Browsing by Author "Benavides, Felipe"
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Item ALS deficiency caused by an exon 2 deletion and a novel missense variant in the gene encoding ALS(2019) Dominguez, Gonzalo; Poggi, Helena; Arancibia, Mónica; Benavides, Felipe; Martínez, AlejandroContext ALS deficiency (ACLSD), caused by mutations in IGFALS, is characterized by a mild short stature, low concentrations of IGF-I and IGFBP-3, and a normal growth hormone (GH) stimulation test response. To our knowledge, no larger deletions have been reported. Case description A 17-year-old adolescent male was evaluated due to delayed puberty and short stature. He had a height of 154.4 cm (SDS -2.84), a weight of 53.3 kg (SDS -1.41), a BMI of 22.4 kg/m2 (SDS +0.31), a Tanner 2 pubertal stage with a testicular volume of 10 mL, and a bone age of 16 years (SDS -1.33). After biochemical evaluation, low IGF-I levels, undetectable IGFBP-3 levels, and a normal response to the GH stimulation test were observed, suggesting GH insensitivity. ACLSD was confirmed by ALS measurement (116 ng/mL, SDS -3.19) and genetic analysis of IGFALS. An apparently homozygous missense variant, p. Pro624Leu, was found in exon 2 of the proband; this mutation was observed on one allele of the proband's father but was absent in the mother and siblings. Deletion/duplication analysis by multiplex ligation-dependent probe amplification (MLPA) was consistent with a deletion encompassing a significant part of exon 2 on one allele in the proband and in his mother and siblings. Conclusion This is the first report of a large deletion in a patient with ACLSD. Deletion/duplication analysis should be considered in the genetic study of ACLSD, especially when homozygosity for a pathogenic variant cannot be confirmed by the study of the parents or when no variants are found but ALS concentrations are very low.Item Association between phenotype and deletion size in 22q11.2 microdeletion syndrome: systematic review and meta-analysis(2019) Rozas, M. Fernanda; Benavides, Felipe; León, Luis; Repetto, GabrielaBackground: Chromosome 22q11.2 microdeletion syndrome, a disorder caused by heterozygous loss of genetic material in chromosome region 22q11.2, has a broad range of clinical symptoms. The most common congenital anomalies involve the palate in 80% of patients, and the heart in 50–60% of them. The cause of the phenotypic variability is unknown. Patients usually harbor one of three common deletions sizes: 3, 2 and 1.5 Mb, between low copy repeats (LCR) designated A-D, A-C and A-B, respectively. This study aimed to analyze the association between these 3 deletion sizes and the presence of congenital cardiac and/or palatal malformations in individuals with this condition. A systematic review and meta-analysis were conducted, merging relevant published studies with data from Chilean patients to increase statistical power. Results: Eight articles out of 432 were included; the data from these studies was merged with our own, achieving a total of 1514 and 487 patients to evaluate cardiac and palate malformations, respectively. None of the compared deleted chromosomal segments were statistically associated with cardiac defects (ORAB v/s AC-AD: 0.654 [0.408–1.046]; OR AD v/s AB-AC: 1.291 [0.860–1.939]) or palate anomalies (ORAB v/s AC-AD: 1.731 [0.708–4.234]; OR AD v/s AB-AC: 0.628 [0.286–1.382]). Conclusions: The lack of association between deletion size and CHD or PA found in this meta-analysis suggests that deletion size does not explain the incomplete penetrance of these 2 major manifestations, and that the critical region for the development of heart and palatal abnormalities is within LCR A-B, the smallest region of overlap among the three deletion sizes.Item Case fatality rate and associated factors in patients with 22q11 microdeletion syndrome: a retrospective cohort study(BMJ Publishing Group, 2014) Repetto, Gabriela; Guzmán, Maria Luisa; Delgado, Iris; Loyola, Hugo; Palomares, Mirta; Lay-Son, Guillermo; Vial, Cecilia; Benavides, Felipe; Espinoza, Karena; Alvarez, PatriciaOBJECTIVE: Chromosome 22q11.2 deletion is the most commonly occurring known microdeletion syndrome. Deaths related to the syndrome have been reported, but the magnitude of death has not been quantified. This study evaluated the deletion's impact on survival and its clinical manifestations in a large cohort of Chilean patients. DESIGN: Demographic and clinical data of individuals with 22q11 deletions diagnosed between 1998 and 2013 were collected