RESUMO
PURPOSE: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system. METHODS: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences. RESULTS: Metabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models. CONCLUSION: A general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients.
Assuntos
Proteínas Ferro-Enxofre , Peixe-Zebra , Animais , Humanos , Proteínas Ferro-Enxofre/genética , Proteínas Ferro-Enxofre/metabolismo , Masculino , Feminino , Fenótipo , Fibroblastos/metabolismo , Fibroblastos/patologia , Citosol/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Microcefalia/genética , Microcefalia/patologia , Lactente , MetalochaperonasRESUMO
Mutations in KDM5C are an important cause of X-linked intellectual disability in males. KDM5C encodes a histone demethylase, suggesting that alterations in chromatin landscape may contribute to disease. We used primary patient cells and biochemical approaches to investigate the effects of patient mutations on KDM5C expression, stability and catalytic activity. We report and characterize a novel nonsense mutation, c.3223delG (p.V1075Yfs*2), which leads to loss of KDM5C protein. We also characterize two KDM5C missense mutations, c.1439C>T (p.P480L) and c.1204G>T (p.D402Y) that are compatible with protein production, but compromise stability and enzymatic activity. Finally, we demonstrate that a c.2T>C mutation in the translation initiation codon of KDM5C results in translation re-start and production of a N-terminally truncated protein (p.M1_E165del) that is unstable and lacks detectable demethylase activity. Patient fibroblasts do not show global changes in histone methylation but we identify several up-regulated genes, suggesting local changes in chromatin conformation and gene expression. This thorough examination of KDM5C patient mutations demonstrates the utility of examining the molecular consequences of patient mutations on several levels, ranging from enzyme production to catalytic activity, when assessing the functional outcomes of intellectual disability mutations.
Assuntos
Histona Desmetilases/genética , Deficiência Intelectual/genética , Mutação , Adolescente , Adulto , Idoso , Criança , Cromatina/enzimologia , Cromatina/genética , Estabilidade Enzimática , Feminino , Genes Ligados ao Cromossomo X , Histona Desmetilases/metabolismo , Histonas/metabolismo , Humanos , Lactente , Deficiência Intelectual/enzimologia , Masculino , Metilação , Adulto JovemRESUMO
Opitz-Kaveggia syndrome (also known as FG syndrome) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. We report here that the original family for whom the condition is named and five other families have a recurrent mutation (2881C>T, leading to R961W) in MED12 (also called TRAP230 or HOPA), a gene located at Xq13 that functions as a thyroid receptor-associated protein in the Mediator complex.
Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação , Receptores dos Hormônios Tireóideos/genética , Substituição de Aminoácidos/genética , Arginina/genética , Família , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Complexo Mediador , Hipotonia Muscular/genética , Linhagem , Síndrome , Triptofano/genéticaRESUMO
Uniparental disomy (UPD) for imprinted chromosomes can cause abnormal phenotypes due to absent or overexpression of imprinted genes. UPD(14)pat causes a unique constellation of features including thoracic skeletal anomalies, polyhydramnios, placentomegaly, and limited survival; its hypothesized cause is overexpression of paternally expressed RTL1, due to absent regulatory effects of maternally expressed RTL1as. UPD(14)mat causes a milder condition with hypotonia, growth failure, and precocious puberty; its hypothesized cause is absence of paternally expressed DLK1. To more clearly establish how gains and losses of imprinted genes can cause disease, we report six individuals with copy number variations of the imprinted 14q32 region identified through clinical microarray-based comparative genomic hybridization. Three individuals presented with UPD(14)mat-like phenotypes (Temple syndrome) and had apparently de novo deletions spanning the imprinted region, including DLK1. One of these deletions was shown to be on the paternal chromosome. Two individuals with UPD(14)pat-like phenotypes had 122-154kb deletions on their maternal chromosomes that included RTL1as but not the differentially methylated regions that regulate imprinted gene expression, providing further support for RTL1 overexpression as a cause for the UPD(14)pat phenotype. The sixth individual is tetrasomic for a 1.7Mb segment, including the imprinted region, and presents with intellectual disability and seizures but lacks significant phenotypic overlap with either UPD(14) syndrome. Therefore, the 14q32 imprinted region is dosage sensitive, with deletions of different critical regions causing UPD(14)mat- and UPD(14)pat-like phenotypes, while copy gains are likely insufficient to recapitulate these phenotypes.
