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Purpose Mutations in the peripherin/retinal degeneration slow (RDS) gene are a known cause of various types of central retinal dystrophies. The purpose of this study was to determine the prevalence of mutations in the peripherin/RDS gene in Spanish patients with different types of autosomal dominant macular dystrophy. Methods Ophthalmic and electrophysiological examination was performed in patients from 61 unrelated autosomal dominant macular dystrophy (adMD) Spanish families. Screening for mutations in the peripherin/RDS gene by denaturing gradient gel electrophoresis (DGGE) and direct genomic sequencing was performed in index patients and extended to the family when positive. Results We report four novel mutations in peripherin/RDS and a relatively high frequency (23%) of mutations in this gene in families with adMD. Thirteen different mutations were found in fifteen adMD families. Three novel missense, four nonsense and a cis-acting splicing mutation IVS2+2T>C, were found in a Spanish population while five more missense mutations were also reported in other populations. The Arg142Trp and Arg172Trp mutations, present in several populations, were both detected in two independent Spanish families. All the missense mutations produce an amino acid substitution in the second intradiscal loop of the peripherin, while the nonsense mutations presumably generate a truncated protein. Conclusions A high frequency (23%) of mutations in the peripherin/RDS gene was found in a cohort of 61 unrelated patients with various types of autosomal dominant central retinal dystrophies as compared with a low prevalence (1.3%) of mutations in this gene causing retinitis pigmentosa in a Spanish population. Different macular dystrophy phenotypes according to the mutations in peripherin/RDS are shown. However, a limited phenotype variation was observed for these mutations within the family.

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by mutations in the survival motor neuron1 gene (SMN1). Global carrier frequency is around 1 in 50 and carrier detection is crucial to define couples at risk to have SMA offspring. Most SMA carriers have one SMN1 copy and are currently detected using quantitative methods. A few, however, have two SMN1 genes in cis (2/0 carriers), complicating carrier diagnosis in SMA. We analyzed our experience in detecting 2/0 carriers from a cohort of 1562 individuals, including SMA parents, SMA relatives, and unrelated individuals of the general population. Interestingly, in three couples who had an SMA child, both the parents had two SMN1 copies. Families of this type have not been previously reported. Our results emphasize the importance of performing a detailed carrier study in SMA parents with two SMN1 copies. Expanding the analysis to other key family members might confirm potential 2/0 carriers. Finally, when a partner of a known carrier presents two SMN1 copies, the study of both parents will provide a more accurate diagnosis, thus optimizing genetic counseling.

Objective Although KRAS mutation status has been identified as a strong predictor of response to anti-epidermal growth factor receptor (EGFR) therapies, not all wild-type patients respond. The lethal-7 (let-7) family of microRNAs regulates KRAS activity. A functional polymorphism (rs61764370) has been described in the let-7 complementary site (LCS6). We hypothesized a possible association between this KRAS let-7 LCS6 polymorphism and the response to anti-EGFR treatments in KRAS and BRAF wild-type metastatic colorectal cancer patients (mCRC). Materials and methods We studied the association of the KRAS let-7 LCS6 polymorphism with the response in 100 refractory mCRC patients treated with anti-EGFR antibodies. To assess the real effect of this polymorphism in relation to the treatment administered, we also studied this association in an independent cohort of patients treated exclusively with chemotherapy. The KRAS let-7 LCS6 polymorphism was genotyped using the BioMark system in blood and tumor DNA samples. The BRAF V600E mutation was analyzed in tumor samples. Results The KRAS let-7 LCS6 G-allele showed a statistically significant association with nonresponse to anti-EGFR-based treatment: 31.9% of patients with the P T/T genotype presented a complete or a partial response versus no patients with T/G or G/G genotypes (P = 0.004). No statistically significant differences were observed in the patients who received chemotherapy only. Conclusion These data support the pharmacogenetic role of the KRAS let-7 LCS6 polymorphism in predicting the efficacy of anti-EGFR-based therapy in mCRC patients with the KRAS and the BRAF wild-type genotype. Pharmacogenetics and Genomics 23:142-147 (c) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Most alpha-thalassemia (alpha-thal) mechanisms are deletions of one or both alpha-globin genes and less than 5.0-10.0% are point mutations. Hb Agrinio [alpha 29(B10)Leu -> Pro, CTG>CCG (alpha 2)] is a hyperunstable a chain structural variant in which the thalassemic phenotype is determined by a post translational precipitation of the structurally anomalous chain in erythroid precursors. This study involved 14 cases with Hb Agrinio from three families. Selective sequencing of the alpha 2 gene showed a CTG(Leu)>CCG(Pro) mutation at codon 29. The mutation was found in a heterozygous state in 11 cases and in a homozygous state in three cases. These are the first cases with Hb Agrinio described in Spain. In all cases where a leucine is exchanged for a proline, an unstable hemoglobin (Hb) will occur both in the alpha and the beta chain. Some of these are as unstable as Hb Agrinio and their presence is difficult to detect except by DNA sequencing.

