Papers by Miguel Del Campo Casanelles
Los estudios sobre los procesos responsables del ensamblaje de las especies en comunidades ecológ... more Los estudios sobre los procesos responsables del ensamblaje de las especies en comunidades ecológicas tradicionalmente han considerado a las especies como unidades de estudio. Sin embargo, dentro de las especies existe gran cantidad de variación genotípica y fenotípica que puede finalmente ser decisiva en el resultado de las interacciones con el resto de especies en la comunidad (competencia, mutualismo, etc.) Recientemente se ha propuesto una nueva regla de ensamblaje de las comunidades que sugiere que la composición genética de una población afecta a la estructura y composición de la comunidad (es decir al fenotipo de la comunidad). Apoyando esta regla, varios estudios han demostrado que los cambios en la diversidad genética de poblaciones de plantas conllevan cambios predecibles en sus comunidades asociadas de herbívoros y predadores. Más allá de la visión poblacional, la nueva genética de comunidades pretende demostrar 1) que el genotipo particular de ciertos individuos es responsable del fenotipo de la comunidad, 2) que el fenotipo de la comunidad es heredable, y por lo tanto 3) que las comunidades evolucionan. Tras explicar estos tres conceptos, se discute el valor que esta aproximación puede tener desde el punto de vista de la biología de la conservación. Palabras clave: diversidad genética, diversidad de especies, estructura de comunidades, evolución de comunidades, fenotipo extendido, reglas de ensamblaje.
American journal of medical genetics. Part A, Jan 21, 2015
Despite remarkable progress in identifying causal genes for many types of genetic lipodystrophies... more Despite remarkable progress in identifying causal genes for many types of genetic lipodystrophies in the last decade, the molecular basis of many extremely rare lipodystrophy patients with distinctive phenotypes remains unclear. We conducted whole exome sequencing of the parents and probands from six pedigrees with neonatal onset of generalized loss of subcutaneous fat with additional distinctive phenotypic features and report de novo heterozygous null mutations, c.424C>T (p.Q142*) and c.479_480delTT (p.F160*), in CAV1 in a 7-year-old male and a 3-year-old female of European origin, respectively. Both the patients had generalized fat loss, thin mottled skin and progeroid features at birth. The male patient had cataracts requiring extraction at age 30 months and the female patient had pulmonary arterial hypertension. Dermal fibroblasts of the female patient revealed negligible CAV1 immunofluorescence staining compared to control but there were no differences in the number and morp...
Molecular Autism, 2015
Background: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with high... more Background: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with high heritability. Recent findings support a highly heterogeneous and complex genetic etiology including rare de novo and inherited mutations or chromosomal rearrangements as well as double or multiple hits. Methods: We performed whole-exome sequencing (WES) and blood cell transcriptome by RNAseq in a subset of male patients with idiopathic ASD (n = 36) in order to identify causative genes, transcriptomic alterations, and susceptibility variants. Results: We detected likely monogenic causes in seven cases: five de novo (SCN2A, MED13L, KCNV1, CUL3, and PTEN) and two inherited X-linked variants (MAOA and CDKL5). Transcriptomic analyses allowed the identification of intronic causative mutations missed by the usual filtering of WES and revealed functional consequences of some rare mutations. These included aberrant transcripts (PTEN, POLR3C), deregulated expression in 1.7% of mutated genes (that is, SEMA6B, MECP2, ANK3, CREBBP), allele-specific expression (FUS, MTOR, TAF1C), and nonsense mediated decay (RIT1, ALG9). The analysis of rare inherited variants showed enrichment in relevant pathways such as the PI3K-Akt signaling and the axon guidance. Conclusions: Integrative analysis of WES and blood RNAseq data has proven to be an efficient strategy to identify likely monogenic forms of ASD (19% in our cohort), as well as additional rare inherited mutations that can contribute to ASD risk in a multifactorial manner. Blood transcriptomic data, besides validating 88% of expressed variants, allowed the identification of missed intronic mutations and revealed functional correlations of genetic variants, including changes in splicing, expression levels, and allelic expression.