Assuntos
Cromossomos Humanos Par 14 , Variações do Número de Cópias de DNA , Estudos de Associação Genética , Família Multigênica , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Duplicação Cromossômica , Hibridização Genômica Comparativa , Fácies , Feminino , Loci Gênicos , Impressão Genômica , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Dissomia Uniparental , Adulto JovemRESUMO
Intellectual developmental disorders (IDD), characterized by significant impairment of cognitive functions, with limitations of learning, adaptive behavior and skills, are frequent (2.5% of the population affected) and present with significant co-morbidity. The burden of IDD, in terms of emotional suffering and associated health care costs, is significant; prevention and treatment therefore are important. A systematic literature review, updated in 2013, identified 89 inborn errors of metabolism (IEMs), which present with IDD as prominent feature and are amenable to causal therapy. Therapeutic effects include improvement and/or stabilization of psychomotor/cognitive development, behavior/psychiatric disturbances, seizures, neurologic and systemic manifestations. The levels of available evidence for the various treatments range from Level 1b, c (n=5); Level 2a, b, c (n=14); Level 4 (n=53), and Levels 4-5 (n=27). For a target audience comprising clinical and biochemical geneticists, child neurologists and developmental pediatricians, five experts translated....this data into a 2-tiered diagnostic algorithm: The first tier comprises metabolic "screening" tests in urine and blood, which are relatively accessible, affordable, less invasive, and have the potential to identify 60% of all treatable IEMs. The second tier investigations for the remaining disorders are ordered based on individual clinical signs and symptoms. This algorithm is supported by an App www.treatable-id.org, which comprises up-to-date information on all 89 IEMs, relevant diagnostic tests, therapies and a search function based on signs and symptoms. These recommendations support the clinician in early identification of treatable IEMs in the child with IDD, allowing for timely initiation of therapy with the potential to improve neurodevelopmental outcomes. The need for future studies to determine yield and usefulness of these recommendations, with subsequent updates and improvements to developments in the field, is outlined.
Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiência Intelectual/diagnóstico , Internet , Algoritmos , Criança , Custos e Análise de Custo , Deficiências do Desenvolvimento/economia , Deficiências do Desenvolvimento/terapia , Diretrizes para o Planejamento em Saúde , Humanos , Deficiência Intelectual/economia , Deficiência Intelectual/terapia , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/economia , Erros Inatos do Metabolismo/terapiaRESUMO
Genetic testing for intellectual disability, global developmental delay and other neurodevelopmental disorders has advanced considerably in the last five to ten years and can be an important diagnostic tool for clinicians. This article provides a clinical and ethical framework for understanding these advances, future directions and the current limitations of these approaches.
Assuntos
Deficiências do Desenvolvimento , Testes Genéticos/métodos , Deficiência Intelectual , Criança , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Testes Genéticos/tendências , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genéticaRESUMO
SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.
Assuntos
Transtornos Dismórficos Corporais/genética , Deficiências do Desenvolvimento/genética , Haploinsuficiência , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos Mentais/genética , Fatores de Transcrição SOXD/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Cromossomos Humanos Par 12 , Feminino , Humanos , MasculinoRESUMO
We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers.
Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas , Fatores de Crescimento Neural/genética , Duplicações Segmentares Genômicas/genética , Deleção de Sequência , Proteínas Vesiculares de Transporte de Acetilcolina/genética , Criança , Pré-Escolar , Mapeamento Cromossômico , Cromossomos Humanos Par 10 , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Feminino , Variação Genética , Recombinação Homóloga , Humanos , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , PenetrânciaRESUMO
Down syndrome (DS), or trisomy 21, is a common disorder associated with several complex clinical phenotypes. Although several hypotheses have been put forward, it is unclear as to whether particular gene loci on chromosome 21 (HSA21) are sufficient to cause DS and its associated features. Here we present a high-resolution genetic map of DS phenotypes based on an analysis of 30 subjects carrying rare segmental trisomies of various regions of HSA21. By using state-of-the-art genomics technologies we mapped segmental trisomies at exon-level resolution and identified discrete regions of 1.8-16.3 Mb likely to be involved in the development of 8 DS phenotypes, 4 of which are congenital malformations, including acute megakaryocytic leukemia, transient myeloproliferative disorder, Hirschsprung disease, duodenal stenosis, imperforate anus, severe mental retardation, DS-Alzheimer Disease, and DS-specific congenital heart disease (DSCHD). Our DS-phenotypic maps located DSCHD to a <2-Mb interval. Furthermore, the map enabled us to present evidence against the necessary involvement of other loci as well as specific hypotheses that have been put forward in relation to the etiology of DS-i.e., the presence of a single DS consensus region and the sufficiency of DSCR1 and DYRK1A, or APP, in causing several severe DS phenotypes. Our study demonstrates the value of combining advanced genomics with cohorts of rare patients for studying DS, a prototype for the role of copy-number variation in complex disease.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 21/genética , Síndrome de Down/genética , Trissomia/genética , Humanos , Lactente , Metanálise como Assunto , FenótipoRESUMO
OBJECTIVE: To measure the co-morbidities associated with Down syndrome compared with those in other children with special health care needs (CSHCN). Additionally, to examine reported access to care, family impact, and unmet needs for children with Down syndrome compared with other CSHCN. STUDY DESIGN: An analysis was conducted on the nationally representative 2005 to 2006 National Survey of Children with Special Health Care Needs. Bivariate analyses compared children with Down syndrome with all other CSHCN. Multivariate analyses examined the role of demographic, socioeconomic, and medical factors on measures of care receipt and family impact. RESULTS: An estimated 98,000 CSHCN have Down syndrome nationally. Compared with other CSHCN, children with Down syndrome had a greater number of co-morbid conditions, were more likely to have unmet needs, faced greater family impacts, and were less likely to have access to a medical home. These differences become more pronounced for children without insurance and from low socioeconomic status families. CONCLUSIONS: Children with Down syndrome disproportionately face greater disease burden, more negatively pronounced family impacts, and greater unmet needs than other CSHCN. Promoting medical homes at the practice level and use of those services by children with Down syndrome and other CSHCN may help mitigate these family impacts.
