Diversity of oncopharmacogenetic profile within Spanish population.

Consensus guidelines for genotype-guided fluoropyrimidine dosing based on variation in the dihydropyrimidine dehydrogenase (DPYD) gene before treatment have been firmly established. The prior pharmacogenetic report avoids the serious toxicity that inevitably occurred in a non-negligible percentage of the treated patients. The precise description of the allelic distribution of the variants of interest in our reference populations is information of great interest for the management of the prescription of these antineoplastic drugs. We characterized the allelic distribution of the UGT1A1*28 variant (rs3064744), as well as the DPYD*2A (rs3918290) variant, c.1679T>G (rs55886062), c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182; HapB3) in series of 5251 patients who are going to receive treatment with irinotecan and fluoropyrimidines, representative of Valencian, Aragonese and Western Andalusian populations.

Contingent prenatal screening for frequent aneuploidies with cell-free fetal DNA analysis.

OBJECTIVE: To analyze the results of contingent screening for common aneuploidies at our center from June 2017 to June 2019. MATERIALS AND METHODS: Traditional screening tests were performed using a combination of biochemical markers and ultrasound measurements in the first and second trimesters to assess the risk of trisomies 21 (T21), 18 (T18) and 13 (T13). Cell-free DNA (cf-DNA) testing was offered (Harmony test) to pregnant women at high risk (>1/280 for T21 and > 1/150 for T13 and T18) and a normal early morphology scan. In positive cases, prenatal sampling was strongly recommended to confirm the results by gold standard methods (QF-PCR and karyotyping). Newborns' phenotypes were corroborated after birth in all cases. RESULTS: In this prospective study, 8153 pregnant women were enrolled, resulting in 390 at high risk according to traditional screening tests. cfDNA testing was offered to 383 women. Traditional screening tests showed a false negative rate of 9.68% for T21. Traditional test sensitivity for T21 was 90.3%, for a false positive rate of 4.17% and a positive predictive value of 7.6%. The positive and negative predictive value for cfDNA testing was 100%. The approach used avoided invasive procedures in 91.3% of women at high risk. The prevalence of chromosomal abnormalities in the population analyzed was 1 in 164, and 1 in 210 for T21. CONCLUSIONS: Our results show that offering cf-DNA testing to women at high risk in traditional tests (including those with risks >1 in 50) significantly reduces false positives and, therefore, the number of invasive tests. Extending the use of cf-DNA testing to intermediate risk categories may be cost effective.

Particularidades genéticas y bioquímicas de la hipercolesterolemia familiar en el suroeste de la Península Ibérica / Genetics and biochemistry of familial hypercholesterolemia in Southwest of the Iberian Peninsula

Hasta el momento, la mayor parte de los casos de hipercolesterolemia familiar (60-80%) se atribuyen a variantes patogénicas en el gen LDLR. Solo un 1-5% de los casos se produce por variantes en el gen APOB y un 0-3% por variantes en el gen PCSK9. Existen gran variedad en mutaciones patogénicas conocidas del gen LDLR mientras que, para las que afectan al gen APOB, la de mayor incidencia es p.Arg3527Gln, descrita predominantemente en poblaciones de Centroeuropa y América del Norte. En la Península Ibérica el gen predominante afectado es el del receptor de LDL, similar al resto del mundo, siendo la afectación del gen APOB descrita en individuos del noroeste y anecdótica en el resto del territorio. Analizamos genéticamente la población asistida en el primer año de una consulta de lípidos del suroeste de España con puntuación≥6 puntos de las clínicas de lípidos holandesas y describimos los hallazgos genéticos, bioquímicos y clínicos. Los primeros hallazgos muestran indicios de una posible mayor prevalencia de pacientes con mutación en el gen APOB respecto a otros territorios. Encontramos hechos históricos que darían una posible explicación a este hecho, apoyando así dicha presunción.(AU)

So far, most cases of hypercholesterolaemia (60-80%) are attributed to pathogenic variants in the LDLR gene. Only 1-5% of cases are caused by variants in the APOB gene, and 0-3% by variants in the PCSK9 gene. There is a large variety in known pathogenic mutations of the LDLR gene, while for those affecting the APOB gene, the highest incidence is p.Arg3527Gln, described predominantly in Central European and North American populations. In the Iberian Peninsula the predominant gene affected is that of the LDL receptor, similar to the rest of the world, with the involvement of the APOB gene being described in individuals from the northwest, and anecdotal in the rest of the territory. A genetics analysis was performed on the population attending the first year of a lipid clinic in southwestern Spain with a 6-point score from the Dutch lipid clinics. The genetic, biochemical and clinical findings are described. The first findings show indications of a possible higher prevalence of patients with mutation in the APOB gene compared to other territories. Historical evidence is presented that could give a possible explanation to this, thus supporting the assumption.(AU)

Genetics and biochemistry of familial hypercholesterolemia in Southwest of the Iberian Peninsula. / Particularidades genéticas y bioquímicas de la hipercolesterolemia familiar en el suroeste de la Península Ibérica.

