Identification of 22q11.2 deletion syndrome via newborn screening for severe combined immunodeficiency: two years’ experience in Catalonia (Spain)

22q11.2 deletion; Newborn screening; Severe combined immunodeficiencyeDeleción 22q11.2; Examen de recién nacidos; Inmunodeficiencia combinada graveSupressió 22q11.2; Cribratge de nounats; Immunodeficiència combinada greuBackground: The current scenario of newborn screening is changing as DNA studies are being included in the programs of several countries. Severe combined immunodeficiency (SCID) disorders can be detected using quantitative PCR assays to measure T-cell receptor excision circles (TRECs), a byproduct of correct T-cell development. However, in addition to SCID, other T-cell-deficient phenotypes such as 22q11.2 deletion syndrome 22q11.2 duplication syndrome, CHARGE syndrome, and trisomy 21 are detected. Methods: We present our experience with the detection of 22q11.2 deletion syndrome and 22q11.2 duplication syndrome in a series of 103,903 newborns included in the newborn screening program of Catalonia (Spain). Results: Thirty newborns tested were positive (low TREC levels) and five were found to have copy number variations at the 22q11 region (4 deletions and 1 duplication) when investigated with array comparative genomic hybridization technology and MLPA. Conclusion: Newborn screening for SCID enables detection of several conditions, such as 22q syndromes, which should be managed by prompt, proactive approaches with adequate counseling for families by a multidisciplinary team

A Novel Intragenic Duplication in the HDAC8 Gene Underlying a Case of Cornelia de Lange Syndrome

Cornelia de Lange syndrome; Genetic disorder; Intragenic duplicationSíndrome de Cornelia de Lange; Trastorno genético; Duplicación intragénicaSíndrome de Cornelia de Lange; Trastorn genètic; Duplicació intragènicaCornelia de Lange syndrome (CdLS) is a multisystemic genetic disorder characterized by distinctive facial features, growth retardation, and intellectual disability, as well as various systemic conditions. It is caused by genetic variants in genes related to the cohesin complex. Single-nucleotide variations are the best-known genetic cause of CdLS; however, copy number variants (CNVs) clearly underlie a substantial proportion of cases of the syndrome. The NIPBL gene was thought to be the locus within which clinically relevant CNVs contributed to CdLS. However, in the last few years, pathogenic CNVs have been identified in other genes such as HDAC8, RAD21, and SMC1A. Here, we studied an affected girl presenting with a classic CdLS phenotype heterozygous for a de novo ~32 kbp intragenic duplication affecting exon 10 of HDAC8. Molecular analyses revealed an alteration in the physiological splicing that included a 96 bp insertion between exons 9 and 10 of the main transcript of HDAC8. The aberrant transcript was predicted to generate a truncated protein whose accessibility to the active center was restricted, showing reduced ease of substrate entry into the mutated enzyme. Lastly, we conclude that the duplication is responsible for the patient’s phenotype, highlighting the contribution of CNVs as a molecular cause underlying CdLS.This work was supported by the Spanish Ministry of Health-ISCIII Fondo de Investigación Sanitaria (FIS) (Ref. PI19/01860, to F.J.R. and J.P.) and Diputación General de Aragón-FEDER: European Social Fund (Grupo de Referencia B32_17R/B32_20R, to J.P.). A.L.-P. is supported by a “Juan de la Cierva-Incorporación” postdoctoral grant from MICIU (Spanish Ministry of Science and Universities), M.G.-S. is supported by a Predoctoral Fellowship from the Diputación General de Aragón, and C.L.-C. is supported by a Predoctoral Fellowship from the MH-ISCIII. This work was also supported by Spanish government grants RTI2018-094434-B-I00 (MCIU/AEI/FEDER, UE) and DTS20-00024 (ISCIII) to P.G.-P., as well as funds from the European JPIAMR network “EPIC-Alliance” to P.G.-P. The computational support of the “Centro de Computación Científica CCC-UAM” is gratefully recognized. This work was also partially supported by Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-funded with ERDF funds, Grant No. FIS PI20/01767) to A.P. and by Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-funded with ERDF funds, Grant No. FIS PI18/000687 to E.F.T