from medical records and death certificates. Case fatality rate was calculated and compared with national vital statistics. OR with 95% CI analysis was used to assess the association between clinical manifestations and death. SETTING: Genetic services in tertiary care centres in Chile, following patients with 22q11.2 deletion. OUTCOMES: Fatality rate and associated factors. RESULTS: 59 of 419 patients (14.1%) died during the study period at a median of 3.4 months (range 0 to 32 years of age). Factors associated with death included congenital heart disease (OR 5.27; 95% CI 2.06 to 13.99; p<0.0001), hypocalcaemia (OR 4.27; 95% CI 1.67 to 11.15; p<0.002) and airway malacia (OR 13.37; 95% CI 1.19 to 110.51; p<0.002). Patients with deletions and defects such as tetralogy of Fallot with or without pulmonary atraesia, truncus arteriosus or ventricular septal defect, had a 2.6-fold to 4.6-fold higher death rate compared with nationwide reports for the same types of defects. CONCLUSIONS: In this cohort, we observed a death rate of 14.1%, implying that one in seven patients with 22q11 deletion died during the study period. Significant associations with cardiac defects, hypocalcaemia and airway malacia were observed. Furthermore, the death risk in patients with 22q11 deletion and cardiac defects exceeded the global figures observed in Chile for infants with structurally similar but apparently isolated anomalies. These observations indicate a need to identify patients who may require specific perioperative management to improve survival.Item Deletion size analysis of 1680 22q11.2DS subjects identifies a new recombination hotspot on chromosome 22q11.2(2018) Guo, Tingwei; Diacou, Alexander; Nomaru, Hiroko; McDonald-McGinn, Donna M.; Hestand, Matthew; Demaerel, Wolfram; Zhang, Liangtian; Zhao, Yingjie; Ujueta, Francisco; Shan, Jidong; Montagna, Cristina; Zheng, Deyou; Crowley, Terrence B.; Kushan-Wells, Leila; Bearden, Carrie E.; Kates, Wendy R.; Gothelf, Doron; Schneider, Maude; Eliez, Stephan; Breckpot, Jeroen; Swillen, Ann; Vorstman, Jacob; Zackai, Elaine; Benavides, Felipe; Repetto, Gabriela; Emanuel, Beverly S.; Bassett, Anne S.; Vermeesch, Joris R.; Marshall, Christian R.; Morrow, Bernice E.Recurrent, de novo, meiotic non-allelic homologous recombination events between low copy repeats, termed LCR22s, leads to the 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome/DiGeorge syndrome). Although most 22q11.2DS patients have a similar sized 3 million base pair (Mb), LCR22A-D deletion, some have nested LCR22A-B or LCR22A-C deletions. Our goal is to identify additional recurrent 22q11.2 deletions associated with 22q11.2DS, serving as recombination hotspots for meiotic chromosomal rearrangements. Here, using data from Affymetrix 6.0 microarrays on 1680 22q11.2DS subjects, we identified what appeared to be a nested proximal 22q11.2 deletion in 38 (2.3%) of them. Using molecular and haplotype analyses from 14 subjects and their parent(s) with available DNA, we found essentially three types of scenarios to explain this observation. In eight subjects, the proximal breakpoints occurred in a small sized 12 kb LCR distal to LCR22A, referred to LCR22Aþ, resulting in LCR22Aþ-B or LCR22Aþ-D deletions. Six of these eight subjects had a nested 22q11.2 deletion that occurred during meiosis in a parent carrying a benign 0.2 Mb duplication of the LCR22A-LCR22Aþregion with a breakpoint in LCR22Aþ. Another six had a typical de novo LCR22A-D deletion on one allele and inherited the LCR22A-Aþduplication from the other parent thus appearing on microarrays to have a nested deletion. LCR22Aþmaps to an evolutionary breakpoint between mice and humans and appears to serve as a local hotspot for chromosome rearrangements on 22q11.2.Item Diagnóstico molecular en pacientes con retinoblastoma: reporte de una serie de casos(Elsevier, 2016) Ossandón, Diego; Zanolli, Mario; Lopez, Juan Pablo; Benavides, Felipe; Perez, Veronica; Repetto, GabrielaObjectives To report the benefits of genetic diagnosis in patients with retinoblastoma. Method Observational study. Patients with retinoblastoma and their families were included. Demographic and clinical data were recorded. Blood and tumor samples were obtained. Next generation sequencing was performed on the samples. When deletion 13 q syndrome was suspected, cytogenetics microarray was performed (Cytoscan® HD, Affymetrix, Santa Clara, CA, USA), with a high density chip of 1.9 million of non-polymorphic probes and 750 thousand SNP probes. Results Of the 7 