So far, most cases of hypercholesterolaemia (60-80%) are attributed to pathogenic variants in the LDLR gene. Only 1-5% of cases are caused by variants in the APOB gene, and 0-3% by variants in the PCSK9 gene. There is a large variety in known pathogenic mutations of the LDLR gene, while for those affecting the APOB gene, the highest incidence is p.Arg3527Gln, described predominantly in Central European and North American populations. In the Iberian Peninsula the predominant gene affected is that of the LDL receptor, similar to the rest of the world, with the involvement of the APOB gene being described in individuals from the northwest, and anecdotal in the rest of the territory. A genetics analysis was performed on the population attending the first year of a lipid clinic in southwestern Spain with a 6-point score from the Dutch lipid clinics. The genetic, biochemical and clinical findings are described. The first findings show indications of a possible higher prevalence of patients with mutation in the APOB gene compared to other territories. Historical evidence is presented that could give a possible explanation to this, thus supporting the assumption.

Hallazgo casual mediante array de polimorfismo de nucleótido simple. Síndrome de Warkany / Casual finding using single nucleotide polymorphisms arrays: warkany syndrome

Introducción: La trisomía del cromosoma 8, conocida como síndrome de Warkany, es una rara enfermedad genética que cursa con un fenotipo muy variable. Su principal característica clínica es la discapacidad intelectual, facies dismórficas y pliegues plantares profundos. Presentamos el caso de un paciente de 10 años de edad, con facies gargoloides, retraso mental y rigidez en las articulaciones. El estudio inicial del cariotipo, en el que se analizaron 20 metafases, fue normal. Se solicitó array de polimorfismos de nucleótido único (SNPs) al laboratorio. Resultados: Se detectó una ganancia completa del cromosoma 8, que se interpretó como una trisomía 8 en mosaico de aproximadamente un 20%, y que era compatible con la clínica que presentaba el paciente. Discusión: Este caso muestra las limitaciones que tiene el análisis de solo 20 metafases en el cariotipo en pacientes con aneuploidías en mosaico. En estos casos estaría recomendado ampliar el estudio a al menos 30 metafases de cara a detectar mosaicismos en baja proporción

Introduction: Chromosome 8 trisomy, known as Warkany syndrome, is a rare genetic disease that has a very variable phenotype. Its main clinical characteristic is intellectual disability, dysmorphic facies, and deep plantar folds. The case is presented of a 10-year-old patient with gargoyle-like facies, mental retardation, and joint stiffness. The initial study of the karyotype, in which 20 metaphases were analysed, was normal. A single nucleotide polymorphisms (SNPs) array was requested from the laboratory. Results: A complete gain of chromosome 8 was detected, which was interpreted as a mosaic trisomy 8 of approximately 20%, and which was compatible with the clinical presentation of the patient. Discussion: This case shows the limitations of the analysis of only 20 metaphases in the karyotype in patients with mosaic aneuploidies. In these cases it would be recommended to extend the study to at least 30 metaphases in order to detect mosaicisms in low proportion

Estudios genéticos en diagnóstico prenatal. Recomendación (2018) / Genetic studies in prenatal diagnosis. Recommendation (2018)

El término diagnóstico prenatal comprende todas las modalidades de diagnóstico dirigidas a detectar durante la gestación una anomalía congénita que incluya trastornos estructurales o funcionales. Un porcentaje de las mismas se debe a factores genéticos. El presente documento pretende detallar las indicaciones actuales de las pruebas invasivas y de las no invasivas, describir las pruebas de laboratorio que se utilizan en el diagnóstico prenatal de alteraciones genéticas y proponer esquemas de trabajo para el estudio de estas alteraciones genéticas

The term prenatal diagnosis includes all diagnostic modalities aimed at detecting a congenital anomaly during pregnancy that includes structural or functional disorders. A percentage of them are due to genetic factors. This document intends to detail the current indications of invasive and non-invasive tests, describe the laboratory tests used in the prenatal diagnosis of genetic alterations, and propose work schemes for the study of these genetic alterations

Noonan syndrome: Severe phenotype and PTPN11 mutations / Síndrome de Noonan: fenotipo grave y mutaciones en el gen PTPN11

