Variable expression and penetrance in Portuguese families with Familial Hypercholesterolemia with mild phenotype.

Familial hypercholesterolemia is an Mendelian dominant disorder characterized by defects of the low density lipoprotein receptor (LDLR) that result in a defective removal of LDL from plasma, which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and arteries (atherosclerosis). Diagnosis severe clinical phenotype FH with Dutch Lipid Clinic Network Criteria, encompassing history of premature ASCVD, tendon xanthomas, and a family history of hypercholesterolemia and premature ASCVD in relatives is rare in the Portuguese FH patients. There is a variability of the phenotype in FH individuals with clinical diagnosis or genetic mutation (carriers and patients) probably due to environmental factors in the last century, a Mediterranean diet, or a diet without fat food, trans fat food, no smoking, no sedentary life that can interfere with our metabolism, or are consequences of polygenic, epigenetic, acquired defects, modifiers genes and beta-globin asymptomatic carriers. We have several concepts/mechanisms in genetics that are transversal to hereditary diseases and common in FH, such as somatic mosaicism, germinal mosaicism, variable expression and variable penetrance of mutations. A negative blood genetic test result does not exclude FH, because the pathogenic LDLR mutation can be expressed only in the liver (a mutation in somatic tissue) or occasionally there is a vertical transmission from partner to future child by a mutation on germinal line - germinal mosaicism. Unlike north European countries, the most FH carriers and patients had less severe phenotypes, for example with have children and young adult carriers with LDL-R mutation had normal TC and LDL-C, old women had a milder phenotype without ASCVD events, tendon xanthomas are seen in <1% patients, and most homozygous FH patients are under combined therapy.

Molecular diagnosis of familial hypercholesterolemia: an important tool for cardiovascular risk stratification.

UNLABELLED: Familial hypercholesterolemia (FH) is associated with an increased risk of premature coronary heart disease. Molecular identification of these patients can reduce the burden of mortality from cardiovascular disorders simply by the correct identification of the disease early in life, followed by counseling and appropriate lifestyle modifications, and therapeutic measures when required. Recent studies show that, in Portugal, this disease is severely under-diagnosed. After more than 10 years of research through the Portuguese FH Study, it is now possible to translate the original research results into clinical application. AIMS: The main aims of the present work were to determine whether clinical characterization is sufficient to identify these individuals at high risk of developing CHD and to evaluate the clinical applicability of molecular diagnosis for FH. METHODS: All patients described in this study were recruited for the Portuguese FH Study. The diagnostic criteria used to select the index patients were adapted from the Simon Broome Heart Research Trust. To analyze the usefulness of the molecular diagnosis, graphs of total and LDL cholesterol values by age were constructed for 622 possible FH patients. The lipid profile of patients genetically identified as having FH, before and under medication, were analyzed to assess whether these patients were receiving appropriate treatment. The data are shown separately for children and adults and for female and male propositi (index cases and hypercholesterolemic relatives), both with and without a detectable mutation in the LDLR gene. RESULTS: The Portuguese FH Study has already genetically identified 404 individuals (171 index patients and 233 relatives) among more than one thousand individuals sent for study. A total of 78 different mutations in the LDLR gene were found in 171 index patients, 2 different mutations were found in the apoB gene of 4 patients and 2 patients had a unique PCSK9 mutation. Statistical analysis revealed that there are significant differences between total cholesterol (p < 0.001) and apoB (p = 0.026) values in the group of children (male and female) with and without a mutation in LDLR. For female children LDL values were also significantly different (p < 0.001) between subgroups but for male children this difference did not reach statistical significance. In adult women there is a statistically significant difference for total cholesterol (p = 0.049), LDL cholesterol (p = 0.031) and apoB (p = 0.003) values in the subgroups with and without a LDLR mutation. In adult males there is a statistical difference for total cholesterol (p = 0.002). LDL cholesterol (p = 0.003) and apoB (p = 0.0023) in subgroups with and without an LDLR mutation. Nevertheless there was considerable dispersion of values and individually it is not possible to distinguish between patients with and without a mutation in the LDLR gene, based only on lipid profile. CONCLUSIONS: By analysis of the clinical data of 696 possible FH patients, the present report shows evidence that clinical characterization is not sufficient to distinguish between patients with genetic or environmental dyslipidemia, and so molecular diagnosis is useful in clinical practice, allowing correct identification of FH patients and their relatives, and the early implementation of therapeutic measures to reduce the elevated cardiovascular risk of these patients. In general, molecular diagnosis of FH is feasible and could be obtained in 1-2 months if the technology is available. In Portugal the test will be offered to the population by our Institute at a cost of about 500 euros, like many other genetic tests or exams such as nuclear magnetic resonance.

The deletions of 22q11--the Portuguese experience.

The patients with a chromosome 22q11 deletion have a variable phenotype which includes DiGeorge (DG) and Velocardiofacial (VCF) syndromes. The aim of the present study is to characterize the phenotype of DG and VCF using facial biometry in 12 portuguese patients. We found 4/12 patients with the DG phenotype: 3/4 had telecanthus, small mouth and retrognathia; 1/4 had telecanthus, short nose with bulbous tip and a normal mouth. These patients had major cardiac defects associated with hypoplastic or absent thymus and monosomy 22q11. We did not find velopharyngeal insufficiency in patients with the so called DG phenotype 8/12 patients had the VCF phenotype: typical facies with variable features. Four of these had velopharyngeal insufficiency and learning disabilities. Four patients had cardiac defects and 5/8 had monosomy 22q11. Probably this clinical variability is due to mutations in critical genes involved in embryonic development.