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Unbalanced X;autosome translocations are a rare occurrence with a wide variability in clinical presentation in which the X chromosome unbalance is usually mitigated by a favorable X inactivation pattern. In most cases, this compensation mechanism is incomplete, and the patients show a syndromic clinical presentation. We report the case of a family with 4 women, of 3 different generations, carrying an unbalanced X;7 translocation with a derivative X;7 chromosome and showing a skewed X inactivation pattern with a preferential activation of the normal X. None of the carriers show intellectual disability, and all of them have a very mild clinical presentation mainly characterized by gynecological/hormonal issues and autoimmune disorders. We underline the necessity of family testing for a correct genetic consultation, especially in the field of prenatal diagnosis. We indeed discuss the fact that X;autosome translocations may lead to self-immunization, as skewed X chromosome inactivation has already been proved to be related to autoimmune disorders.

Background Familial Mediterranean fever (FMF) and tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) represent two forms of periodic monogenic autoinflammatory diseases, characterized by recurrent and auto-limiting attacks of fever and systemic inflammation. Both the diseases are due to the aberrant activation of inflammasome platforms. Several variants in the Mediterranean Fever (MEFV) gene and TNF Receptor Superfamily Member 1A (TNFRS1A) gene are respectively at the basis of FMF and TRAPS. Objectives The aim of this study is to report the genotype and phenotype prevalence of a cohort of patients referring to our laboratory with a suspicious diagnosis of FMF or TRAPS. Methods We retrospectively collected genetic and demographic data of patients undergoing MEFV (NM_000243) and TNFRS1A (NM_001065) genetic test at our laboratory. Both genes were analysed by direct sequencing on both strands. Data were statistically analysed for descriptive and inferential purposes. Results A total of 168 cases were collected, most of which were Caucasian subjects (88.0%). The most common clinical manifestation was periodic fever, occurring in 121 cases, with musculoskeletal, intestinal and cutaneous symptoms, polyserositis and lymphadenopathy occurring at variable rates. Demographic and clinical characteristics are resumed in tab.1. MEFV genotyping, performed in 159 patients, identified 8 different pathogenic variants (p.Phe479Leu, p.Met680Ile, p.Met694Val, p.Met694Ile, p.Lys695Arg, p.Val726Ala, p.Ala744Ser, p. Arg761His), associated with different geographic provenience and symptoms (tab.2, 4). Analysis of TNFRS1A gene in 80 subjects revealed the presence of the pathogenic variant p.Cys102Tyr in 3 patients (3.75%); tab.3, 5. According to Eurofever scoring system, the MEFV variant p.Ala744Ser was significantly associated to the likelihood of having FMF and to the severity of the disease. A higher prevalence of MEFV pathogenic variants was observed in Egyptians and patients living in Southern Italy. Conclusion Our data report MEFV and TNFRS1A genotypes identified in a cohort of patients referring to an Italian center, affected by periodic fever and other systemic symptoms. Only the MEFV variant p.Ala744Ser appeared to be significantly correlated with the Eurofever classification score. References [1] Vitale A, Rigante D, Lucherini OM, De Palma A, Orlando I, Gentileschi S, Sota J, Simpatico A, Fabiani C, Galeazzi M, Frediani B, Cantarini L. The diagnostic evaluation of patients with a suspected hereditary periodic fever syndrome: experience from a referral center in Italy. Intern Emerg Med. 2017;12(5):605-611. [2] Federici S, Sormani MP, Ozen S, Lachmann HJ, Amaryan G, Woo P, Kon-Paut I, Dewarrat N, Cantarini L, Insalaco A, Uziel Y, Rigante D, Quartier P, Demirkaya E, Herlin T, Meini A, Fabio G, Kallinich T, Martino S, Butbul AY, Olivieri A, Kuemmerle-Deschner J, Neven B, Simon A, Ozdogan H, Touitou I, Frenkel J, Hofer M, Martini A, Ruperto N, Gattorno M; Paediatric Rheumatology International Trials Organisation (PRINTO) and Eurofever Project. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis. 2015;74(5):799-805. Disclosure of Interests None declared

