RESUMEN
The mild activity of basaltic volcanoes is punctuated by violent explosive eruptions that occur without obvious precursors. Modelling the source processes of these sudden blasts is challenging. Here, we use two decades of ground deformation (tilt) records from Stromboli volcano to shed light, with unprecedented detail, on the short-term (minute-scale) conduit processes that drive such violent volcanic eruptions. We find that explosive eruptions, with source parameters spanning seven orders of magnitude, all share a common pre-blast ground inflation trend. We explain this exponential inflation using a model in which pressure build-up is caused by the rapid expansion of volatile-rich magma rising from depth into a shallow (<400 m) resident magma conduit. We show that the duration and amplitude of this inflation trend scales with the eruption magnitude, indicating that the explosive dynamics obey the same (scale-invariant) conduit process. This scale-invariance of pre-explosion ground deformation may usher in a new era of short-term eruption forecasting.
RESUMEN
BACKGROUND: Array-comparative genomic hybridization (array-CGH) is a widely used technique to detect copy number variants (CNVs) associated with developmental delay/intellectual disability (DD/ID). AIMS: Identification of genomic disorders in DD/ID. MATERIALS AND METHODS: We performed a comprehensive array-CGH investigation of 1,015 consecutive cases with DD/ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs. RESULTS: We identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries probably affecting the regulatory landscape. DISCUSSION AND CONCLUSION: We show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects.
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Proteínas de Unión al ADN/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Adolescente , Adulto , Niño , Preescolar , Efectos de la Posición Cromosómica/genética , Aberraciones Cromosómicas , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/patología , Femenino , Estudios de Asociación Genética , Genómica , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Linaje , Fenotipo , Eliminación de Secuencia/genética , Adulto JovenRESUMEN
We provide data on fetal growth pattern on the molecular subtypes of Beckwith-Wiedemann syndrome (BWS): IC1 gain of methylation (IC1-GoM), IC2 loss of methylation (IC2-LoM), 11p15.5 paternal uniparental disomy (UPD), and CDKN1C mutation. In this observational study, gestational ages and neonatal growth parameters of 247 BWS patients were compared by calculating gestational age-corrected standard deviation scores (SDS) and proportionality indexes to search for differences among IC1-GoM (n = 21), UPD (n = 87), IC2-LoM (n = 147), and CDKN1C mutation (n = 11) patients. In IC1-GoM subgroup, weight and length are higher than in other subgroups. Body proportionality indexes display the following pattern: highest in IC1-GoM patients, lowest in IC2-LoM/CDKN1C patients, intermediate in UPD ones. Prematurity was significantly more prevalent in the CDKN1C (64%) and IC2-LoM subgroups (37%). Fetal growth patterns are different in the four molecular subtypes of BWS and remarkably consistent with altered gene expression primed by the respective molecular mechanisms. IC1-GoM cases show extreme macrosomia and severe disproportion between weight and length excess. In IC2-LoM/CDKN1C patients, macrosomia is less common and associated with more proportionate weight/length ratios with excess of preterm birth. UPD patients show growth patterns closer to those of IC2-LoM, but manifest a body mass disproportion rather similar to that seen in IC1-GoM cases.
Asunto(s)
Síndrome de Beckwith-Wiedemann/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Metilación de ADN , Desarrollo Fetal/genética , Impresión Genómica , Disomía Uniparental , Antropometría , Síndrome de Beckwith-Wiedemann/clasificación , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/patología , Cromosomas Humanos Par 11/química , Feto , Expresión Génica , Genotipo , Edad Gestacional , Humanos , Recién Nacido , Mutación , Fenotipo , Nacimiento PrematuroRESUMEN
Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.
Asunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Proteínas de Unión al ADN/genética , Cara/anomalías , Estudios de Asociación Genética , Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/genética , Mutación , Proteínas de Neoplasias/genética , Enfermedades Vestibulares/diagnóstico , Enfermedades Vestibulares/genética , Facies , Femenino , Humanos , Masculino , Fenotipo , Análisis de Secuencia de ADNRESUMEN
OBJECTIVE: Noonan syndrome (NS) is a common autosomal dominant developmental disorder, mainly characterized by congenital heart defects, short stature, and a variable degree of developmental delay. We have reviewed the prenatal findings in NS and we have correlated them with genotype and postnatal phenotype. METHODS: The cohort consisted of 47 patients with molecular diagnosis of NS. Prenatal and postnatal phenotypes were assessed by analysis of medical records, and clinical follow-up. Postnatal clinical phenotype, congenital heart disease, neuropsychomotor development, and growth pattern were arbitrarily scored in terms of severity. RESULTS: Mean age at diagnosis of NS was 7 years (ranging from birth to 38 years). Abnormal maternal serum triple screen was present in 36% of cases, nuchal translucency > 2.5 mm in 41%, polyhydramnios in 38% and fetal anomalies at prenatal ultrasonography in 21%. No statistical association was observed between prenatal findings and NS genotype or scores of postnatal clinical phenotype, congenital heart disease, neuropsychomotor development, or short stature. Presence of morphologic fetal anomalies at ultrasonography was associated with developmental delay/intellectual disabilities (p < 0.001) and juvenile myelomonocytic leukaemia (p = 0.006). CONCLUSIONS: Abnormal prenatal findings are frequent in NS pregnancies, though they are not specific and most are not useful for the prediction of the postnatal phenotype.
Asunto(s)
Enfermedades Fetales/diagnóstico , Síndrome de Noonan/diagnóstico , Diagnóstico Prenatal/métodos , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Anomalías Congénitas/diagnóstico , Anomalías Congénitas/epidemiología , Anomalías Congénitas/genética , Femenino , Enfermedades Fetales/epidemiología , Enfermedades Fetales/genética , Genotipo , Humanos , Lactante , Recién Nacido , Italia/epidemiología , Masculino , Síndrome de Noonan/epidemiología , Síndrome de Noonan/genética , Medida de Translucencia Nucal , Fenotipo , Polihidramnios/diagnóstico , Polihidramnios/epidemiología , Embarazo , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
Megalencephaly is as a rule accompanied by macrocephaly, an occipitofrontal circumference (OFC) greater than the 98th percentile. Megalencephaly is divided into an anatomic type (developmental) and a metabolic type. Metabolic megalencephaly refers to various storage and degenerative encephalopathies. The differential diagnosis includes Alexander's disease, Canavan's disease, glutaric aciduria type 1, GM1 and GM2 gangliosidosis, merosin-deficient variant of congenital muscular dystrophy and megalencephalic leukoencephalopathy with subcortical cysts (MLC). The distinctive features of this syndrome are enlarged cranial circumference, present at birth or starting in the first year of life, and magnetic resonance imaging (MRI) evidence of diffuse with matter abnormalities with subcortical cysts in the tips of the temporal lobes and in frontoparietal subcortical areas. Mutations in the MLC1 gene have been found as causative of MLC in 60-70 % of affected subjects, without genotype-phenotype correlation. The child we describe presented with progressive macrocephaly not associated with dysmorphic features and large abdominoscrotal hydrocele. At the age of 8 months, encephalic MRI showed anomalies suggestive for MLC and brainstem auditory evoked potentials (BAEP) documented alterations of signal conduction in right tracts. At the time, clinical neurologic examination was normal. Extensive metabolic assays were within normal range. Sequence analysis for MLC1 gene revealed a compound heterozygosity for two mutations in MLC1 gene, inherited from healthy non consanguineous parents.
Asunto(s)
Proteínas de la Membrana/genética , Mutación , Quistes/complicaciones , Quistes/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/complicaciones , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Humanos , Masculino , Megalencefalia/etiologíaRESUMEN
Microdeletions and microduplications in the human genome, termed genomic disorders, contribute to a high proportion of human multisystemic neurodevelopmental diseases and are detected by array-based comparative genomic hybridization (aCGH). In general, most genomic disorders are associated with craniofacial and skeletal features and behavioural abnormalities, in addition to learning disability and developmental delay (LD/DD). Specifically, recognition of a characteristic 'facial gestalt' has been the key to distinguish one genomic disorder from the other. Here, we report our experience concerning the relevance of abnormal eyebrow pattern as a diagnostic indicator of specific genomic disorders.