A Novel Intragenic Duplication in the HDAC8 Gene Underlying a Case of Cornelia de Lange Syndrome

Cornelia de Lange syndrome (CdLS) is a multisystemic genetic disorder characterized by distinctive facial features, growth retardation, and intellectual disability, as well as various systemic conditions. It is caused by genetic variants in genes related to the cohesin complex. Single-nucleotide variations are the best-known genetic cause of CdLS; however, copy number variants (CNVs) clearly underlie a substantial proportion of cases of the syndrome. The NIPBL gene was thought to be the locus within which clinically relevant CNVs contributed to CdLS. However, in the last few years, pathogenic CNVs have been identified in other genes such as HDAC8, RAD21, and SMC1A. Here, we studied an affected girl presenting with a classic CdLS phenotype heterozygous for a de novo ~32 kbp intragenic duplication affecting exon 10 of HDAC8. Molecular analyses revealed an alteration in the physiological splicing that included a 96 bp insertion between exons 9 and 10 of the main transcript of HDAC8. The aberrant transcript was predicted to generate a truncated protein whose accessibility to the active center was restricted, showing reduced ease of substrate entry into the mutated enzyme. Lastly, we conclude that the duplication is responsible for the patient’s phenotype, highlighting the contribution of CNVs as a molecular cause underlying CdLS

Clinical utility of chromosomal microarray analysis in invasive prenatal diagnosis

Novel methodologies for detection of chromosomal abnormalities have been made available in the recent years but their clinical utility in prenatal settings is still unknown. We have conducted a comparative study of currently available methodologies for detection of chromosomal abnormalities after invasive prenatal sampling. A multicentric collection of a 1-year series of fetal samples with indication for prenatal invasive sampling was simultaneously evaluated using three screening methodologies: (1) karyotype and quantitative fluorescent polymerase chain reaction (QF-PCR), (2) two panels of multiplex ligation-dependent probe amplification (MLPA), and (3) chromosomal microarray-based analysis (CMA) with a targeted BAC microarray. A total of 900 pregnant women provided informed consent to participate (94% acceptance rate). Technical performance was excellent for karyotype, QF-PCR, and CMA (~1% failure rate), but relatively poor for MLPA (10% failure). Mean turn-around time (TAT) was 7 days for CMA or MLPA, 25 for karyotype, and two for QF-PCR, with similar combined costs for the different approaches. A total of 57 clinically significant chromosomal aberrations were found (6.3%), with CMA yielding the highest detection rate (32% above other methods). The identification of variants of uncertain clinical significance by CMA (17, 1.9%) tripled that of karyotype and MLPA, but most alterations could be classified as likely benign after proving they all were inherited. High acceptability, significantly higher detection rate and lower TAT, could justify the higher cost of CMA and favor targeted CMA as the best method for detection of chromosomal abnormalities in at-risk pregnancies after invasive prenatal sampling

Pandemic Phase-Adjusted Analysis of COVID-19 Outcomes Reveals Reduced Intrinsic Vulnerability and Substantial Vaccine Protection From Severe Acute Respiratory Syndrome Coronavirus 2 in Patients With Breast Cancer