Background The thiopurine S-methyltransferase (TPMT)/azathioprine (AZA) gene-drug pair is one of the most well-known pharmacogenetic markers. Despite this, few studies investigated the implementation of TPMT testing and the combined evaluation of genotype and phenotype in multidisciplinary clinical settings where patients are undergoing chronic therapy with AZA. Methods A total of 356 AZA-treated patients for chronic autoimmune diseases were enrolled. DNA was isolated from whole blood and the samples were analyzed for the c.460G>A and c.719A>G variants by the restriction fragment length polymorphism (RFLP) technique and sequenced for the c.238G>C variant. The TPMT enzyme activity was determined in erythrocytes by a high-performance liquid chromatography (HPLC) assay. Results All the patients enrolled were genotyped while the TPMT enzyme activity was assessed in 41 patients. Clinical information was available on 181 patients. We found no significant difference in the odds of having adverse drug reactions (ADRs) in wild-type patients and variant allele carriers, but the latter had an extra risk of experiencing hematologically adverse events. The enzyme activity was significantly associated to genotype. Conclusions TPMT variant allele carriers have an extra risk of experiencing hematologically adverse events compared to wild-type patients. Interestingly, only two out of 30 (6.6%) patients had discordant results between genotype, phenotype and onset of ADRs.

Aim: To investigate mitochondrial DNA (mtDNA) copy number and D-loop region methylation in carriers of SOD1, TARDBP, FUS and C9orf72 mutations. Methods: Investigations were performed in blood DNA from 114 individuals, including amyotrophic lateral sclerosis (ALS) patients, presymptomatic carriers and noncarrier family members. Results: Increased mtDNA copy number (p = 0.0001) was observed in ALS patients, and particularly in those with SOD1 or C9orf72 mutations. SOD1 mutation carriers showed also a significant decrease in D-loop methylation levels (p = 0.003). An inverse correlation between D-loop methylation levels and the mtDNA copy number (p = 0.0005) was observed. Conclusion: Demethylation of the D-loop region could represent a compensatory mechanism for mtDNA upregulation in carriers of ALS-linked SOD1 mutations.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that primarily involves skeletal, ocular, and cardiovascular systems with large inter- and intra-familial variability in terms of age of onset, severity, and aortic disease. The causal gene, FBN1, encodes for fibrillin 1, a multi-domain glycoprotein essential for many biological functions, including deposition and formation of elastic fibers. Reports describing chromosomal alterations involving FBN1 are rare, but in the last years their number has increased after copy number state analyses, such as multiplex ligation-dependent probe amplification and microarray-based comparative genomic hybridization, were adopted as routine diagnostic tools. Herein we report a patient with MFS and an atypical facial appearance and neuropsychiatric involvement likely not attributable to MFS due to a 15q21.1 deletion that involves part of FBN1 and 13 additional contiguous genes listed in OMIM. We compare his phenotype with those of the few patients described in the literature who share similar 15q11.2 deletions. This report expands the phenotype of patients with 15q11.2 deletion involving FBN1 and its contiguous genes, and suggests a possible role for these other genes in the pathogenesis of the observed unusual clinical signs that are not explained by FBN1 haploinsufficiency. © 2016 Wiley Periodicals, Inc.

Double heterozygosity (DH) for BRCA1 and BRCA2 mutations is a very rare finding, particularly in non-Ashkenazi individuals, and only a few cases have been reported to date. In addition, little is known on the pathological features of the tumors that occur in DH cases and on their family history of cancer. Four carriers of pathogenic mutations in both BRCA1 and BRCA2 were identified among women who underwent genetic counseling for hereditary susceptibility to breast and ovarian carcinoma at three different Italian institutions. Clinical, pathological, and family history data were collected from medical records and during genetic counseling sessions. All identified DH cases developed breast carcinoma and three of them were also diagnosed with ovarian carcinoma. Mean ages of breast and ovarian cancer diagnosis were 42.7 and 48.6 years, respectively. The majority of breast cancers showed a BRCA1-related phenotype, being negative for hormone receptors and HER2. Two cases reported different gastrointestinal tumors among relatives. Although the individuals described in this study show more severe clinical features in comparison to previously reported BRCA1 and BRCA2 DH cases, our observations support the hypothesis of a non specific phenotype of DH cases in terms of age of disease onset. In addition, our observations indicate that in DH patients breast carcinogenesis appears to be driven mainly by the mutations in BRCA1. The possible association of DH for BRCA gene mutations with gastrointestinal tumors is in keeping with previous reports, but needs to be confirmed by further analyses.

