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.

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.

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.

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.

[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.