cases were analyzed 4 were male. The mean age at diagnosis was 21 months (range 5–36). Three cases had bilateral retinoblastoma, and 4 unilateral. None had family history. In all patients, blood was analyzed, and a study was performed on the tissue from 2 unilateral enucleated tumors, in which 6 mutations were identified, all de novo. Just one was novel (c.164delC; case 1). One case of unilateral tumor revealed blood mosaicism, showing that his condition was inheritable, and that there is a high risk of developing retinoblastoma in the unaffected eye. The patient also has an increased risk of presenting with other primary tumors. Conclusion Molecular diagnosis of RB1 in patients with retinoblastoma impacts on the decision process, costs, treatment, and prognosis of patients, as well as their families.Item Efecto de las variantes de VKORC1 y CYP2C9 sobre la dosis de anticoagulantes orales en individuos chilenos(Sociedad Medica de Santiago, 2015) Benavides, Felipe; Grossman, Nicole; Poggi, Helena; Nieto, Elena; Bertrán, Antonio; Araos, Daniel; Vásquez, Marcos; Ibarra, Ignaz; Caceres, Felipe; Espinoza, Karena; Lagos, Marcela; Repetto, GabrielaBACKGROUND: The dose of oral anticoagulants (OAC) shows great variability among patients. Pharmacogenetic studies have shown that common variants in genes CYP2C9 (*2 and *3) and VKORC1 (-1639G>A) are associated with lower requirements of OAC. AIM: To study the association between average maintenance doses of oral anticoagulant therapy required to maintain a stable INR and CYP2C9 and VKORC1 gene variants in Chilean adults. MATERIAL AND METHODS: Prospective study of patients on anticoagulant treatment and with a stable international normalized ratio (INR) for prothrombin time for at least three months. Patients were classified as having high or low acenocoumarol or warfarin requirements. Peripheral blood DNA genotyping was performed by polymerase chain reaction and restriction fragment polymorphism or sequencing and electrophoresis. RESULTS: The study included 185 patients, 125 on acenocoumarol and 60 on warfarin. Patients with VKORC1-1639A allele were more likely to require lower doses of both drugs than patients with the G allele (Odds ratio [OR] for acenocoumarol 9.06, and OR for warfarin = 18.7). There was no association between CYP2C9*2 and*3 and acenocoumarol or warfarin requirements. CONCLUSIONS: There is an association between VKORC1-1639A variant and anticoagulant doses.Item Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome(2018) Poli, Cecilia; Ebstein, Frédéric; Nicholas, Sarah K.; Guzman, Marietta M. de; Forbes, Lisa R.; Chinn, Ivan K.; Mace, Emily M.; Vogel, Tiphanie P.; Carisey, Alexandre F.; Benavides, Felipe; Coban-Akdemir, Zeynep H.; Gibbs, Richard A.; Jhangiani, Shalini N.; Muzny, Donna M.; Carvalho, Claudia M. B.; Schady, Deborah A.; Jain, Mahim; Rosenfeld, Jill A .; Emrick, Lisa; Lewis, Richard A.; Lee, Brendan; Undiagnosed Diseases Network members; Zieba, Barbara A.; Küry, Sébastien; Krüger, Elke; Lupski, James R.; Bostwick, Bret L.; Orange, Jordan S.The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.Item No association between genetic variants in MAOA, OXTR, and AVPR1a and cooperative strategies(2020-12) Rivera-Hechem, María; Rodríguez-Sickert, Carlos; Guzmán, Ricardo A.; Ramírez-Parada, Tadeo; Benavides, Felipe; Landaeta-Torres, Víctor; Repetto, Gabriela; Aspé-Sánchez, MauricioThe effort to understand the genetic basis of human sociality has been encouraged by the diversity and heritability of social traits like cooperation. This task has remained elusive largely because most studies of sociality and genetics use sample sizes that are often unable to detect the small effects that single genes may have on complex social behaviors. The lack of robust findings could also be a consequence of a poor characterization of social phenotypes. Here, we explore the latter possibility by testing whether refining measures of cooperative phenotypes can increase the replication of previously reported associations between genetic variants and cooperation in small samples. Unlike most previous studies of sociality and genetics, we characterize cooperative phenotypes based on strategies rather than actions. Measuring strategies help differentiate between similar actions with different underlaying social motivations while controlling for expectations and learning. In an admixed Latino sample (n = 188), we tested whether cooperative strategies were associated with three genetic variants thought to influence