Objective We surveyed the datasheets of 29 laboratories concerning prenatal diagnosis of de novo apparently balanced chromosome rearrangements to assess the involvement of specific chromosomes, the breakpoints distribution and the impact on the pregnancy outcome. Method By means of a questionnaire, data on 269.371 analyses performed from 1983 to 2006 on amniotic fluid, chorionic villus and fetal blood samples were collected. Results A total of 246 balanced anomalies were detected at frequencies of 72% for reciprocal translocations, 18% for Robertsonian translocations, 7% for inversions and 3% for complex chromosome rearrangements. The total frequencies of balanced rearrangements were 0.09%, 0.08% and 0.05% on amniotic fluid, chorionic villus and fetal blood samples. Conclusion A preferential involvement of chromosomes 22, 7, 21, 3, 9 and 11 and a less involvement of chromosomes X, 19, 12, 6 and 1 was observed. A nonrandom distribution of the breakpoints across chromosomes was noticed. Association in the location of recurrent breakpoints and fragile sites was observed for chromosomes 11, 7, 10 and 22, while it was not recorded for chromosome 3. The rate of pregnancy termination was about 20%, with frequencies decreasing from complex chromosomal rearrangements (33%), reciprocal translocations (24%) to inversions (11%) and Robertsonian translocations (3%). Copyright © 2009 John Wiley & Sons, Ltd.

We describe two families in which three fetuses had a de novo 6q imbalance and abnormal phenotypes. We determined the boundaries and the parental origin of the chromosomal alterations by segregation analysis using a panel of short tandem repeats (STRs) located on 6q. Cases 1 and 2 (family A) were two sibs with 6q imbalance involving different regions. Case 1 was a female fetus with arthrogryposis, who had a complex rearrangement resulting in two deleted regions (6q22 and 6q25.1-q25.2) and a duplication of 6q23-q25.1. This latter imbalance was reported previously and is associated with joint contractures and short neck, also present in this fetus. The sib (case 2) had intrauterine growth restriction (IUGR) and agenesis of the ductus venosus. This male died shortly after birth; postnatal karyotype and molecular investigations showed a 6q21 de novo deletion. Case 3 (family B) had a prenatally detected deletion of 6q14-q16. Autopsy of the fetus documented minor facial anomalies and contractures of the limbs. All rearrangements were de novo and of paternal origin. Our data and the consistent number of cases of de novo 6q alterations previously reported suggest that chromosome arm 6q could be prone to rearrangements resulting in heterogeneous phenotypes. In family A, chromosome 6q imbalances involving different chromosomal regions were present in two consecutive pregnancies. In such cases counseling should suggest the impossibility of excluding recurrence of a chromosomal imbalance, and should discuss the option of early prenatal diagnosis in subsequent pregnancies.