PURPOSE Although representing the majority of newly diagnosed cancers, patients with breast cancer appear less vulnerable to COVID-19 mortality compared with other malignancies. In the absence of patients on active cancer therapy included in vaccination trials, a contemporary real-world evaluation of outcomes during the various pandemic phases, as well as of the impact of vaccination, is needed to better inform clinical practice. METHODS We compared COVID-19 morbidity and mortality among patients with breast cancer across prevaccination (February 27, 2020-November 30, 2020), Alpha-Delta (December 1, 2020-December 14, 2021), and Omicron (December 15, 2021-January 31, 2022) phases using OnCovid registry participants (ClinicalTrials.gov identifier: NCT04393974). Twenty-eight-day case fatality rate (CFR28) and COVID-19 severity were compared in unvaccinated versus double-dosed/boosted patients (vaccinated) with inverse probability of treatment weighting models adjusted for country of origin, age, number of comorbidities, tumor stage, and receipt of systemic anticancer therapy within 1 month of COVID-19 diagnosis. RESULTS By the data lock of February 4, 2022, the registry counted 613 eligible patients with breast cancer: 60.1% (n = 312) hormone receptor-positive, 25.2% (n = 131) human epidermal growth factor receptor 2-positive, and 14.6% (n = 76) triple-negative. The majority (61%; n = 374) had localized/locally advanced disease. Median age was 62 years (interquartile range, 51-74 years). A total of 193 patients (31.5%) presented >= 2 comorbidities and 69% (n = 330) were never smokers. In total, 392 (63.9%), 164 (26.8%), and 57 (9.3%) were diagnosed during the prevaccination, Alpha-Delta, and Omicron phases, respectively. Analysis of CFR28 demonstrates comparable estimates of mortality across the three pandemic phases (13.9%, 12.2%, 5.3%, respectively; P = .182). Nevertheless, a significant improvement in outcome measures of COVID-19 severity across the three pandemic time periods was observed. Importantly, when reported separately, unvaccinated patients from the Alpha-Delta and Omicron phases achieved comparable outcomes to those from the prevaccination phase. Of 566 patients eligible for the vaccination analysis, 72 (12.7%) were fully vaccinated and 494 (87.3%) were unvaccinated. We confirmed with inverse probability of treatment weighting multivariable analysis and following a clustered robust correction for participating center that vaccinated patients achieved improved CFR28 (odds ratio [OR], 0.19; 95% CI, 0.09 to 0.40), hospitalization (OR, 0.28; 95% CI, 0.11 to 0.69), COVID-19 complications (OR, 0.16; 95% CI, 0.06 to 0.45), and reduced requirement of COVID-19-specific therapy (OR, 0.24; 95% CI, 0.09 to 0.63) and oxygen therapy (OR, 0.24; 95% CI, 0.09 to 0.67) compared with unvaccinated controls. CONCLUSION Our findings highlight a consistent reduction of COVID-19 severity in patients with breast cancer during the Omicron outbreak in Europe. We also demonstrate that even in this population, a complete severe acute respiratory syndrome coronavirus 2 vaccination course is a strong determinant of improved morbidity and mortality from COVID-19

SARS-CoV-2 omicron (B.1.1.529)-related COVID-19 sequelae in vaccinated and unvaccinated patients with cancer: results from the OnCovid registry