Introduction and objective: Noonan syndrome (NS) is a genetic disorder characterized by a wide range of distinctive features and health problems. It caused in 50% of cases by missense mutations in PTPN11 gene. It has been postulated that it is possible to predict the disease course based into the impact of mutations on the protein. Patients and methods: We report two cases of severe NS phenotype including hydrops fetalis. PTPN11 gene was studied in germinal cells of both patients by sequencing. Results: Two different mutations (p.Gly503Arg and p.Met504Val) was detected in PTPN11 gene. Discussion: These mutations have been reported previously, and when they were germinal variants, patients presented classic NS, NS with other malignancies and recently, p.Gly503Arg has been also observed in a patient with severe NS and hydrops fetalis, as our cases. Therefore, these observations shade light on that it is not always possibly to determine the genotype-phenotype relation based into the impact of mutations on the protein in NS patients with PTPN11 mutations

Introducción y objetivo: El síndrome de Noonan (SN) es un trastorno genético caracterizado por una amplia gama de signos distintivos y problemas de salud. Está causado en el 50% de los casos por mutaciones missense en el gen PTPN11. Se ha postulado que es posible predecir el curso de la enfermedad en función del impacto de las mutaciones en la proteína. Pacientes y métodos: Presentamos 2 casos de fenotipo severo de SN con hydrops fetalis. En ambos casos se realizó la secuenciación del gen PTPN11 en células germinales. Resultados: Se identificaron 2 mutaciones diferentes en dicho gen (p.Gly503Arg y p.Met504Val). Discusión: Estas mutaciones ya han sido identificadas previamente, y cuando se presentan en línea germinal, los pacientes pueden presentar SN clásico, SN con alteraciones malignas o recientemente, p.Gly503Arg se ha observado en un paciente con SN e hydrops fetalis, como los 2 casos que presentamos. Por tanto, estas observaciones muestran, que en pacientes con SN y mutaciones en el gen PTPN11, no es siempre posible determinar la relación genotipo-fenotipo en función del impacto de la mutación en la proteína

Noonan syndrome: Severe phenotype and PTPN11 mutations.

INTRODUCTION AND OBJECTIVE: Noonan syndrome (NS) is a genetic disorder characterized by a wide range of distinctive features and health problems. It caused in 50% of cases by missense mutations in PTPN11 gene. It has been postulated that it is possible to predict the disease course based into the impact of mutations on the protein. PATIENTS AND METHODS: We report two cases of severe NS phenotype including hydrops fetalis. PTPN11 gene was studied in germinal cells of both patients by sequencing. RESULTS: Two different mutations (p.Gly503Arg and p.Met504Val) was detected in PTPN11 gene. DISCUSSION: These mutations have been reported previously, and when they were germinal variants, patients presented classic NS, NS with other malignancies and recently, p.Gly503Arg has been also observed in a patient with severe NS and hydrops fetalis, as our cases. Therefore, these observations shade light on that it is not always possibly to determine the genotype-phenotype relation based into the impact of mutations on the protein in NS patients with PTPN11 mutations.

Language and Cognitive Impairment Associated with a Novel p.Cys63Arg Change in the MED13L Transcriptional Regulator.

Mutations in the MED13L gene, which encodes a subunit of a transcriptional regulatory complex, result in a complex phenotype entailing physical and cognitive anomalies. Deep language impairment has been reported in affected individuals, mostly in patients with copy number variations. We report on a child with a nonsynonymous p.Cys63Arg change in MED13L (chr12:116675396A>G, GRCh37) who exhibits profound language impairment in the expressive domain, cognitive delay, behavioral disturbances, and an autism-like phenotype. Because of the brain areas in which MED13L is expressed and because of the functional links between MED13L and the products of selected candidate genes for cognitive disorders involving language deficits, the proband's linguistic phenotype may result from changes in a functional network important for language development and evolution.

Utilidad del estudio molecular de la hipercalcemia hipocalciúrica familiar; detección de una nueva mutación genética / Usefulness of molecular study of familial hypocalciuric hypercalcemia; detection of a new genetic mutation

La hipercalcemia hipocalciúrica familiar representa una causa benigna de hipercalcemia de herencia autosómica dominante que no precisa normalmente tratamiento. Presentamos el caso de un varón de 21 años con perfil bioquímico típico de hipercalcemia hipocalciúrica familiar: hipercalcemia leve, niveles normales de PTH e hipocalciuria. Se solicitó el estudio genético del gen CASR, que objetivó en heterocigosis una variante no descrita previamente en la literatura. El padre, con hipercalcemia leve, también era portador de dicha variante. Aunque se trata de una enfermedad sin repercusiones clínicas importantes, es de utilidad realizar la confirmación genética de la hipercalcemia hipocalciúrica familiar para diferenciarla del hiperparatiroidismo primario y para ofrecer un asesoramiento genético adecuado a los pacientes (AU)

