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PRMT7 encodes for an arginine methyltransferase that methylates arginine residues on various protein substrates and has been shown to play a role in various developmental processes. Mutations in PRMT7 have been recently shown to be implicated in a phenotype with intellectual disability, short stature and brachydactyly, and considered to be a phenocopy of pseudohypoparathyroidism. We report a patient with short stature, psychomotor delay, hearing loss and brachydactyly, for whom whole exome sequencing detected two mutations in PRMT7 and parental segregation studies detected biallelic mutation inheritance. Few patients with biallelic PRMT7 mutations have been reported so far in the literature. We report a new patient and review all reported cases to date to delineate the clinical manifestations that may help in diagnosis this disorder, known as Short Stature, Brachydactyly, Intellectual Developmental Disability, and Seizures syndrome, allowing appropriate management and genetic counselling.

Resumen El presente estudio describe la implementacion de un test de cribado de portadores de enfermedades geneticas autosomicas recesivas y enfermedades ligadas al cromosoma X en un programa de donacion de ovocitos (donantes de ovocitos y parejas masculinas de las receptoras). El test empleado basado en tecnologia Next-Generation Sequencing (NGS), cubria 200 genes (68 mediante analisis completo de secuencia codificante y 132 por estrategia dirigida de analisis) asociados a 314 enfermedades (277 enfermedades autosomicas recesivas y 22 ligadas al cromosoma X). El resultado obtenido tras 2,5 anos mostro un alto grado de aceptacion (implementacion > 80%). Se identificaron un 56,4% de individuos (761/1.350) portadores de al menos una mutacion patogenica. Asimismo se identifico que el 1,9% de las candidatas a donantes eran portadoras de una enfermedad ligada al cromosoma X por lo que se excluyeron del programa de Donacion de Ovocitos. La carga mutacional media fue de 0,84 mutaciones por muestra. Se identificaron un 3,4% de preasignaciones donante-receptor con alto riesgo reproductivo para alguna enfermedad genetica recesiva (fibrosis quistica, hiperplasia suprarrenal congenita, sordera congenita no-sindromica, alfa-talasemia, fiebre mediterranea familiar, enfermedad de Niemann-Pick, dishormonogenesis tiroidea tipo 6 e hipoplasia de cartilago-pelo). La asignacion definitiva se realizo teniendo en cuenta los resultados de los estudios geneticos. El estado de portador heterocigoto para una enfermedad autosomica recesiva no fue motivo de exclusion del programa de Donacion de Ovocitos, pero implico la seleccion de una receptora cuya pareja masculina no fuera portadora de la misma enfermedad. El asesoramiento genetico de donantes y receptores en las diferentes etapas del proceso clinico de la donacion de ovocitos fue esencial para disminuir la ansiedad, conseguir una buena comprension de los resultados y poder otorgar las recomendaciones pertinentes sobre el riesgo reproductivo propio o de sus familiares, cuando fue necesario.

Resumen El desarrollo en los ultimos anos de las denominadas tecnologias de secuenciacion masiva permite actualmente obtener millones de secuencias de ADN a una velocidad sin precedentes y a un coste cada vez mas reducido. Estas tecnologias estan permitiendo la consecucion de logros cientificos trascendentales, con la identificacion de nuevos genes y la resolucion de las bases geneticas de enfermedades mendelianas a la cabeza. Su potencial ha permitido el desarrollo de nuevas aplicaciones y pruebas biologicas que van a revolucionar, en un futuro proximo, el diagnostico postnatal y prenatal de enfermedades geneticas. En el presente articulo se ofrece una vision general de la tecnologia y se examinan sus ventajas e inconvenientes respecto a metodos convencionales asi como algunas de las principales estrategias, incluyendo metodos de estrategias de diagnostico prenatal dirigidas a la deteccion de aneuploidias y sindromes de delecion/duplicacion.

Background Copy number variations (CNV) have become an important source of human genome variability noteworthy to consider when studying genetic susceptibility to complex diseases. As recent studies have found evidences for the potential involvement of CNVs in psychiatric disorders, we have studied the dosage effect of structural genome variants as a possible susceptibility factor for different psychiatric disorders in a candidate gene approach. Methods After selection of 68 psychiatric disorders’ candidate genes overlapping with CNVs, MLPA assays were designed to determine changes in copy number of these genes. The studied sample consisted of 724 patients with psychiatric disorders (accounting for anxiety disorders, mood disorders, eating disorders and schizophrenia) and 341 control individuals. Results CNVs were detected in 30 out of the 68 genes screened, indicating that a considerable proportion of neuronal pathways genes contain CNVs. When testing the overall burden of rare structural genomic variants in the different psychiatric disorders compared to control individuals, there was no statistically significant difference in the total amount of gains and losses. However, 14 out of the 30 changes were only found in psychiatric disorder patients but not in control individuals. These genes include GRM7, previously associated to major depression disorder and bipolar disorder, SLC6A13, in anxiety disorders, and S100B, SSTR5 and COMT in schizophrenia. Conclusions Although we have not been able to found a clear association between the studied CNVs and psychiatric disorders, the rare variants found only within the patients could account for a step further towards understanding the pathophysiology of psychiatric disorders.