Background COVID-19 sequelae can affect about 15% of patients with cancer who survive the acute phase of SARS-CoV-2 infection and can substantially impair their survival and continuity of oncological care. We aimed to investigate whether previous immunisation affects long-term sequelae in the context of evolving variants of concern of SARS-CoV-2. Methods OnCovid is an active registry that includes patients aged 18 years or older from 37 institutions across Belgium, France, Germany, Italy, Spain, and the UK with a laboratory-confirmed diagnosis of COVID-19 and a history of solid or haematological malignancy, either active or in remission, followed up from COVID-19 diagnosis until death. We evaluated the prevalence of COVID-19 sequelae in patients who survived COVID-19 and underwent a formal clinical reassessment, categorising infection according to the date of diagnosis as the omicron (B.1.1.529) phase from Dec 15, 2021, to Jan 31, 2022; the alpha (B.1.1.7)-delta (B.1.617.2) phase from Dec 1, 2020, to Dec 14, 2021; and the pre-vaccination phase from Feb 27 to Nov 30, 2020. The prevalence of overall COVID-19 sequelae was compared according to SARS-CoV-2 immunisation status and in relation to post-COVID-19 survival and resumption of systemic anticancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974. Findings At the follow-up update on June 20, 2022, 1909 eligible patients, evaluated after a median of 39 days (IQR 24-68) from COVID-19 diagnosis, were included (964 [ 50 center dot 7%] of 1902 patients with sex data were female and 938 [49 center dot 3%] were male). Overall, 317 (16 center dot 6%; 95% CI 14 center dot 8-18 center dot 5) of 1909 patients had at least one sequela from COVID-19 at the first oncological reassessment. The prevalence of COVID-19 sequelae was highest in the prevaccination phase (191 [19 center dot 1%; 95% CI 16 center dot 4-22 center dot 0] of 1000 patients). The prevalence was similar in the alpha-delta phase (110 [16 center dot 8%; 13 center dot 8- 20 center dot 3] of 653 patients, p=0 center dot 24), but significantly lower in the omicron phase (16 [6 center dot 2%; 3 center dot 5-10 center dot 2] of 256 patients, p<0 center dot 0001). In the alpha- delta phase, 84 (18 center dot 3%; 95% CI 14 center dot 6-22 center dot 7) of 458 unvaccinated patients and three (9 center dot 4%; 1 center dot 9- 27 center dot 3) of 32 unvaccinated patients in the omicron phase had sequelae. Patients who received a booster and those who received two vaccine doses had a significantly lower prevalence of overall COVID-19 sequelae than unvaccinated or partially vaccinated patients (ten [7 center dot 4%; 95% CI 3 center dot 5-13 center dot 5] of 136 boosted patients, 18 [9 center dot 8%; 5 center dot 8-15 center dot 5] of 183 patients who had two vaccine doses vs 277 [ 18 center dot 5%; 16 center dot 5-20 center dot 9] of 1489 unvaccinated patients, p=0 center dot 0001), respiratory sequelae (six [4 center dot 4%; 1 center dot 6-9 center dot 6], 11 [6 center dot 0%; 3 center dot 0-10 center dot 7] vs 148 [9 center dot 9%; 8 center dot 4- 11 center dot 6], p= 0 center dot 030), and prolonged fatigue (three [2 center dot 2%; 0 center dot 1-6 center dot 4], ten [5 center dot 4%; 2 center dot 6-10 center dot 0] vs 115 [7 center dot 7%; 6 center dot 3-9 center dot 3], p=0 center dot 037)

SARS-CoV-2 omicron (B.1.1.529)-related COVID-19 sequelae in vaccinated and unvaccinated patients with cancer: results from the OnCovid registry