Equivalent levels of X-linked gene products between males and females are reached by means of X chromosome inactivation (XCI). In the human and murine embryonic tissues, both the paternally and maternally derived X chromosomes (X(P) and X(M)) may be inactivated. In murine extra-embryonic tissues, X(P) is imprinted and always silenced; humans, unlike mice, can inactivate the X(M) in extra-embryonic lineages without an adverse outcome. This difference is probably due to the presence of imprinted placental genes on the murine X chromosome, but not on the human homologue, essential for placental development and function. An example is the paternally imprinted Esx1 gene; mice with a null maternally derived Esx1 allele show intrauterine growth restriction (IUGR) because of placental insufficiency. We investigated the imprinting status of the human orthologous Esx1 gene (ESX1L) in placental samples of four normal full-term and 13 IUGR female fetuses, in which we determined the XCI pattern. Our findings demonstrated that IUGR as well as normal placentas display XCI heterogeneity, thus indicating that the IUGR phenotype is not correlated with a preferential pattern of XCI in placentas. Moreover, ESX1L is equally expressed in IUGR and normal placentas, and shows the same methylation pattern in the presence of both random and skewed XCI. These findings provide evidence that ESX1L is not imprinted in human third-trimester placentas and there is no parent-of-origin effect of chromosome X associated with placental insufficiency.

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

The CD14 receptor is an important mediator of inflammatory reactions, and its expression is under genetic control. The allelic variant of the C260T polymorphism located in the promoter region of the CD14 gene is associated with receptor expression and ischemic risk. To date, most studies assessing the functional implications of the C260T polymorphism have been performed under proinflammatory conditions (e.g., acute coronary syndromes), and whether gene sequence variations of the CD14 receptor have any functional effect on systemic inflammation in patients in a stable phase of their atherosclerotic disease process is unknown. Eighty-two patients with stable coronary artery disease were studied. High-sensitivity C-reactive protein (hs-CRP) was used as a measurement of systemic inflammation. The genotype distribution of the C260T polymorphism of the CD14 gene was as follows: CC in 18 of 82 patients (22%), TC in 48 of 82 patients (58.5%), and TT in 16 of 82 patients (19.5%). TT subjects had increased hs-CRP levels compared with carriers of the C allele (p = 0.04). A higher percentage of T allele homozygotes had hs-CRP levels >0.3 mg/dl (p = 0.01). Homozygosis status of the T allele was independently associated with hs-CRP levels >0.3 mg/dl (p = 0.004). In conclusion, these observations may support the findings in large-scale studies that T homozygotes of this functional polymorphism are at increased ischemic risk.

We report the case of a young boy with fine hair, mild nail dysplasia, blocked nasolacrimal ducts, absence of central incisors, bilateral oligodactyly of feet and anal stenosis. His father showed the same spectrum of anomalies with mild expression. He had mild nail dysplasia, blocked nasolacrimal ducts, inferior dental cysts with consequent premature tooth loss, frequent dental decays consequent to enamel abnormality and cutaneous syndactyly of the second and third right toe. The acro-dermato-ungual-lacrimal-tooth syndrome was suspected and molecular analysis of the P63 gene was performed, but no mutation was found. Although P63 gene analysis was negative, we think that both cases show clinical overlap with the acro-dermato-ungual-lacrimal-tooth syndrome and confirm the wide expression of this condition, even in the same family.

Objective Canavan disease (OMIM 271900 ) is a severe autosomal recessive neurodegenerative disorder characterized by spongy degeneration of the brain and caused by mutations in the gene encoding for aspartoacylase (ASPA). The enzyme is responsible for the catalyses of the brain-specific compound N-acetylaspartate (NAA). Design and methods We report the case of two Egyptian sibling patients suspected of Canavan disease (CD) showing clinical deterioration, white matter degeneration, megalencephaly and severe intellectual impairment. The patients underwent magnetic resonance imaging (MRI) and biochemical analysis of NAA in biological fluid samples (serum and urine). Subsequently, in order to determine the mutation responsible for CD in these two sibs, a molecular biological examination was performed. Results MRI findings and quantification of high NAA excretion (1378.5 and 680.1 μmol NAA/mmol creatinine in urine of 4 months and 4 years old patients, respectively) confirmed the diagnosis of CD and prompted a search for the responsible mutation. The molecular biological analysis revealed homozygosity for the substitution T530C (Ile177Thr) in the exon 4 of the ASPA gene in both sibs. A total loss of enzymatic activity was also recorded. Conclusions The substitution T530C (Ile177Thr) results in a novel missense mutation causing a CD phenotype with severe clinical characteristics. This mutation was not previously described in the literature. In these two sibs, urinary concentration of NAA appears to correlate inversely to symptom severity and CD progression.