Polymorphisms of the ITPA gene have been associated with anemia during combination therapy in hepatitis C virus (HCV)-monoinfected patients. Our aim was to confirm this association in HIV/HCV-coinfected patients. In this prospective, observational study, 73 HIV/HCV-coinfected patients treated with pegylated interferon plus ribavirin (RBV) were enrolled. Two single nucleotide polymorphisms within or adjacent to the ITPA gene (rs1127354 and rs7270101) were genotyped. The associations between the ITPA genotype and anemia or treatment outcome were examined. Fifty-nine patients (80.8%) had CC at rs1127354, whereas 14 (19.2%) had a CA/AA ITPA genotype. Percent decreases from baseline hemoglobin level were significantly greater in patients with the CC genotype than in those with the CA/AA genotype at week 4 (P = 0.0003), week 12 (P < 0.0001), and week 36 (P = 0.0102) but not at the end of treatment. RBV dose reduction was more often needed in patients with the CC genotype than in those with the CA/AA genotype (odds ratio [OR] = 11.81; 95% confidence interval [CI] = 1.45 to 256.17; P = 0.0039), as was erythropoietin therapy (OR = 8.28; 95% CI = 1.04 to 371.12; P = 0.0057). Risk factors independently associated with percent hemoglobin nadir decrease were RBV dose reduction (OR = 11.72; 95% CI = 6.82 to 16.63; P < 0.001), baseline hemoglobin (OR = 1.69; 95% CI = 0.23 to 3.15; P = 0.024), and body mass index (OR = -0.7; 95% CI = -1.43 to 0.03; P = 0.061). ITPA polymorphism was not an independent predictor of sustained virological response. Polymorphisms at rs1127354 in the ITPA gene influence hemoglobin levels during combination HCV therapy and the need for RBV dose reduction and erythropoietin use in HIV/HCV-coinfected patients.

Introduction: Bilateral salpingo-oophorectomy (BSO) is a common procedure for preventing breast and ovarian cancer in high-risk women. The goal of this study was to determine the incidence of subsequent breast cancer (BC) in a high-risk population and to identify clinical and epidemiological predictors of BC following BSO. Materials and methods: One hundred and thirty-three consecutive high-risk women, tested for BRCA1 and BRCA2 mutations due to family history, underwent preventive or therapeutic BSO at one of the study hospitals. One hundred and three patients had breast tissue at risk and were considered evaluable for the event-free survival analysis. Twenty-five women harbored a deleterious mutation in BRCA1 and 25 in BRCA2 genes. Results: Fifteen cases of invasive BC were diagnosed with a median interval of 49 months after BSO. Multivariate analysis showed that a prior BC after 50 years of age (p = 0.004), age over 50 years at the time of BSO (p = 0.005), and prior replacement or contraceptive hormonal treatment (p = 0.007) were significantly associated with a shorter event-free survival. Conclusion: In conclusion, age at prior diagnosis of cancer, age at BSO and prior hormonal treatment may be predictors of breast cancer after BSO. (C) 2010 Elsevier Ltd. All rights reserved.

Homozygous mutations of the telomeric SMN1 gene lead to degeneration of motor neurons causing spinal muscular atrophy (SMA). A highly similar centromeric gene (SMN2) can only partially compensate for SMN1 deficiency. The c.859G>C variant in SMN2 has been recently reported as a positive disease modifier. We identified the variant in 10 unrelated chronic SMA patients with a wide spectrum of phenotypes ranging from type II patients who can only sit to adult walkers. Haplotype analysis strongly suggests that the variant originated from a common ancestor. Our results confirm that the c.859G>C variant is a milder SMN2 allele and predict a direct correlation between SMN activity and phenotypic severity.

Objective: There is probably an association between genetic factors, personality traits and response to psychotherapy. We propose the new concept of "psychotherapygenetics" as a strategy to study how genetic factors may influence psychotherapeutic response. The aim was to examine the association between polymorphisms of the serotonin transporter gene (SERT) and the dopamine 4-receptor gene (DRD4) with adherence to psychotherapy. Method: We performed a prospective study of 110 patients with borderline personality disorder (BPD) who participated in dialectical behavioral therapy (DBT). Three polymorphisms were examined: the 5-HTTLPR and the VNTR on the SERT gene and the 7-repeat allele (D4.7) on the DRD4 gene. The dropout rate and the mean number of sessions attended were used as an adherence index. Results: The presence of the 12-repeat allele on the VNTR polymorphism of SERT was associated with higher adherence to psychotherapy. There was no significant association between the 5-HTTLPR or D4.7 polymorphisms and adherence. Conclusions: Our preliminary results show a correlation between certain genetic variations and adherence to DBT in patients with BPD. A "psychotherapygenetics" approach could be useful to study how genetic variables may influence patients' psychotherapy response. (C) 2009 SEP y SEPB. Published by Elsevier Espana, S.L. All rights reserved.