Background COVID-19 sequelae can affect about 15% of patients with cancer who survive the acute phase of SARS-CoV-2 infection and can substantially impair their survival and continuity of oncological care. We aimed to investigate whether previous immunisation affects long-term sequelae in the context of evolving variants of concern of SARS-CoV-2. Methods OnCovid is an active registry that includes patients aged 18 years or older from 37 institutions across Belgium, France, Germany, Italy, Spain, and the UK with a laboratory-confirmed diagnosis of COVID-19 and a history of solid or haematological malignancy, either active or in remission, followed up from COVID-19 diagnosis until death. We evaluated the prevalence of COVID-19 sequelae in patients who survived COVID-19 and underwent a formal clinical reassessment, categorising infection according to the date of diagnosis as the omicron (B.1.1.529) phase from Dec 15, 2021, to Jan 31, 2022; the alpha (B.1.1.7)-delta (B.1.617.2) phase from Dec 1, 2020, to Dec 14, 2021; and the pre-vaccination phase from Feb 27 to Nov 30, 2020. The prevalence of overall COVID-19 sequelae was compared according to SARS-CoV-2 immunisation status and in relation to post-COVID-19 survival and resumption of systemic anticancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974. Findings At the follow-up update on June 20, 2022, 1909 eligible patients, evaluated after a median of 39 days (IQR 24-68) from COVID-19 diagnosis, were included (964 [ 50 center dot 7%] of 1902 patients with sex data were female and 938 [49 center dot 3%] were male). Overall, 317 (16 center dot 6%; 95% CI 14 center dot 8-18 center dot 5) of 1909 patients had at least one sequela from COVID-19 at the first oncological reassessment. The prevalence of COVID-19 sequelae was highest in the prevaccination phase (191 [19 center dot 1%; 95% CI 16 center dot 4-22 center dot 0] of 1000 patients). The prevalence was similar in the alpha-delta phase (110 [16 center dot 8%; 13 center dot 8- 20 center dot 3] of 653 patients, p=0 center dot 24), but significantly lower in the omicron phase (16 [6 center dot 2%; 3 center dot 5-10 center dot 2] of 256 patients, p<0 center dot 0001). In the alpha- delta phase, 84 (18 center dot 3%; 95% CI 14 center dot 6-22 center dot 7) of 458 unvaccinated patients and three (9 center dot 4%; 1 center dot 9- 27 center dot 3) of 32 unvaccinated patients in the omicron phase had sequelae. Patients who received a booster and those who received two vaccine doses had a significantly lower prevalence of overall COVID-19 sequelae than unvaccinated or partially vaccinated patients (ten [7 center dot 4%; 95% CI 3 center dot 5-13 center dot 5] of 136 boosted patients, 18 [9 center dot 8%; 5 center dot 8-15 center dot 5] of 183 patients who had two vaccine doses vs 277 [ 18 center dot 5%; 16 center dot 5-20 center dot 9] of 1489 unvaccinated patients, p=0 center dot 0001), respiratory sequelae (six [4 center dot 4%; 1 center dot 6-9 center dot 6], 11 [6 center dot 0%; 3 center dot 0-10 center dot 7] vs 148 [9 center dot 9%; 8 center dot 4- 11 center dot 6], p= 0 center dot 030), and prolonged fatigue (three [2 center dot 2%; 0 center dot 1-6 center dot 4], ten [5 center dot 4%; 2 center dot 6-10 center dot 0] vs 115 [7 center dot 7%; 6 center dot 3-9 center dot 3], p=0 center dot 037)

Las dobleces de los cromosomas mitóticos y su relación con la estructura del núcleo interfásico

