Molecular testing for fragile X: Analysis of 5062 tests from 1105 fragile X families - Performed in 12 clinical laboratories in Spain

This is an open access article distributed under the Creative Commons Attribution License.-- et al.Fragile X syndrome is the most common inherited form of intellectual disability. Here we report on a study based on a collaborative registry, involving 12 Spanish centres, of molecular diagnostic tests in 1105 fragile X families comprising 5062 individuals, of whom, 1655 carried a full mutation or were mosaic, three cases had deletions, 1840 had a premutation, and 102 had intermediate alleles. Two patients with the full mutation also had Klinefelter syndrome. We have used this registry to assess the risk of expansion from parents to children. From mothers with premutation, the overall rate of allele expansion to full mutation is 52.5%, and we found that this rate is higher for male than female offspring (63.6% versus 45.6%; P < 0.001). Furthermore, in mothers with intermediate alleles (45-54 repeats), there were 10 cases of expansion to a premutation allele, and for the smallest premutation alleles (55-59 repeats), there was a 6.4% risk of expansion to a full mutation, with 56 repeats being the smallest allele that expanded to a full mutation allele in a single meiosis. Hence, in our series the risk for alleles of < 59 repeats is somewhat higher than in other published series. These findings are important for genetic counselling. © 2014 María-Isabel Tejada et al.Thanks are due to the agreements between GIRMOGEN and the Real Patronato sobre Discapacidad of the Spain’s Ministry for Health, Social Services and Equality (Spain) to carry out this study.Peer Reviewe

The Helicase PIF1 Facilitates Resection over Sequences Prone to Forming G4 Structures

DNA breaks are complex lesions that can be repaired either by non-homologous end joining (NHEJ) or by homologous recombination (HR). The decision between these two routes of DNA repair is a key point of the DNA damage response (DDR) that is controlled by DNA resection. The core machinery catalyzing the resection process is well established. However, little is known about the additional requirements of DNA resection over DNA structures with high complexity. Here, we found evidence that the human helicase PIF1 has a role in DNA resection, specifically for defined DNA regions, such as those prone to form G-quadruplexes. Indeed, PIF1 is recruited to the site of DNA damage and physically interacts with proteins involved in DNA resection, and its depletion causes DNA damage sensitivity and a reduction of HR efficiency. Moreover, G4 stabilization by itself hampers DNA resection, a phenomenon suppressed by PIF1 overexpressio

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Se presentan los resúmenes de las comunicaciones del VI Congreso Internacional CONFOCO

Geodivulgar: Geología y Sociedad

Con el lema “Geología para todos” el proyecto Geodivulgar: Geología y Sociedad apuesta por la divulgación de la Geología a todo tipo de público, incidiendo en la importancia de realizar simultáneamente una acción de integración social entre estudiantes y profesores de centros universitarios, de enseñanza infantil, primaria, de educación especial y un acercamiento con público con diversidad funcional

Síndrome de temblor-ataxia asociado al SXF (FXTAS)

Se le llama FXTAS a un nuevo síndrome descrito por primera vez en el año 2001, consistente en un desorden neurológico multisistémico, temblor y ataxia (inestabilidad al caminar) como signos principales (Hagerman y cols., 2001), en pacientes portadores de premutación (PM) en el gen FMR1, no en pacientes con mutación completa.Peer reviewe

Nuevas patalogías causadas por la premutación

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Analysis of the molecular parameters that could predict the risk of manifesting premature ovarian failure in female premutation carriers of fragile X syndrome

[Objective]: To study three molecular parameters (number of CGG repeats, X-inactivation ratio, and expression of FMR1 mRNA) in premutation carriers of fragile X syndrome with and without premature ovarian failure (POF) to find differences between these two groups that could be useful in reproductive counseling. [Design]: A retrospective clinical and molecular genetic study of 42 known premutation carriers of fragile X syndrome aged 40 years or older, 25 with POF and 17 without. A blood sample to obtain mRNA was taken from all of them. They all lived in five autonomous communities in northern Spain. [Results]: Although the relationship among mRNA levels, X-inactivation ratio, and CGG repeats seems to be similar both in women with POF and in those without: in women with POF, the effect of the CGG repeats on the mRNA levels was statistically significant (P = 0.0437), but in women without POF, it was not (P = 0.0724). Moreover, we confirmed previous results on the nonlinear association between CGG repeat number and the manifestation of POF, showing that the likelihood of having POF was significantly higher with fewer than 100 CGG repeats compared with 100 or more CGG repeats (odds ratio = 13.09, P = 0.0240). [Conclusions]: Our present work suggests that mRNA and X-inactivation studies in blood are not relevant in predicting POF in female premutation carriers of fragile X syndrome. However, having a permutation of fewer than 100 repeats could represent a significant risk of POF. © 2008 by The North American Menopause Society.Peer Reviewe

Técnicas de diagnóstico y prevención

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Next generation sequencing as second-tier test in newborn screening programs

Resumen del póster presentado a la European Human Genetics Conference, celebrada en Barcelona (España) del 21 al 24 de mayo de 2016.-- et al.[Introduction]: Newborn screening is a publicly-funded health program for the diagnosis and intervention of genetic disorders that may otherwise have serious clinical consequences. In order to reduce false positives and negatives, shorten diagnosis time and provide genetic counseling, we are evaluating next generation sequencing (NGS) as a second-tier test. [Methods]: We use dried blood spot samples from positively-identified newborns to prepare NGS libraries. We have developed a panel of 71 genes commonly affected in the disorders detected by these programs. A bioinformatics pipeline identifies rare genetic variants that may be disease causing. Following technical validation, we have retrospectively analyzed 109 samples to establish the sensitivity and specificity and are prospectively analyzing positive hits in real time to assess clinical utility and cost-effectiveness. [Results]: Retrospectively, biallelic mutations were identified in 85.3% of the samples and single allele mutations in 7.3%. Samples in which no mutations were detected (7.3%) corresponded to hypothyroidism in half of the cases. In samples with previous genetic diagnosis (n=33), 100% concordance was found and a second mutation was identified in two samples. In the prospective phase, current turnaround time is 9 days. Among15 cystic fibrosis (CF) samples analyzed we have found biallelic mutations in 13% cases, single mutations in 53.3% and no mutations in 33.3%. These data are compatible with the high rate of false positives for CF. [Conclusion]: We have successfully developed an NGS panel that may allow to bypass or redirect confirmatory tests and provide earlier genetic counseling in newborn screening programs.Grant support: RETOS2014/5938/IPeer reviewe