Asunto(s)
Cejas/anomalías , Enfermedades Genéticas Congénitas/diagnóstico , Anomalías Múltiples/genética , Humanos , FenotipoRESUMEN
Ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) syndrome is an autosomal dominant form of ectodermal dysplasia associated with limb anomalies and orofacial clefting. The TP63 gene has been shown to be the cause of the disease, and some tentative genotype-phenotype correlations have been reported. We describe a familial case of EEC syndrome, diagnosed in two siblings affected by severe ectrodactyly and mild ectodermal dysplasia, without clefting. Moreover, one of the siblings had a history of delayed developmental milestones in the first years of life. Family history revealed mild hand malformations in the father and grandfather, who were not available for clinical evaluation. The TP63 gene molecular study showed in both siblings a heterozygous H208D mutation, which has not been previously reported to our knowledge, suggesting that this molecular lesion is associated with EEC syndrome without orofacial clefting.
Asunto(s)
Displasia Ectodérmica/genética , Deformidades Congénitas del Pie/genética , Deformidades Congénitas de la Mano/genética , Mutación/genética , Transactivadores/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Niño , Labio Leporino/genética , Fisura del Paladar/genética , Femenino , Genotipo , Humanos , Masculino , Fenotipo , Hermanos , Factores de TranscripciónRESUMEN
Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene, and characterized by typical face, moderate-to-severe mental retardation, epilepsy, Hirschsprung disease, and multiple congenital anomalies, including genital anomalies (particularly hypospadias in males), congenital heart defects, agenesis of the corpus callosum, and eye defects. Since the first delineation by Mowat et al. [Mowat et al. (1998); J Med Genet 35:617-623], approximately 179 patients with ZEB2 mutations, deletions or cytogenetic abnormalities have been reported primarily from Europe, Australia and the United States. Genetic defects include chromosome 2q21-q23 microdeletions (or different chromosome rearrangements) in few patients, and ZEB2 mutations in most. We report on clinical and genetic data from 19 Italian patients, diagnosed within the last 5 years, including six previously published, and compare them with patients already reported. The main purpose of this review is to underline a highly consistent phenotype and to highlight the phenotypic evolution occurring with age, particularly of the facial characteristics. The prevalence of MWS is likely to be underestimated. Knowledge of the phenotypic spectrum of MWS and of its changing phenotype with age can improve the detection rate of this condition.
Asunto(s)
Anomalías Múltiples/genética , Envejecimiento/fisiología , Anomalías Craneofaciales/genética , Proteínas de Homeodominio/genética , Fenotipo , Proteínas Represoras/genética , Anomalías Múltiples/diagnóstico , Adolescente , Niño , Preescolar , Cromosomas Artificiales Bacterianos , Dextranos/metabolismo , Femenino , Colorantes Fluorescentes/metabolismo , Heterocigoto , Enfermedad de Hirschsprung/genética , Humanos , Hibridación Fluorescente in Situ , Indoles/metabolismo , Lactante , Discapacidad Intelectual/genética , Italia , Masculino , Mutación , Hibridación de Ácido Nucleico , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Síndrome , Adulto Joven , Caja Homeótica 2 de Unión a E-Box con Dedos de ZincRESUMEN
Using array comparative genome hybridisation (CGH) 41 de novo reciprocal translocations and 18 de novo complex chromosome rearrangements (CCRs) were screened. All cases had been interpreted as "balanced" by conventional cytogenetics. In all, 27 cases of reciprocal translocations were detected in patients with an abnormal phenotype, and after array CGH analysis, 11 were found to be unbalanced. Thus 40% (11 of 27) of patients with a "chromosomal phenotype" and an apparently balanced translocation were in fact unbalanced, and 18% (5 of 27) of the reciprocal translocations were instead complex rearrangements with >3 breakpoints. Fourteen fetuses with de novo, apparently balanced translocations, all but two with normal ultrasound findings, were also analysed and all were found to be normal using array CGH. Thirteen CCRs were detected in patients with abnormal phenotypes, two in women who had experienced repeated spontaneous abortions and three in fetuses. Sixteen patients were found to have unbalanced mutations, with up to 4 deletions. These results suggest that genome-wide array CGH may be advisable in all carriers of "balanced" CCRs. The parental origin of the deletions was investigated in 5 reciprocal translocations and 11 CCRs; all were found to be paternal. Using customized platforms in seven cases of CCRs, the deletion breakpoints were narrowed down to regions of a few hundred base pairs in length. No susceptibility motifs were associated with the imbalances. These results show that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.