sociality in humans—MAOA-uVNTR, OXTR rs53576, and AVPR1 RS3. We found no association between cooperative strategies and any of the candidate genetic variants. Since we were unable to replicate previous observations our results suggest that refining measurements of cooperative phenotypes as strategies is not enough to overcome the inherent statistical power problem of candidate gene studies.Item Partial microduplication in the histone acetyltransferase complex member KANSL1 is associated with congenital heart defects in 22q11.2 microdeletion syndrome patients(Nature, 2017) Leon, Luis; Benavides, Felipe; Karena, Espinoza; Vial, Cecilia; Alvarez, Patricia; Palomares, Mirta; Lay-Son, Guillermo; Miranda, Macarena; Repetto, Gabriela22q11.2 microdeletion syndrome (22q11.2DS) is the most common microdeletion disorder in humans, with an incidence of 1/4000 live births. It is caused by a heterozygous deletion of 1.5–3 Mb on chromosome region 22q11.2. Patients with the deletion present features that include neuropsychiatric problems, craniofacial abnormalities and cardiovascular malformations. However, the phenotype is highly variable and the factors related to the clinical heterogeneity are not fully understood. About 65% of patients with 22q11.2DS have congenital heart defects (CHD). The main goal of this study was to identify common CNVs in 22q11.2DS patients that could be associated with the incomplete penetrance of CHD. Analysis of genomic DNA from 253 patients with 22q11.2DS using array technology showed an association between a microduplication located in region 17q21.31 and CHD (p-value = 0.023, OR = 2.75, 95% CI = 1.17–7.03). This region includes the first three exons of KANSL1 gene. Bioinformatic analysis showed that KANSL1 and CRKL, a gene in the commonly deleted region of 22q11.2DS, are part of the same regulatory module in a miRNA-mRNA network. These results show that a KANSL1 microduplication, in combination with the 22q11.2 deletion, is associated with increased risk of CHD in these patients, suggesting that KANSL1 plays a role as a modifier gene in 22q11.2DS patients.Item Síndrome de Rett: análisis molecular del gen MECP2 en pacientes chilenas(2019) Aron, Carolina; Rauch, Geraldinne; Benavides, Felipe; Repetto, GabrielaEl síndrome de Rett (RTT) es un trastorno neurológico progresivo caracterizado por producir una regresión del desarrollo psicomotor en niñas previamente sanas. La mayoría de los casos son causados por variantes patogénicas en el gen MECP2, que codifica para la proteína methyl CpGbinding protein 2. Objetivo: Describir la frecuencia y el tipo de variantes patogénicas en MECP2 en mujeres chilenas con diagnóstico clínico de RTT. Pacientes y Método: Se invitó a participar en este estudio a mujeres chilenas con sospecha clínica de RTT. Se reunió información clínica mediante un cuestionario. Se analizaron variantes patogénicas en MECP2 mediante el método de secuenciación de Sanger y se utilizó Multiple Ligation-dependant Probe Amplification (MLPA) para la detección de duplicaciones y deleciones. Resultado: El estudio incluyó 14 pacientes con sospecha de RTT, de las cuales 8 (57%) pacientes tuvieron variantes patogénicas. Las restantes permanecen sin diagnóstico molecular. Conclusión: Variantes patogénicas en MECP2 están presentes en pacientes chilenas con RTT. Es probable que haya otros genes o diagnósticos involucrados en las pacientes sin hallazgos en MECP2. A partir de este trabajo, el diagnóstico molecular está disponible en Chile.Item Somatic Mosaicism for Paternal Uniparental Disomy of 11p15.5 Region in Adrenal and Liver Tissues in a Newborn with Atypical Beckwith-Wiedemann Syndrome(2019) Urzúa, Abraham; Burattini, Sofía; Pinochet, Constanza; Benavides, Felipe; Repetto, GabrielaBeckwith-Wiedemann syndrome (BWS) is characterized by overgrowth and increased risk of embryonic tumors. It results from alterations in genes controlled by imprinting centers H19DMR (Imprinting Center [IC] 1) and KvDMR (IC2). Strategies for diagnostic confirmation include methylation analysis and CDKN1C sequencing. We present a newborn with placentomegaly, hyperinsulinism and adrenal cytomegaly, but no typical external features of BWS. The patient had normal genetic studies in blood. However, adrenal and liver tissues showed hypermethylation of IC1 and hypomethylation of IC2. Microsatellite analysis confirmed mosaic paternal uniparental disomy. This study demonstrates the importance of analyzing additional tissues to reduce underdiagnosis of somatic mosaicism in BWS.