We report clinical and behavioural evaluation data in 42 Italian girls with triple X syndrome whose diagnosis was made prenatally between 1998 and 2006 in three Italian centres. At initial evaluation, reproductive and medical histories were collected. Clinical assessment of the child was performed by a clinical geneticist and included a detailed personal history, physical evaluation and auxological measurements. To analyse how parents coped with specific events in the prenatal and postnatal periods, we conducted an interview that included 35 specific questions designed to elicit retrospective judgements on prenatal communication, present and future worries, needs and expectations. In a subset of probands, we also administered the formal Italian Temperament Questionnaire assessment test that investigates adaptation, general environment and socialisation. This test also assesses the emotional component of temperament. Clinical results in the affected children are similar to those previously reported with evidence of increased growth in the pre-puberal age and an average incidence of congenital malformation and health needs. Median age for the time first words were pronounced was 12 months, showing a slight delay in language skills, which tended to improve by the time they reached school age. Parental responses to the interview demonstrated residual anxiety but with a satisfactory adaptation to and a positive recall of the prenatal counselling session. Parental adaptation of the 47,XXX girls require indeed a proper educational support. This support seems to be available in Italy. An integrated approach to prenatal counselling is the best way to manage the anxiety and falsely imagined consequences that parents feel after being told that their foetus bears such a genetic abnormality.

We describe a sib recurrence for achondroplasia with parents of average stature. The three sibs shared the paternal allele and all carried the same causal mutation in the fibroblast growth factor receptor 3 gene (FGFR3): G > A nt1138 (Gly380Arg). We were able to identify this mutation on sperm DNA confirming paternal germinal mosaicism. Our family shows that a more precise definition of the recurrence risk is feasible using this approach, based on a single DNA test, which could be offered in selected cases.

BACKGROUND: Relative little attention has been devoted until now to the combined effects of gene polymorphisms of the hemostatic pathway as risk factors for Myocardial Infarction (MI), the main thrombotic complication of Coronary Artery Disease (CAD). The aim of this study was to evaluate the combined effect of ten common prothrombotic polymorphisms as a determinant of MI. METHODOLOGY/PRINCIPAL FINDINGS: We studied a total of 804 subjects, 489 of whom with angiographically proven severe CAD, with or without MI (n = 307; n = 182; respectively). An additive model considering ten common polymorphisms [Prothrombin 20210G>A, PAI-1 4G/5G, Fibrinogen beta -455G>A, FV Leiden and "R2", FVII -402G>A and -323 del/ins, Platelet ADP Receptor P2Y12 -744T>C, Platelet Glycoproteins Ia (873G>A), and IIIa (1565T>C)] was tested. The prevalence of MI increased linearly with an increasing number of unfavorable alleles (chi(2) for trend = 10.68; P = 0.001). In a multiple logistic regression model, the number of unfavorable alleles remained significantly associated with MI after adjustment for classical risk factors. As compared to subjects with 3-7 alleles, those with few (/=8) alleles had an increased MI risk (OR 2.49, 95%CIs 1.03-6.01). The number of procoagulant alleles correlated directly (r = 0.49, P = 0.006) with endogenous thrombin potential. CONCLUSIONS: The combination of prothrombotic polymorphisms may help to predict MI in patients with advanced CAD.

The aim of this study was to explore the role of variants of the gene encoding arachidonate 5-lipoxygenase-activating protein (ALOX5AP) as possible susceptibility factors for coronary artery disease (CAD) and myocardial infarction (MI) in patients with or without angiographically proven CAD. A total of 1431 patients with or without angiographically documented CAD were examined simultaneously for seven ALOX5AP single-nucleotide polymorphisms, allowing reconstruction of the at-risk haplotypes (HapA and HapB) previously identified in the Icelandic and British populations. Using a haplotype-based approach, HapA was not associated with either CAD or MI. On the other hand, HapB and another haplotype within the same region (that we named HapC) were significantly more represented in CAD versus CAD-free patients, and these associations remained significant after adjustment for traditional cardiovascular risk factors by logistic regression (HapB: odds ratio (OR) 1.67, 95% confidence interval (CI) 1.04-2.67; P=0.032; HapC: OR 2.41, 95% CI 1.09-5.32; P=0.030). No difference in haplotype distributions was observed between CAD subjects with or without a previously documented MI. Our angiography-based study suggests a possible modest role of ALOX5AP in the development of the atheroma rather than in its late thrombotic complications such as MI.