Mosaicism is defined as the coexistence of cells with different genetic composition within an individual, caused by postzygotic somatic mutation. Although somatic mosaicism for chromosomal abnormalities is a well-established cause of developmental and somatic disorders and has also been detected in different tissues, its frequency and extent in the adult normal population are still unknown. We provide here a genome-wide survey of mosaic genomic variation obtained by analyzing Illumina 1M SNP array data from blood or buccal DNA samples of 1991 adult individuals from the Spanish Bladder Cancer/EPICURO genome-wide association study. We found mosaic abnormalities in autosomes in 1.7% of samples, including 23 segmental uniparental disomies, 8 complete trisomies, and 11 large (1.5-37 Mb) copy-number variants. Alterations were observed across the different autosomes with recurrent events in chromosomes 9 and 20. No case-control differences were found in the frequency of events or the percentage of cells affected, thus indicating that most rearrangements found are not central to the development of bladder cancer. However, five out of six events tested were detected in both blood and bladder tissue from the same individual, indicating an early developmental origin. The high cellular frequency of the anomalies detected and their presence in normal adult individuals suggest that this type of mosaicism is a widespread phenomenon in the human genome. Somatic mosaicism should be considered in the expanding repertoire of inter- and intraindividual genetic variation, some of which may cause somatic human diseases but also contribute to modifying inherited disorders and/or late-onset multifactorial traits. © 2010 The American Society of Human Genetics. All rights reserved., This work was supported by the Intramural Research Program of the NCI Division of Cancer Epidemiology and Genetics (to N.R., D.S., and S.J.C.), the Asociacion Espanola Contra el Cancer (to F.X.R., N.M., and L.A.P.-J.), EU-6FP grants LSHG-CT-2006-037627 (to L.A.P.-J.) and HEALTH-STREP-2006-037739-DropTop (to N.M. and F.X.R.), Fondo de Investigacion Sanitaria grants PI076832 (to L.A.P.-J.) and PI061614 (to F.X.R.), Consolider ONCOBIO (to F.X.R.), National Institutes of Health grant R01 CA089715-06A2 (to N.M. and F.X.R.), Red Tematica de Investigacion Cooperativa en Cancer (to N.M. and A.C.), Fundacio La Marato de TV3 (to N.M.), and EU-7FP grant agreements #201663-UROMOL (to N.M. and F.X.R.) and #201333-DECanBIO (to N.M.). B.R.-S. and G.M. were supported by a postdoctoral fellowship (FIS CD06/00019) and a predoctoral fellowship (FI09/00205) of the Fondo Investigación Sanitaria, respectively.

Resumen La tecnologia de microarrays, de reciente implantacion en el diagnostico prenatal internacional, se ha convertido en uno de los pilares de este diagnostico en cuanto a su capacidad de deteccion y objetividad de resultados. La presente guia comprende una exposicion general de la tecnologia, incluyendo aspectos tecnicos y diagnosticos a tener en cuenta. En concreto, se definen: los distintos tipos de muestras prenatales que se van a utilizar (biopsia de vellosidades corionicas, liquido amniotico, sangre procedente de cordon umbilical o material procedente de restos abortivos) asi como las particularidades de cada una de ellas; que puntos hay que tener en cuenta de cara a la elaboracion de un consentimiento informado y de la emision de un informe de microarray prenatal, especialmente en el caso de la posible definicion de variantes de significado incierto; las limitaciones inherentes a la tecnica que deben ser tenidas en cuenta a la hora de recomendar su uso diagnostico; asi como un algoritmo pormenorizado de situaciones clinicas, donde se recomienda el uso de microarrays y su incorporacion a la rutina clinica en el contexto de otras pruebas geneticas, incluyendo embarazos con antecedentes familiares o hallazgos sugerentes de un sindrome concreto, translucencia nucal incrementada en el primer trimestre o cardiopatia congenita en el segundo trimestre y hallazgos ecograficos no relacionados con un sindrome conocido o especifico. Esta guia ha sido coordinada por la Asociacion Espanola de Diagnostico Prenatal (AEDP), la Asociacion Espanola de Genetica Humana (AEGH) y la Sociedad Espanola de Genetica Clinica y Dismorfologia (SEGCyD).

Anxiety disorders are complex and common psychiatric illnesses associated with considerable morbidity and social cost. We have studied the molecular basis of the cooccurrence of panic and phobic disorders with joint laxity. We have identified an interstitial duplication of human chromosome 15q24-26 (named DUP25), which is significantly associated with panic/agoraphobia/social phobia/joint laxity in families, and with panic disorder in nonfamilial cases. Mosaicism, different forms of DUP25 within the same family, and absence of segregation of 15q24-26 markers with DUP25 and the psychiatric phenotypes suggest a non-Mendelian mechanism of disease-causing mutation. We propose that DUP25, which is present in 7% control subjects, is a susceptibility factor for a clinical phenotype that includes panic and phobic disorders and joint laxity.