Variable and Severe Phenotypic Expression of the "Lebanese Allele" in Two Sisters with Familial Hypercholesterolemia.

The "Lebanese allele" {LDLR c.2043 C>A (p.cys681X)} is a nonsense mutation in the low-density lipoprotein receptor (LDLR) gene that results in a truncated non-functioning LDLR protein. We report two sisters of Lebanese descent who presented with familial hypercholesterolemia (FH) and were both heterozygous for the Lebanese allele, but had very distinct LDL-C levels and clinical phenotypes. Whereas one of the sisters had LDL-C in the expected range of Heterozygous FH (HeFH) with the Lebanese allele (LDL-C of 292 mg/dl), the other sister had a more severe LDL-C phenotype in the Homozygous FH (HoFH) range (LDL-C of 520 mg/dl) along with manifest atherosclerosis. Surprisingly, she did not demonstrate a compound heterozygote or double heterozygote status. We discuss different mechanisms that are purported to play a role in modifying the phenotype of FH, including different variants and polygenic modifiers. HeFH patients with the Lebanese allele can have a wide spectrum of LDL-C levels that range from the typical heterozygous to homozygous phenotypes.

Vascular Genetics: Presentations, Testing, and Prognostics.

PURPOSE OF REVIEW: Numerous studies have begun to unravel the genetic basis of not only aortic disease but also other forms of commonly encountered vascular diseases. The goal of this review is to provide clinicians a reference to help identify and diagnose different types of vascular disease with a genetic underpinning. RECENT FINDINGS: Ongoing studies have identified numerous genes involved in the TGF-ß signaling pathway that are also associated with thoracic aortic aneurysm and dissection, and it is possible to test for pathogenic variants in these genes in the clinical setting using commercially available genetic testing panels. Additional studies have begun to identify genetic variants associated with an increased risk of bicuspid aortic valve, abdominal aortic aneurysm, and fibromuscular dysplasia. With increased availability of low-cost genetic testing, clinicians are now able to not only definitively diagnose some vascular syndromes but also provide information on the risk of disease in other family members, as well as provide guidance in terms of family planning. As the cost of genetic testing continues to drop with the benefit of increasing insurance coverage, genetic data will increasingly become part of clinical care for many patients with vascular disease.

A Case for Inclusion of Genetic Counselors in Cardiac Care.

Recent advances in genetic testing for heritable cardiac diseases have led to an increasing involvement of the genetic counselor in cardiology practice. We present a series of cases collected from a nationwide query of genetics professionals regarding issues related to cost and utilization of genetic testing. Three themes emerged across cases: (1) choosing the most appropriate genetic test, (2) choosing the best person to test, and (3) interpreting results accurately. These cases demonstrate that involvement of a genetic counselor throughout the evaluation, diagnosis, and continuing management of individuals and families with inherited cardiovascular conditions helps to promote the efficient use of healthcare dollars.