Platelet membrane receptors play a pivotal role in thrombus formation. Expression of platelet membrane receptors are under genetic control and gene sequence variations of receptors pivotal to thrombotic formation have been hypothesized to contribute to different degrees of individual response to aspirin. The aim of the present study was to investigate the impact of functional genetic polymorphisms of platelet membrane receptors on aspirin sensitivity assessed by means of the PFA-100 system in patients with coronary artery disease. Gene sequence variations of three platelet membrane receptors (GPIa/IIa, P2Y12, GPIIb/IIIa) pivotal to thrombus formation were assessed in 76 patients with coronary artery disease on chronic aspirin treatment. Patients with reduced sensitivity to aspirin were defined when closure-times of collagen/epinephrine cartridgesor =193 seconds and coined as PFA-100 non-responders. PFA-100 non-responders were observed in 33% of patients. Patients with diabetes mellitus were more frequently PFA-100 non-responders. Closure times of collagen/ADP coated cartridges were reduced in PFA-100 non-responders. The genotype distribution was similar in PFA-100 responder and non-responder patients for all three genotypes and did not vary in contemporaneous carriers of allelic variants. In conclusion, in vitro determined sensitivity to aspirin assessed using PFA-100 is not associated with gene sequence variations of platelet membrane receptors key to thrombus formation.

Objectives— Metabolic activity of cytochrome P450 (CYP) 3A4 has been associated with clopidogrel response variability. Because metabolic activity of CYP3A4 is genetically regulated, we hypothesized that genetic variations of this enzyme may contribute to clopidogrel response variability. Methods and Results— The CYP3A4*1B, CYP3A4*3, IVS7+258A>G, IVS7+894C>T, and IVS10+12G>A polymorphisms of the CYP3A4 gene were assessed in 82 patients in a steady phase of clopidogrel therapy. Glycoprotein (platelet glycoprotein (GP) IIb/IIIa receptor activation and platelet aggregation were assessed. A cohort of 45 clopidogrel-naïve patients was studied to determine the modulating effects of these polymorphisms after loading dose (300 mg) administration. Only the IVS7+258A>G, IVS7+894C>T, and IVS10+12G>A polymorphisms were sufficiently polymorphic. During the steady phase of clopidogrel treatment, IVS10+12A allele carriers had reduced GP IIb/IIIa activation ( P =0.025) and better responsiveness ( P =0.02); similarly, clopidogrel-naïve patients carriers of the IVS10+12A allele had reduced GP IIb/IIIa activation during the first 24 hours after a loading dose ( P =0.025), increased platelet inhibition ( P =0.006), and a more optimal drug response ( P =0.003). This polymorphism did not influence platelet aggregation profiles. No association was observed between the other polymorphisms and clopidogrel responsiveness. Conclusions— The IVS10+12G>A polymorphism of the CYP3A4 gene modulates platelet activation in patients treated with clopidogrel and may therefore contribute to clopidogrel response variability.

The human oxidised low-density lipoprotein receptor 1 (OLR1) gene is a functional candidate for atherosclerosis. An association of the OLR1 gene with acute myocardial infarction (AMI) or coronary artery disease (CAD) has recently been reported. In the present study a total of 677 Italian subjects, 327 CAD-free, 350 CAD, of which 190 with AMI and 160 AMI-free, was genotyped for the following four OLR1 single nucleotide polymorphisms: exon 4 K167N, IVS4 –73C>T, IVS4 –14A>G, and 3′UTR 188 C>T. No statistically significant difference was observed in allele or genotype distribution of the exon 4, intron 4, or 3′UTR SNPs in CAD patients compared to CAD-free subjects, or within CAD, in AMI patients compared to AMI-free patients. A correlation was found between the K167N G/G genotype and the increased number of obstructed vessels. Even if the OLR1 genotype frequency distribution data in CAD or AMI subjects here reported do not fully confirm the positive results of some other association studies, an association with a marker of CAD severity was observed.