European journal of human genetics : EJHG, Jan 8, 2015
Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the id... more Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the identification of novel imbalances in individuals with intellectual disability (ID), autistic disorders and congenital malformations. Here we report a 'genotype…
PLoS ONE, 2014
Context: Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phen... more Context: Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus. Objective: To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. Patients: 5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency. Methods: SF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3). Results: Two novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4 th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI. Conclusions: Glu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations.
The American Journal of Human Genetics, 2012
Already 40 genes have been identified for autosomal-recessive nonsyndromic hearing impairment (ar... more Already 40 genes have been identified for autosomal-recessive nonsyndromic hearing impairment (arNSHI); however, many more genes are still to be identified. In a Dutch family segregating arNSHI, homozygosity mapping revealed a 2.4 Mb homozygous region on chromosome 11 in p15.1-15.2, which partially overlapped with the previously described DFNB18 locus. However, no putative pathogenic variants were found in USH1C, the gene mutated in DFNB18 hearing impairment. The homozygous region contained 12 additional annotated genes including OTOG, the gene encoding otogelin, a component of the tectorial membrane. It is thought that otogelin contributes to the stability and strength of this membrane through interaction or stabilization of its constituent fibers. The murine orthologous gene was already known to cause hearing loss when defective. Analysis of OTOG in the Dutch family revealed a homozygous 1 bp deletion, c.5508delC, which leads to a shift in the reading frame and a premature stop codon, p.Ala1838ProfsX31. Further screening of 60 unrelated probands from Spanish arNSHI families detected compound heterozygous OTOG mutations in one family, c.6347C>T (p.Pro2116Leu) and c. 6559C>T (p.Arg2187X). The missense mutation p.Pro2116Leu affects a highly conserved residue in the fourth von Willebrand factor type D domain of otogelin. The subjects with OTOG mutations have a moderate hearing impairment, which can be associated with vestibular dysfunction. The flat to shallow ''U'' or slightly downsloping shaped audiograms closely resembled audiograms of individuals with recessive mutations in the gene encoding a-tectorin, another component of the tectorial membrane. This distinctive phenotype may represent a clue to orientate the molecular diagnosis.
Alcoholism: Clinical and Experimental Research, 2006
Background: Accurate estimates of the prevalence and characteristics of fetal alcohol syndrome (F... more Background: Accurate estimates of the prevalence and characteristics of fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD) in a Western European population are lacking and are of particular interest in settings where the usual pattern of alcohol consumption is thought to be daily drinking with meals. To address these issues, an epidemiology study of FAS and other FASD was undertaken in Italian schools. Methods: Primary schools (n 5 25) in 2 health districts of the Lazio region were randomly selected and recruited for the study. Five hundred forty-three children, 50% of those enrolled in first-grade classes, received parental permission to participate in a 2-tiered, active case ascertainment screening process. Detailed evaluation of children selected in a preliminary screening phase was carried out on those who were small for height, weight, and head circumference and/or referred by teachers for suspected learning and behavioral problems. Detailed evaluation was carried out on each child's: (1) physical growth and dysmorphology, (2) psychological development and behavior, and (3) prenatal exposure to alcohol and other risk factors for FASD via maternal interviews. A group of 67 randomly selected children without FASD from the same classes was utilized as a comparison group. Results: Using 2 denominators for prevalence estimation, a conservative one and a strict samplebased estimate, the prevalence of FAS in this province of Italy was 3.7 to 7.4 per 1,000 children. When cases of partial FAS (PFAS) and a case of alcohol-related neurodevelopmental deficits (ARND) were added to FAS cases, the rate of FASD was 20.3 to 40.5 per 1,000 and estimated at 35 per 1,000 overall or between 2.3 and 4.1% of all children. This exceeds previously published estimates of both FAS and FASD for the western world. Detailed data are presented that demonstrate the utility of the guidelines of the revised Institute of Medicine diagnostic criteria for FASD. Children with FASD are significantly more impaired/affected (po0.05) than randomly selected comparison children on all measures of growth deficiency, key facial features of FASD, overall dysmorphology scores, language comprehension, nonverbal IQ, and behavior. Maternal reports of current drinking were significantly higher for mothers of FASD children than comparison mothers, but reported rates of overall drinking during pregnancy were not significantly different. In contrast to expectations, daily drinking among mothers of the comparison group was not common. However, dysmorphology scores of the children were significantly correlated with drinking in the second and third trimesters, drinks per current drinking day, and current drinks per month. Finally, children with the physical features of FASD had lower IQs; nonverbal IQ was significantly correlated with head circumference and negatively correlated with overall dysmorphology score, smooth philtrum, and several other facial and physical anomalies characteristic of FAS. Conclusions: Using careful measures of ascertainment in a primary school setting, these results provide relatively high estimates of the prevalence of FASD and raise the question of whether FASD is more common in the western world than previously estimated.