Familial hypocalciuric hypercalcemia is a benign cause of hypercalcemia of autosomal dominant inheritance that does not normally require treatment. The case is presented on a 21 year-old male with a typical familial hypocalciuric hypercalcemia biochemical profile: mild hypercalcaemia, normal PTH levels, and hypocalciuria. A genetic study was requested on the CASR gene, which showed a heterozygous variant not previously described in the literature. The father, with mild hypercalcaemia, was also a carrier of this variant. Although it is a disease with no significant clinical repercussions, it is useful to perform genetic confirmation of familial hypocalciuric hypercalcemia to differentiate it from primary hyperparathyroidism and to provide adequate genetic counselling to patients (AU)

Predisposición genética al cáncer infantil / Genetic predisposition to childhood cancer

No disponible

Neuropatía óptica de Leber: utilidad de la secuenciación masiva en el estudio de mutaciones mitocondriales en aparente homoplasmia / Leber hereditary optic neuropathy: Usefulness of next generation sequencing to study mitochondrial mutations on apparent homoplasmy

Fundamento y objetivo: La neuropatía óptica hereditaria de Leber se caracteriza por una pérdida de visión aguda o subaguda, producida por mutaciones en el ADN mitocondrial. Pacientes y métodos: Presentamos el estudio molecular realizado en una familia en la que solo uno de sus miembros presentaba signos de la enfermedad. Resultados: En el caso índice y en la madre se detectó la mutación m.11778G>A en el gen MT-ND4 en heteroplasmia. La hermana del caso índice, sin manifestaciones oculares, acudió a consulta para consejo genético. El estudio de dicha mutación por secuenciación Sanger mostró que la portaba en homoplasmia. Sin embargo, mediante secuenciación de última generación (NGS) se pudo comprobar que se encontraba realmente en heteroplasmia. Conclusiones: Confirmar que una mutación se encuentra en homoplasmia es importante cara al consejo genético. Hemos observado que la NGS permite distinguir entre grados elevados de heteroplasmia y verdaderas homoplasmias y, por tanto, es de utilidad en el estudio de pacientes en los que se detectan mutaciones en homoplasmia con metodologías de menor sensibilidad analítica (AU)

Background and objective: Leber hereditary optic neuropathy is characterized by acute and subacute visual loss, produced by mitochondrial DNA mutations. Patients and methods: The molecular study of a family with only one affected member is presented. Results: In the index case and in her mother, the mitochondrial mutation m.11778G>A in the MT-ND4 was detected in the heteroplasmic state. The index case's sister, without ocular manifestations, asked for genetic counseling. The study of the mentioned mutation by Sanger sequencing identified it in an apparent homoplasmic state. However, by means of next-generation sequencing (NGS), the mutation was actually in a heteroplasmic state. Conclusions: Regarding genetic counseling, verifying a mutation in homoplasmic state is really important. We have observed that NGS allows us to discriminate between high levels of heteroplasmy and homoplasmy, meaning that it is a useful technique for the analysis of apparent homoplasmic results obtained with less sensitive technique, as Sanger sequencing (AU)

[Leber hereditary optic neuropathy: Usefulness of next generation sequencing to study mitochondrial mutations on apparent homoplasmy]. / Neuropatía óptica de Leber: utilidad de la secuenciación masiva en el estudio de mutaciones mitocondriales en aparente homoplasmia.

BACKGROUND AND OBJECTIVE: Leber hereditary optic neuropathy is characterized by acute and subacute visual loss, produced by mitochondrial DNA mutations. PATIENTS AND METHODS: The molecular study of a family with only one affected member is presented. RESULTS: In the index case and in her mother, the mitochondrial mutation m.11778G>A in the MT-ND4 was detected in the heteroplasmic state. The index case's sister, without ocular manifestations, asked for genetic counseling. The study of the mentioned mutation by Sanger sequencing identified it in an apparent homoplasmic state. However, by means of next-generation sequencing (NGS), the mutation was actually in a heteroplasmic state. CONCLUSIONS: Regarding genetic counseling, verifying a mutation in homoplasmic state is really important. We have observed that NGS allows us to discriminate between high levels of heteroplasmy and homoplasmy, meaning that it is a useful technique for the analysis of apparent homoplasmic results obtained with less sensitive technique, as Sanger sequencing.