Introduction Clopidogrel inhibits the ADP subtype P2Y12 receptor. Recently, polymorphisms of this receptor have been associated with different degrees of platelet aggregation in healthy volunteers and have been suggested to modulate clopidogrel response. However, the role of gene sequence variations of the P2Y12 receptor in patients treated with clopidogrel has not yet been assessed. Materials and methods The T744C polymorphism of the P2Y12 receptor gene was assessed in 119 patients: 36 undergoing coronary stenting receiving a 300 mg loading dose (Group A) and 83 on long-term clopidogrel (75 mg/day) treatment (Group B). Patients were divided into 2 subgroups according to the presence or absence of the C allele: carriers (CT heterozygotes and CC homozygotes) and non-carriers (TT homozygotes). Platelet aggregation, assessed by light transmittance aggregometry following ADP, collagen, TRAP and epinephrine stimuli, and platelet activation (GP IIb/IIIa activation and P-selectin expression), assessed by whole blood flow cytometry in ADP and TRAP-stimulated platelets, were performed. Platelet function was assessed at baseline and 4 and 24 h following clopidogrel loading dose in Group A and when patients where on clopidogrel treatment for at least 1 month in Group B. Results The genotype distribution of Group A was: 22 / 36 (61.1%) non-carriers and 14 / 36 (38.9%) carriers of the C allele; Group B: 57 / 83 (68.7%) non-carriers and 26 / 83 (31.3%) carriers of the C allele. There were no differences between groups for all the assessed platelet function assays. Conclusions The T744C polymorphism of the P2Y12 receptor gene does not modulate platelet response to clopidogrel either in the early or long-term phases of treatment. This specific gene polymorphism alone is therefore unlikely to be the cause of variability in individual response to antiplatelet therapy.

A broad variability in patient response to dual antiplatelet treatment has been described during the first month of treatment. Data on platelet function profiles in patients on dual antiplatelet therapy for a more sustained period are limited. Whether gene sequence variations of the glycoprotein Ia/IIa receptor influence platelet aggregation in these patients is also unknown. The aim of this study was to characterize platelet aggregation profiles in patients on dual antiplatelet treatment (aspirin plus clopidogrel) for1 month and to assess whether these may be influenced by the C807T polymorphism of the glycoprotein Ia gene. We included 82 patients, who were divided into 2 groups: carriers (CT + TT genotypes; n = 51) and noncarriers (CC genotype; n = 31) of the mutant T allele. Platelet aggregation was assessed using light transmittance aggregometry after stimuli with adenosine diphosphate (20 micromol/L), collagen (6 microg/ml), and epinephrine (20 micromol/L). A significant variability in the distribution of platelet aggregation was observed in the overall study population, as well as in carriers and noncarriers of the T allele. T allele carriers had increased platelet aggregation compared with noncarriers after stimuli with adenosine diphosphate, collagen, and epinephrine (p0.05 for all platelet aggregation assays). Thus, platelet aggregation varied significantly in patients on long-term dual antiplatelet treatment and was increased in T allele carriers of the 807C/T polymorphism of the glycoprotein Ia gene. These findings may contribute to the increased ischemic risk observed in these patients.