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Deleción Cromosómica , Trastornos de los Cromosomas/genética , Translocación Genética , Anomalías Múltiples/genética , Aborto Habitual/genética , Adulto , Preescolar , Rotura Cromosómica , Trastornos de los Cromosomas/patología , Pintura Cromosómica , Femenino , Enfermedades Fetales/genética , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Discapacidad Intelectual/genética , Masculino , Hibridación de Ácido Nucleico , Oogénesis , Fenotipo , Diagnóstico Prenatal , EspermatogénesisAsunto(s)
Anomalías Múltiples/genética , Párpados/anomalías , Adulto , Labio Leporino/genética , Fisura del Paladar/genética , Proteínas de Unión al ADN/genética , Displasia Ectodérmica/genética , Femenino , Humanos , Recién Nacido , Masculino , Mutación Puntual , Síndrome , Transactivadores/genética , Factores de Transcripción , Proteínas Supresoras de Tumor/genéticaRESUMEN
Sotos syndrome is characterized by pre- and post-natal overgrowth, typical craniofacial features, advanced bone age, and developmental delay. Some degree of phenotypic overlap exists with other overgrowth syndromes, in particular with Weaver syndrome. Sotos syndrome is caused by haploinsufficiency of the NSD1 (nuclear receptor SET domain containing gene 1) gene. Microdeletions involving the gene are the major cause of the syndrome in Japanese patients, whereas intragenic mutations are more frequent in non-Japanese patients. NSD1 aberrations have also been described in some patients diagnosed as Weaver syndrome. Some authors have suggested a certain degree of genotype-phenotype correlation, with a milder degree of overgrowth, a more severe mental retardation, and a higher frequency of congenital anomalies in microdeleted patients. Data on larger series are needed to confirm this suggestion. We report here on microdeletion and mutation analysis of NSD1 in 59 patients with congenital overgrowth. Fourteen novel mutations, two previously described and one microdeletion were identified. All patients with a NSD1 mutation had been clinically classified as "classical Sotos," although their phenotype analysis demonstrated that some major criteria, such as overgrowth and macrocephaly, could be absent. All patients with confirmed mutations shared the typical Sotos facial gestalt. A high frequency of congenital heart defects was present in patients with intragenic mutations, supporting the relevance of the NSD1 gene in the pathogenesis of this particular defect.
Asunto(s)
Trastornos del Crecimiento/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Proteínas Nucleares/genética , Adolescente , Niño , Preescolar , Cromatografía Líquida de Alta Presión/métodos , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Análisis Mutacional de ADN , Femenino , Trastornos del Crecimiento/congénito , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina , Humanos , Hibridación Fluorescente in Situ , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Proteínas Nucleares/metabolismo , Polimorfismo Genético , SíndromeRESUMEN
"Oligodontia" is the absence of 6 or more teeth, except the third molars. Genetic factors are important in determining hypodontia: in fact, this is an autosomal dominant trait relatively common in population. In particular, the agenesis of lateral incisors is fairly common, with autosomal dominant and variable expression inheritance. The incidence of hypodontia in primary dentition is 0.1-0.7% and there is no difference between females and males; instead, hypodontia in permanent dentition is most common in females compared with males and the incidence is 6-10% in general population. Oligodontia can interfere with the maxillofacial skeleton growth in children and adolescents. This problem must be tackled by paying attention to the physical and psychological development of the patient. A case of oligodontia in an 8-year-old-boy without 17 permanent teeth likely related to a variable expression genetic disorder is reported. The medical examination of the boy was completely negative, with the exception of the dentition. The child will be followed to value any possible maxillofacial abnormalities that might need an early therapy. The definitive therapeutic approach will be carried out, as soon as possible, using oral endo-osseous systems to allow normal masticatory and phonetic function.
