrected QT interval (QTc) and life-threatening arrhythmias. It is unknown why disease penetrance and expressivity is so variable between individuals hosting identical mutations. We aimed to study whether this can be explained by single nucleotide polymorphisms (SNPs) in KCNQ1&#39;s 3&#39; untranslated region (3&#39;UTR). Methods and results This study was performed in 84 LQT1 patients from the Academic Medical Center in Amsterdam and validated in 84 LQT1 patients from the Mayo Clinic in Rochester. All patients were genotyped for SNPs in KCNQ1&#39;s 3&#39;UTR, and six SNPs were found. Single nucleotide polymorphisms rs2519184, rs8234, and rs10798 were associated in an allele-specific manner with QTc and symptom occurrence. Patients with the derived SNP variants on their mutated KCNQ1 allele had shorter QTc and fewer symptoms, while the opposite was also true: patients with the derived SNP variants on their normal KCNQ1 allele had significantly longer QTc and more symptoms. Luciferase reporter assays showed that the expression of KCNQ1&#39;s 3&#39;UTR with the derived SNP variants was lower than the expression of the 3&#39;UTR with the ancestral SNP variants. Conclusion Our data indicate that 3&#39;UTR SNPs potently modify disease severity in LQT1. The allele-specific effects of the SNPs on disease severity and gene expression strongly suggest that they are functional variants that directly alter the expression of the allele on which they reside, and thereby influence the balance between proteins stemming from either the normal or the mutant KCNQ1 allele