Se ha analizado la frecuencia, localización y posible significado de los dobleces presentes en los cromosomas mitóticos obtenidos con técnicas citogenéticas convencionales. No se trata de un fenómeno aleatorio y los dobleces cromosómicos pueden ser remanentes de una disposición del cromosoma interfásico, facilitando la implicación de ciertas bandas frente a otras en reorganizaciones cromosómicas tales como los fragmentos isoacéntricos y contribuyendo a la elevada frecuencia de deleciones intersticiales e inversiones duplicaciones isodicéntricas de la región 15q11q13.Se han analizado 2262 dobleces centroméricos y 2718 dobleces no centroméricos de cultivos de sangre periférica pertenecientes a 11 individuos de ambos sexos.La frecuencia de los dobleces centroméricos se correlaciona con la longitud relativa de los cromosomas y se han identificado al menos 69 bandas no centroméricas que se doblan con una frecuencia superior a la esperada por azar. El doblez no centromérico más frecuente en las metafases obtenidas a partir de cultivos de linfocitos está situado en 15q11q13, una región bien conocida por su inestabilidad y cuya deleción es una causa frecuente de los síndromes de Prader Willi y Angelman. Estudios de FISH y alta resolución demuestran que el doblez se circunscribe a la banda 15q12.El análisis de metafases obtenidas a partir de líquido amniótico (867 dobleces centroméricos y 1118 no centroméricos) y cultivos de vellosidad corial (737 dobleces centroméricos y 874 no centroméricos) confirman los hallazgos en linfocitos con dos notables discrepancias: en líquido amniótico y vellosidad corial, el doblez 15q11q13 es mucho menos frecuente y los dobleces en Xq21 y Xq22 son mucho más frecuentes, especialmente en las hembras. Un estudio adicional en 100 metafases consecutivas de sangre, líquido amniótico y vellosidad corial confirman estas diferencias entre tejidos. Nuestra hipótesis es que los cromosomas se doblan de forma invariable en el núcleo interfásico, pero que las regiones de replicación más tardía tienen menos tiempo para rectificar los dobleces antes de entrar en metafase. Existen varias líneas de evidencia que apoyan la hipótesis de que los dobleces en los cromosomas metafásicos son un remanente de la organización del cromosoma interfásico:- En el cromosoma 12 hay una correspondencia casi perfecta entre nuestros datos y los dobleces asumidos en el modelo de disposición de este cromosoma en el núcleo interfásico en G0 (G1).- El análisis de los dobleces en los cromosomas 5 y 12 en metafases de alta resolución sugiere que los dobleces únicamente se producen en las bandas G de tinción oscura, lo cual se adapta bien a los modelos actuales de distribución de la heterocromatina (periferia nuclear) y eucromatina (interior nuclear).- Las anomalías cromosómicas son sucesos que se producen en el núcleo interfásico. Una determinada disposición de los cromosomas interfásicos debería favorecer ciertos puntos de rotura frente a otros. Ocho de los nueve puntos de rotura no aleatorios identificados en la formación de una aberración inestable denominada isoacéntrico, coinciden con puntos de doblez. Hemos propuesto un modelo de formación de este tipo de figura basado en la presencia de un doblez. Una de las consecuencias de este modelo es la formación de dos tipos de isoacéntricos: con duplicación y sin duplicación del punto de rotura. Se ha podido confirmar la presencia de ambos tipos de isoacéntricos en cultivos de sangre periférica.El significado de los dobleces en los cromosomas interfásicos es incierto. Proponemos un modelo en que los cromosomas interfásicos plegados en zigzag se unen por sus bandas G de tinción oscura a la envoltura nuclear permitiendo la rápida salida del RNA recién sintetizado al exterior nuclear.We have investigated the frequency, localization and possible significance of bends in mitotic chromosomes in conventional cytogenetic preparations. Bends are not a random phenomena, they may be remnants of a folded chromosome state in the nucleus and may facilitate the preferential involvement of some chromosomal bands in structural reorganizations such as the isoacentric fragments or contribute to the high frequency of interstitial deletions and isodicentric inversion duplications involving the 15q11q13 region.A total of 2262 centromeric and 2718 non-centromeric bends from blood cultures of 11 individuals were recorded. Centromeric bends frequency correlates with relative chromosome length and 69 non-centromeric sites were found not to bend at random. 15q11-13, an unstable chromosome region frequently deleted in patients with Prader Willi or Angelman syndrome, shows the highest bending frequency. FISH and high-resolution cytogenetic studies localize this bend on 15q12.All these findings in lymphocyte cultures are confirmed in amniotic fluid (867 centromeric and 1118 non-centromeric bends analyzed) and corion villus cultures (737 centromeric and 874 non-centromeric bends analyzed) with two important divergences: amniotic fluid and corion villus cultures show a lower frequency of bending on 15q11-13 and a higher frequency of bending on Xq21 as compared with lymphocyte cultures. These differences were confirmed in an independent study performed on 100 consecutive metaphases of blood, amniotic fluid and corion villus cultures. We propose the hypothesis that these bends are present in all interphasic chromosomes and delayed replication regions have less time to rectify them, so having a higher probability of being observed in metaphase.Several evidences support the idea that mitotic bends may be remnants of a folded chromosome state in the nucleus:- The striking correspondence between our bending data and the model of the intranuclear arrangement of human chromosome 12 in G0 (G1) nuclei developed by other authors - Bends in high-resolution chromosomes 5 and 12 strongly suggest that bends are restricted to G dark bands. This finding is in close agreement with the observed peripheral nuclear localization of heterochromatin and the central localization of euchromatin.- A folded chromosome state in the nucleus may facilitate the preferential involvement of some chromosomal bands in structural reorganizations such as the isoacentric fragments. Eight of nine breakage points identified in 86 isoacentric fragments reported in the literature are also non-random bending sites identified in our data. We have proposed a model of isoacentric formation based in chromosome bends. This model produces two types of isoacentric, with and without duplication at the breakpoint. We had found both types of isoacentric in blood cultures.The significance of bends in interphasic chromosomes remains unknown. We have proposed an interphasic chromosome model in that chromosomes form a zigzag anchored to the nuclear periphery. That disposition may provide a shortcut in the migration of newly synthesized RNA to cytoplasm