The enzyme serum paraoxonase plays an important role in antioxidant defences and prevention of atherosclerosis. Metabolic syndrome (MS) is a clinical condition associated with increased oxidant stress and cardiovascular mortality. Two common polymorphisms of serum paraoxonase, PON1 Leu(55)Met and Gln(192)Arg, have been postulated to modulate the cardiovascular risk. We studied 915 subjects with angiographic documentation: 642 subjects with coronary atherosclerosis and 273 with normal coronary arteries. Two hundred and twenty-four subjects met the diagnostic criteria of MS. We found a significant interaction between MS and both the PON1 polymorphisms in determining the risk of coronary artery disease (P

Background An increasing number of foetuses are recognized as having double Y because of the widespread use of prenatal screening using chorionic villus sampling and amniocentesis. 47, XYY karyotype occurs in about one out of 1,000 newborn males, but it is not often detected unless it is diagnosed during prenatal testing. Despite the fact that unbiased follow-up studies demonstrate largely normal post-natal development of young men with 47, XYY, there is a scarcity of controlled studies about the neurological, cognitive and behavioural phenotype which remains the main reason for anxiety and anticipatory negative attitudes of parents. Furthermore, prejudices still exist among professionals and the general population concerning the relationship between this sex chromosome aneuploidy and aggressive and antisocial behaviours. Methods We report on the clinical follow-up of children diagnosed prenatally with a 47,XYY karyotype, whose parents received multidisciplinary counselling and support at time of diagnosis. The specific focus of our study is on auxology, facial features, developmental milestones, behaviour, detection of aggressiveness as well as the evaluation of parental attitudes toward prenatal counselling. Clinical evaluations including auxological measurements and dysmorphological descriptions were as conducted on 13 boys aged 9 month -7 years. The Child Behavior Check List test specific for age and a 15 item questionnaire were administered to both parents. An update of ongoing problems was carried out by means of a telephone interview two years later. Results Our results show that, from birth, weight, height and head circumference were above average values while some facial features such mild hypertelorism are overrepresented when compared to parents' facial features. Language delay was detected in 8 out of 11 children older than 20 months. Parental attitudes were found to be favourable toward prenatal diagnoses of sexual chromosome aneuploidies. Conclusions Our data, although limited, is similar to other observational studies, and serves to alert clinicians about opportunities to delineate new and appropriate educational interventions that target the specific learning challenges of XYY boys. Our experience better defines the early manifestation of XYY and should aid those involved in prenatal counselling and paediatric surveillance.

The gene encoding Arachidonate 5-Lipoxygenase-Activating Protein (ALOX5AP; GeneID: 241; chromosome: 13q12) represents the paradigm of a new class of promising genes identified by powerful genome-wide investigations (Helgadottir A, Nature Genetics 2004), that are currently object of intense studies to confirm their role as possible susceptibility factors for atherothrombosis. Indeed, ALOX5AP encodes the 5-Lipoxygenase-Activating Protein (FLAP; Miller DK, Nature 1990), an essential regulator of the 5-LO/leukotriene pathway, that has been recently implicated in the pathogenesis of atherothrombosis (Funk CD, Nature Review Drug Discovery 2005). We studied a total of 1,431 subjects with or without angiographically documented coronary artery disease (CAD). Seven ALOX5AP single-nucleotide polymorphisms (SG13S25, SG13S377, SG13S114, SG13S89, SG13S32, SG13S41, SG13S35) were examined simultaneously, allowing reconstruction of the at-risk haplotypes “HapA” and “HapB” previously identified in the Icelandic and in the British populations, respectively (Helgadottir A, Nature Genetics 2004). Using a haplotype-based approach, HapA was not associated with either CAD or myocardial infarction (MI). On the other hand, HapB and another haplotype within the same region (that we named “HapC”) were significantly more represented in CAD versus CAD-free subjects, and these associations remained significant after adjustment for traditional cardiovascular risk factors by logistic regression (HapB: OR 1.67, 95% CI 1.04 to 2.67; P=0.032; HapC: OR 2.41, 95% CI 1.09 to 5.32; P=0.030). No difference in haplotype distributions was observed between CAD patients with or without a previous documented MI. Adding our data to current knowledge, some evidence on ALOX5AP as a genetic susceptibility factor for CAD has now emerged in several independent populations (Icelandic, British, Japanese, and Italian). Our study, the first angiography-based to our knowledge, points out a possible role of ALOX5AP in the development of the atheroma rather than in its late complications such as MI.