American journal of medical genetics. Part A, 2017
In October 2015, Zika virus (ZIKV) outbreak the Brazilian Ministry of Health (MoH). In response, ... more In October 2015, Zika virus (ZIKV) outbreak the Brazilian Ministry of Health (MoH). In response, the Brazilian Society of Medical Genetics established a task force (SBGM-ZETF) to study the phenotype of infants born with microcephaly due to ZIKV congenital infection and delineate the phenotypic spectrum of this newly recognized teratogen. This study was based on the clinical evaluation and neuroimaging of 83 infants born during the period from July, 2015 to March, 2016 and registered by the SBGM-ZETF. All 83 infants had significant findings on neuroimaging consistent with ZIKV congenital infection and 12 had confirmed ZIKV IgM in CSF. A recognizable phenotype of microcephaly, anomalies of the shape of skull and redundancy of the scalp consistent with the Fetal Brain Disruption Sequence (FBDS) was present in 70% of infants, but was most often subtle. In addition, features consistent with fetal immobility, ranging from dimples (30.1%), distal hand/finger contractures (20.5%), and feet ...
Ultrasound in Obstetrics and Gynecology, 2006
Journal of the Endocrine Society, 2019
Abstract Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors associated... more Abstract Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors associated with many genes. Recently, the fumarate hydratase gene (FH) has been implicated. We describe a case of a child evaluated for PCC who was found to have a variant in FH. A 7y5mo female was referred to our pediatric endocrinology clinic for evaluation of possible PCC. Family history included 3 relatives with reported early-onset PCC (ages 8-15), including mother (alive), maternal uncle and maternal grandfather (both deceased). There was reported thyroid disease in maternal grandmother, but no other family history of conditions seen with PCC-related syndromes. The patient was healthy aside from obesity until developing headaches 5 mo prior to visit with us. Given her family history, 24-hr urine collection for catecholamines was done which showed marked elevations in urine metanephrines, normetanephrines, norepinephrine, and dopamine compared to lab reference ranges. Contrast-enhanced abdominal CT was normal by report. At the time of her visit, headaches had improved. Exam was notable for high BP at >95th percentile for height (no prior hypertension diagnosis) and obesity; there were no mucosal neuromas and thyroid exam was normal. We arranged for plasma fractionated metanephrine and normetanephrine testing and checked prolactin, gastrin, calcitonin, calcium, phosphorus, and vitamin D levels. All labs were unremarkable. MIBG scan was normal. 24-hr urine free metanephrine testing was repeated and normal. She was seen in our genetics division and tested for PCC-associated genes. A heterozygous variant in FH, c.925C>T (p.Pro309Ser), was found. This variant was classified as of uncertain significance and is present in population databases but has not been described with FH-related disease. FH is associated with autosomal dominant hereditary leiomyomatosis and renal cell cancer (HLRCC), and has early evidence of correlation with hereditary PCC/PGL. We present a case of a child who was initially suspected to have PCC based on family history, headaches, and elevated urine catecholamines but who had normal results on confirmatory testing. She was found to have a FH variant, p.Pro309Ser, classified as uncertain in significance but which we believe may be disease-causing in this family; testing for the variant in her mother is being pursued. To our knowledge, only one case of a FH mutation associated with PCC in a child has been published. On a practical note, the patient’s fluctuating urine catecholamines may have been due to large volume on initial sample, which did not occur on the second sample; it is important to consider urine volume when interpreting urine catecholamine results. This case also highlights the impact on management that targeted genetic testing can have: knowledge of FH’s association with non-PCC conditions prompts consideration of additional screening that might not be performed for PCC alone.