Las Dobleces de los cromosomas mitóticos y su relación con la estructura del núcleo interfásico : Tesis doctoral /

Consultable des del TDXTítol obtingut de la portada digitalitzadaSe ha analizado la frecuencia, localización y posible significado de los dobleces presentes en los cromosomas mitóticos obtenidos con técnicas citogenéticas convencionales. No se trata de un fenómeno aleatorio y los dobleces cromosómicos pueden ser remanentes de una disposición del cromosoma interfásico, facilitando la implicación de ciertas bandas frente a otras en reorganizaciones cromosómicas tales como los fragmentos isoacéntricos y contribuyendo a la elevada frecuencia de deleciones intersticiales e inversiones duplicaciones isodicéntricas de la región 15q11q13. Se han analizado 2262 dobleces centroméricos y 2718 dobleces no centroméricos de cultivos de sangre periférica pertenecientes a 11 individuos de ambos sexos. La frecuencia de los dobleces centroméricos se correlaciona con la longitud relativa de los cromosomas y se han identificado al menos 69 bandas no centroméricas que se doblan con una frecuencia superior a la esperada por azar. El doblez no centromérico más frecuente en las metafases obtenidas a partir de cultivos de linfocitos está situado en 15q11q13, una región bien conocida por su inestabilidad y cuya deleción es una causa frecuente de los síndromes de Prader Willi y Angelman. Estudios de FISH y alta resolución demuestran que el doblez se circunscribe a la banda 15q12. El análisis de metafases obtenidas a partir de líquido amniótico (867 dobleces centroméricos y 1118 no centroméricos) y cultivos de vellosidad corial (737 dobleces centroméricos y 874 no centroméricos) confirman los hallazgos en linfocitos con dos notables discrepancias: en líquido amniótico y vellosidad corial, el doblez 15q11q13 es mucho menos frecuente y los dobleces en Xq21 y Xq22 son mucho más frecuentes, especialmente en las hembras. Un estudio adicional en 100 metafases consecutivas de sangre, líquido amniótico y vellosidad corial confirman estas diferencias entre tejidos. Nuestra hipótesis es que los cromosomas se doblan de forma invariable en el núcleo interfásico, pero que las regiones de replicación más tardía tienen menos tiempo para rectificar los dobleces antes de entrar en metafase. Existen varias líneas de evidencia que apoyan la hipótesis de que los dobleces en los cromosomas metafásicos son un remanente de la organización del cromosoma interfásico: - En el cromosoma 12 hay una correspondencia casi perfecta entre nuestros datos y los dobleces asumidos en el modelo de disposición de este cromosoma en el núcleo interfásico en G0 (G1). - El análisis de los dobleces en los cromosomas 5 y 12 en metafases de alta resolución sugiere que los dobleces únicamente se producen en las bandas G de tinción oscura, lo cual se adapta bien a los modelos actuales de distribución de la heterocromatina (periferia nuclear) y eucromatina (interior nuclear). - Las anomalías cromosómicas son sucesos que se producen en el núcleo interfásico. Una determinada disposición de los cromosomas interfásicos debería favorecer ciertos puntos de rotura frente a otros. Ocho de los nueve puntos de rotura no aleatorios identificados en la formación de una aberración inestable denominada isoacéntrico, coinciden con puntos de doblez. Hemos propuesto un modelo de formación de este tipo de figura basado en la presencia de un doblez. Una de las consecuencias de este modelo es la formación de dos tipos de isoacéntricos: con duplicación y sin duplicación del punto de rotura. Se ha podido confirmar la presencia de ambos tipos de isoacéntricos en cultivos de sangre periférica. El significado de los dobleces en los cromosomas interfásicos es incierto. Proponemos un modelo en que los cromosomas interfásicos plegados en zigzag se unen por sus bandas G de tinción oscura a la envoltura nuclear permitiendo la rápida salida del RNA recién sintetizado al exterior nuclear.We have investigated the frequency, localization and possible significance of bends