Asunto(s)
Anomalías Dentarias/terapia , Niño , Humanos , Masculino , Radiografía , Anomalías Dentarias/diagnóstico por imagenRESUMEN
Asphyxiating thoracic dystrophy (ATD), or Jeune syndrome, is a multisystem autosomal recessive disorder associated with a characteristic skeletal dysplasia and variable renal, hepatic, pancreatic, and retinal abnormalities. We have performed a genome wide linkage search using autozygosity mapping in a cohort of four consanguineous families with ATD, three of which originate from Pakistan, and one from southern Italy. In these families, as well as in a fifth consanguineous family from France, we localised a novel ATD locus (ATD) to chromosome 15q13, with a maximum cumulative two point lod score at D15S1031 (Zmax=3.77 at theta=0.00). Five consanguineous families shared a 1.2 cM region of homozygosity between D15S165 and D15S1010. Investigation of a further four European kindreds, with no known parental consanguinity, showed evidence of marker homozygosity across a similar interval. Families with both mild and severe forms of ATD mapped to 15q13, but mutation analysis of two candidate genes, GREMLIN and FORMIN, did not show pathogenic mutations.
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Asfixia/genética , Mapeo Cromosómico , Cromosomas Humanos Par 15/genética , Osteocondrodisplasias/genética , Tórax/anomalías , Mapeo Cromosómico/métodos , Estudios de Cohortes , Consanguinidad , Femenino , Francia , Marcadores Genéticos , Haplotipos/genética , Humanos , Italia , Masculino , Pakistán , LinajeRESUMEN
A new case of the association of the Beckwith-Wiedemann and prune belly syndrome is reported and the aetiology of the syndromes discussed.
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Síndrome de Beckwith-Wiedemann/etiología , Síndrome del Abdomen en Ciruela Pasa/etiología , Síndrome de Beckwith-Wiedemann/patología , Humanos , Recién Nacido , Masculino , Síndrome del Abdomen en Ciruela Pasa/patologíaRESUMEN
Clinical diagnosis in dysmorphology is made by the recognition of a specific pattern of malformations and through an analytic search for discrete features. We present our personal experience regarding the usefulness of hair morphology as a tool for diagnosis in some metabolic and malformation syndromes. These cases represent only a few illustrative examples; an exhaustive review of the topic can be found elsewhere.
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Anomalías Múltiples/diagnóstico , Cabello/anomalías , Niño , Preescolar , Técnicas y Procedimientos Diagnósticos , Displasia Ectodérmica/diagnóstico , Femenino , Cabello/anatomía & histología , Humanos , Masculino , Síndrome del Pelo Ensortijado/diagnóstico , Enfermedades Mitocondriales/diagnóstico , SíndromeRESUMEN
We describe a girl with peculiar auricular dysmorphism, renal agenesis and supernumerary rib. Some different diagnostic hypotheses are discussed.
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Oído Externo/anomalías , Riñón/anomalías , Costillas/anomalías , Femenino , Humanos , Lactante , Seno Pilonidal , SíndromeRESUMEN
The molecular cause of the alpha-thalassemia/mental retardation syndrome (ATR-X) resides in mutations affecting the XNP/ATR-X gene. Recently molecular defects in the gene have been found in singular cases of a discrete number of X-linked mental retardation (XLMR). ATR-X-affected males are characterised by severe mental retardation, distinct facial dysmorphisms and genital abnormalities, besides a wide spectrum of pathological features and an extremely limited biological fitness. Given that molecular investigation of XNP/ATR-X mutations is made onerous by the length of the gene transcript, we carried out a prenatal diagnosis in a fetus at risk for ATR-X syndrome by initially determining the XNP/ATR-X gene haplotype before considering gene sequencing. Disease-associated haplotype analysis was performed selecting five genic (CA)n repeats that showed high heterozygosity (Het>0.7) in the general population. The fetus segregated an identical allelic pattern to that of the affected child of the family under investigation who shows features suggestive of the ATR-X syndrome. Subsequent mutational analysis of the gene revealed a novel IVS3+1G>T splicing mutation confirming the diagnosis.