Revista de Neurología, 2014
Introduccion. El sindrome de Pallister-Killian se caracteriza por discapacidad intelectual, hipot... more Introduccion. El sindrome de Pallister-Killian se caracteriza por discapacidad intelectual, hipotonia, retraso motor y un fenotipo caracteristico en el que destaca un aspecto facial tosco, alteraciones pigmentarias de la piel y alopecia bitemporal. Es frecuente que se asocie a crisis convulsivas y a malformaciones en otros organos y sistemas. Tiene como causa principal el mosaicismo para la tetrasomia del cromosoma 12p. Casos clinicos. Se presentan tres nuevos casos pediatricos afectos de esta rara entidad, se describen las caracteristicas clinicas y se realiza una revision de la bibliografia. Conclusiones. Debe resaltarse la importancia del conocimiento del sindrome para poder llevar a cabo su diagnostico, puesto que lo habitual es que, sin practicar la biopsia cutanea o el frotis de mucosa bucal, la anomalia cromosomica pasa desapercibida si se usan tecnicas citogeneticas clasicas. Hoy en dia, es posible realizar el diagnostico en sangre mediante array-CGH o array-SNP, si bien la posibilidad de encontrar la anomalia cromosomica depende del porcentaje de mosaicismo.
Pediatria de Atencion Primaria
Revista de neurologia, Jan 7, 2006
Williams syndrome is a developmental disorder with an estimated prevalence of 1 in 7,500 newborns... more Williams syndrome is a developmental disorder with an estimated prevalence of 1 in 7,500 newborns. Its phenotype is characterized by distinctive facial features, mild to moderate mental retardation and general cognitive deficits with a non-uniform profile, having problems in some areas (psychomotricity, visuospatial integration) and relative preservation of others (language, musicality), friendly personality, occasional hypercalcemia of infancy, and a vasculopathy with supravalvular aortic stenosis. Williams syndrome is caused by a submicroscopic deletion of 1.55 Mb in the chromosome band 7q11.23, which includes 26-28 genes. The mutational mechanism consists in a misalignment between regions of almost identical sequence and the subsequent unequal recombination. The reciprocal product of this rearrangement is the duplication of this region, causing a language specific disorder. Clinical-molecular correlations establishment through a good phenotypic characterization and the precise an...
Revista de neurologia, Jan 15, 2005
Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are two neurop... more Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are two neuropsychiatric disorders beginning in childhood that present a high degree of familial aggregation. ASD is characterised by social interaction and communication disorders, whereas patients with ADHD display persistent inattention and/or hyperactive-impulsive behaviour. With the exception of a few cases of autism in which cytogenetic anomalies or mutations have been reported in specific genes, the aetiology of these diseases remains unknown. This is a group of multifactorial diseases with several genes having a lesser effect and there is also an environmental component. Genetic linkage studies have pointed to about 20 chromosomal regions that could well contain genes that grant susceptibility to autism, to ADHD or to both disorders. The challenge to researchers lies in the clinical characterisation, recruitment of patients with ASD and ADHD, gene dosage quantification studies, comparative gen...
Anales españoles de pediatría, 2001
Anales españoles de pediatría, 1997
Cytogenetic and genome research, Jan 14, 2015
Very few cases of constitutional interstitial deletions of the proximal short arm of chromosome 3... more Very few cases of constitutional interstitial deletions of the proximal short arm of chromosome 3 have been reported; however, the proximal 3p deletion is emerging as a clinically recognizable syndrome. We present an intrachromosomal insertion of 3p12.3p14.1 in a phenotypic normal man (46,XY,ins(3)(p25p12.3p14.1)) which is responsible for the unbalanced karyotype in 2 affected offspring, one with a 3p12.3p14.1 interstitial deletion and the other with a reciprocal duplication. The exceptionality of these 2 reciprocal recombinants contributes to a better definition of the proximal 3p deletion syndrome and its duplication counterpart. © 2015 S. Karger AG, Basel.
Uploads
Papers by Miguel Del Campo Casanelles