in mitotic chromosomes in conventional cytogenetic preparations. Bends are not a random phenomena, they may be remnants of a folded chromosome state in the nucleus and may facilitate the preferential involvement of some chromosomal bands in structural reorganizations such as the isoacentric fragments or contribute to the high frequency of interstitial deletions and isodicentric inversion duplications involving the 15q11q13 region. A total of 2262 centromeric and 2718 non-centromeric bends from blood cultures of 11 individuals were recorded. Centromeric bends frequency correlates with relative chromosome length and 69 non-centromeric sites were found not to bend at random. 15q11-13, an unstable chromosome region frequently deleted in patients with Prader Willi or Angelman syndrome, shows the highest bending frequency. FISH and high-resolution cytogenetic studies localize this bend on 15q12. All these findings in lymphocyte cultures are confirmed in amniotic fluid (867 centromeric and 1118 non-centromeric bends analyzed) and corion villus cultures (737 centromeric and 874 non-centromeric bends analyzed) with two important divergences: amniotic fluid and corion villus cultures show a lower frequency of bending on 15q11-13 and a higher frequency of bending on Xq21 as compared with lymphocyte cultures. These differences were confirmed in an independent study performed on 100 consecutive metaphases of blood, amniotic fluid and corion villus cultures. We propose the hypothesis that these bends are present in all interphasic chromosomes and delayed replication regions have less time to rectify them, so having a higher probability of being observed in metaphase. Several evidences support the idea that mitotic bends may be remnants of a folded chromosome state in the nucleus: - The striking correspondence between our bending data and the model of the intranuclear arrangement of human chromosome 12 in G0 (G1) nuclei developed by other authors - Bends in high-resolution chromosomes 5 and 12 strongly suggest that bends are restricted to G dark bands. This finding is in close agreement with the observed peripheral nuclear localization of heterochromatin and the central localization of euchromatin. - A folded chromosome state in the nucleus may facilitate the preferential involvement of some chromosomal bands in structural reorganizations such as the isoacentric fragments. Eight of nine breakage points identified in 86 isoacentric fragments reported in the literature are also non-random bending sites identified in our data. We have proposed a model of isoacentric formation based in chromosome bends. This model produces two types of isoacentric, with and without duplication at the breakpoint. We had found both types of isoacentric in blood cultures. The significance of bends in interphasic chromosomes remains unknown. We have proposed an interphasic chromosome model in that chromosomes form a zigzag anchored to the nuclear periphery. That disposition may provide a shortcut in the migration of newly synthesized RNA to cytoplasm

Psicothema

Resumen tomado de la publicaciónLa presencia de trastornos cognitivos en la esclerosis múltiple (EM) ha sido ampliamente estudiada, sin embargo la toma de decisiones apenas ha sido investigada. El presente estudio examina los procesos de toma de decisiones en pacientes con EM mediante la versión computerizada de la Iowa Gambling Task (IGT). Esta tarea fue aplicada a 18 pacientes con diagnóstico clínico de EM y 18 sujetos control sanos apareados por edad, sexo y nivel educativo. Los resultados muestran que las puntuaciones obtenidas en la IGT difieren significativamente entre los pacientes con EM y los sujetos control sanos: los pacientes con EM realizan menos elecciones favorables en la IGT que los controles. Se plantean posibles explicaciones a la alteración en la toma de decisiones observada en los pacientes con EM.AsturiasColegio Oficial de Psicólogos de Asturias; Calle Ildefonso Sánchez del Rio, 4-1õB; 33001 Oviedo; Tel. +34985285778; Fax +34985281374;ES