AIMS To study the relationship between the toxicity associated with a 5-FU-based therapy and the presence of (i) the large intragenic rearrangements in the DPYD gene and (ii) the IVS14+1G>A mutation. METHODS We used the multiplex ligation-dependent probe amplification technique (MLPA) to study genomic DNA from 234 colorectal cancer patients treated with 5-FU-based chemotherapy. RESULTS We did not detect any deletion/duplication in the DPYD gene. The presence of the IVS14+1G>A mutation was also excluded. CONCLUSIONS Neither the large genomic rearrangements in the DPYD gene nor the IVS14+1G>A mutation play a significant role in the development of serious toxicity associated with a 5-FU containing regimen.

PURPOSE. Several mutations have been described in the RDH12 gene that disturb the activity of the encoded protein, suggesting that RDH12 loss of function disrupts the synthetic pathway of the visual chromophore 11-cis-retinal, therefore resulting in early and progressive retinal degeneration (RD). Mutations in this gene have been related to autosomal recessive Leber congenital amaurosis (LCA) and to a form of autosomal recessive childhood-onset severe retinal dystrophy (CSRD). This study was undertaken to attempt to correlate the genotype and phenotype in Spanish CSRD and LCA patients who harbor RDH12 mutations. METHODS. A complete ophthalmic and electrophysiologic examination was performed according to preexisting protocols. A screening for mutations was then performed using denaturing HPLC on a DNA fragment analysis system. Those fragments bearing an abnormal pattern were sequenced. RESULTS. Ten families bearing RDH12 mutations in homozygous or compound heterozygous form were found. All of them corresponded to patients with severe and early-onset retinal dystrophy. CONCLUSIONS. The RDH12-associated phenotype is not homogeneous, the position and nature of the mutations clearly influence the pathologic expression of this disease. (Invest Ophthalmol Vis Sci. 2009; 50: 1065-1068) DOI: 10.1167/iovs.082083

Artículos especiales The last decade has seen rapid progress and development in the understanding of genetic influences that underlie inter-individual differences in drug action and drug response. Differences in DNA sequences that alter the expression or function of proteins that are targeted by drugs can contribute significantly to variation in the responses of individuals. Many of the genes examined so far are linked to highly penetrant, single-gene traits, but future advances are focused on the more difficult challenge of elucidating multigene determinants of drug response. The interaction of genomics and medicine has the potential to yield a new set of molecular diagnostic tools that can be used to individualize and optimize drug therapy No

The purpose of this study is to describe the spectrum of mutations in the ABCA4 gene found in Spanish patients affected with several retinal dystrophies.

The X-linked form of retinitis pigmentosa (XLRP) is the most severe type because of its early onset and rapid progression. Five XLRP loci have been mapped, although only two genes, RPGR (for RP3) and RP2, have been cloned. In this study, 30 unrelated XLRP Spanish families were screened to determine the molecular cause of the disease.

Limb Girdle Muscular Dystrophy type 2I (LGMD2I) is an autosomal recessive muscular dystrophy caused by mutations in the Fukutin Related Protein(FKRP). This gene is located at 19q13.3 and contains four exons. Immunohistochemical analysis is not possible to date because no specific antibodies have been isolated. Thus, mutational analysis is the method to obtain an accurate molecular diagnosis of the disease. The aim of this work is: 1) to diagnose the patients with clinical features suggesting LGMD2I, 2) to observe the frequency of this pathology in these two populations and, 3) to offer genetic counselling to the affected families. We studied 60 Spanish and 10 Croatian patients presenting a LGMD2I phenotype and in whom we previously excluded a dystrophinopathy, LGMD2A, LGMD2C and LGMD2D. The molecular study was performed following two steps: 1) The analysis of the L276L mutation reccurrent in North European population) by restriction enzyme analysis. 2)The sequencing of the unique coding exon 4. We found four missens mutations in seven patients: E55Q, R143S, L276L and G373S, two of them were novel mutations: E55Q and g373S. Their pathogenia were demonstrate analysing 50 chromosomes from normal controls and 50 chromosomes from other myopathy patients. The L276L mutation was identified in four patients (3Spanish and 1 Croatian) and should be considered the more frequent FKRP mutation in the population studied. The low number of FKRP mutations identified despite the patients were very well classified could indicate the low frequency of LGMD2I in these two populations.

Mutations in the dysferlin (DYSF) gene cause 3 different phenotypes of muscular dystrophies: Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal anterior compartment myopathy.