Assuntos
Efeitos Psicossociais da Doença , Crianças com Deficiência , Síndrome de Down/economia , Síndrome de Down/epidemiologia , Família , Acessibilidade aos Serviços de Saúde , Criança , Comorbidade , Emprego , Feminino , Gastos em Saúde , Necessidades e Demandas de Serviços de Saúde , Inquéritos Epidemiológicos , Disparidades em Assistência à Saúde , Humanos , Masculino , Pessoas sem Cobertura de Seguro de Saúde , Assistência Centrada no Paciente , Classe Social , Estados Unidos/epidemiologiaRESUMO
Opitz and Kaveggia [Opitz and Kaveggia (1974); Z Kinderheilkd 117:1-18] reported on a family of five affected males with distinctive facial appearance, mental retardation, macrocephaly, imperforate anus, and hypotonia. Risheg et al. [Risheg et al. (2007); Nature Genetics 39:451-453] identified an identical mutation (p.R961W) in MED12 in six families with Opitz-Kaveggia syndrome, including a surviving affected man from the original family reported in 1974. The previously described behavior phenotype of hyperactivity, affability, and excessive talkativeness is very frequent in young boys with FG syndrome, along with socially oriented, attention-seeking behaviors. We present case studies of five adult males who were previously published with the clinical diagnosis of FG syndrome and then subsequently proven by Risheg et al. [Risheg et al. (2007); Nature Genetics 39:451-453] to have the recurrent p.R961W mutation. These individuals had episodic and longstanding behavior patterns, sometimes aggressive or self-abusing, that occurred more frequently in puberty and early adulthood. We try to describe the triggers for these behaviors, indicate how these behaviors change with advancing age, and suggest specific recommendations and interventional strategies based on the clinical histories of affected adolescent males with FG syndrome [Graham et al., 2008; Clark et al., 2009]. Young men who exhibit these behaviors may benefit from a careful examination to detect medical problems, use of mood stabilizers if needed, and/or behavioral intervention. The transition to a community living situation can be challenging without careful planning and timely behavioral intervention. They remain impulsive and can have aggressive outbursts when making the transition to adult life, but these challenges can be managed, as demonstrated by these clinical histories.
Assuntos
Anormalidades Múltiplas/fisiopatologia , Agressão/fisiologia , Comportamento/fisiologia , Comportamento Impulsivo/fisiopatologia , Deficiência Intelectual/fisiopatologia , Fenótipo , Comportamento Autodestrutivo/fisiopatologia , Síndrome Acrocalosal/genética , Síndrome Acrocalosal/fisiopatologia , Adolescente , Adulto , Fatores Etários , Agenesia do Corpo Caloso , Anus Imperfurado/genética , Anus Imperfurado/fisiopatologia , Constipação Intestinal/genética , Constipação Intestinal/fisiopatologia , Humanos , Masculino , Complexo Mediador/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/fisiopatologia , Hipotonia Muscular/congênito , Hipotonia Muscular/genética , Hipotonia Muscular/fisiopatologia , Mutação/genéticaRESUMO
In 2006, all clinical genetics practices in Northern New England (Vermont, New Hampshire, and Maine) formed a learning collaborative with the purpose of improving genetic health care and outcomes. This article describes the current status of this effort. The methodology is based on our own modifications of the Institute of Healthcare Improvement "Breakthrough Series" and the Northern New England Cystic Fibrosis Consortium. Because of similarities across practices and the availability of existing published practice parameters, the clinical genetics evaluation of the child with developmental delay or intellectual disability was chosen as the topic to be studied. The aim was to improve the rate of etiological diagnosis of those with developmental delays referred to each genetics center by improving the processes of care. Process and outcomes were evaluated. Four of five sites also evaluated the impact of array comparative genomic hybridization (a-CGH) laboratory testing of such patients. There was significant site-to-site variation in the rate of new diagnoses by a-CGH with the average new diagnosis rate of 11.8% (range 5.4-28.8%). Barriers to implementation of the process and outcome data collection and analysis were significant and related to time pressures, lack of personnel or staff to support this activity, and competing quality improvement initiatives at the institutional home of some genetics centers.
Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Serviços em Genética/organização & administração , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Criança , Atenção à Saúde , Feminino , Testes Genéticos/métodos , Humanos , Cariotipagem , Masculino , New England , Hibridização de Ácido Nucleico , Avaliação de Resultados em Cuidados de Saúde , Projetos Piloto , Garantia da Qualidade dos Cuidados de Saúde , Indicadores de Qualidade em Assistência à SaúdeRESUMO
FG syndrome is a rare X-linked multiple congenital anomaly-cognitive impairment disorder caused by the p.R961W mutation in the MED12 gene. We identified all known patients with this mutation to delineate their clinical phenotype and devise a clinical algorithm to facilitate molecular diagnosis. We ascertained 23 males with the p.R961W mutation in MED12 from 9 previously reported FG syndrome families and 1 new family. Six patients are reviewed in detail. These 23 patients were compared with 48 MED12 mutation-negative patients, who had the clinical diagnosis of FG syndrome. Traits that best discriminated between these two groups were chosen to develop an algorithm with high sensitivity and specificity for the p.R961W MED12 mutation. FG syndrome has a recognizable dysmorphic phenotype with a high incidence of congenital anomalies. A family history of X-linked mental retardation, deceased male infants, and/or multiple fetal losses was documented in all families. The algorithm identifies the p.R961W MED12 mutation-positive group with 100% sensitivity and 90% specificity. The clinical phenotype of FG syndrome defines a recognizable pattern of X-linked multiple congenital anomalies and cognitive impairment. This algorithm can assist the clinician in selecting the patients for testing who are most likely to have the recurrent p.R961W MED12 mutation.
Assuntos
Anormalidades Múltiplas/diagnóstico , Cromossomos Humanos X/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Complexo Mediador/genética , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino , Mutação , Linhagem , Adulto JovemRESUMO
DICER1 encodes an RNase III endonuclease protein that regulates the production of small non-coding RNAs. Germline mutations in DICER1 are associated with an autosomal dominant hereditary cancer predisposition syndrome that confers an increased risk for the development of several rare childhood and adult-onset tumors, the most frequent of which include pleuropulmonary blastoma, ovarian sex cord-stromal tumors, cystic nephroma, and thyroid gland neoplasia. The majority of reported germline DICER1 mutations are truncating sequence-level alterations, suggesting that a loss-of-function type mechanism drives tumor formation in DICER1 syndrome. However, reports of patients with germline DICER1 whole gene deletions are limited, and thus far, only two have reported an association with tumor development. Here we report the clinical findings of three patients from two unrelated families with 14q32 deletions that encompass the DICER1 locus. The deletion identified in Family I is 1.4â¯Mb and was initially identified in a 6-year-old male referred for developmental delay, hypotonia, macrocephaly, obesity, and behavioral problems. Subsequent testing revealed that this deletion was inherited from his mother, who had a clinical history that included bilateral multinodular goiter and papillary thyroid carcinoma. The second deletion is 5.0â¯Mb and was identified in a 15-year-old female who presented with autism, coarse facial features, Sertoli-Leydig cell tumor, and Wilms' tumor. These findings provide additional supportive evidence that germline deletion of DICER1 confers an increased risk for DICER1-related tumor development, and provide new insight into the clinical significance of deletions involving the 14q32 region.
Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 14/genética , RNA Helicases DEAD-box/genética , Deficiências do Desenvolvimento/genética , Neoplasias/genética , Ribonuclease III/genética , Adolescente , Adulto , Criança , Transtornos Cromossômicos/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Masculino , Neoplasias/patologia , Linhagem , SíndromeRESUMO
Opitz and Kaveggia [Opitz and Kaveggia (1974); Z Kinderheilk 117:1-18] reported on a family of five affected males with distinctive facial appearance, mental retardation, macrocephaly, imperforate anus and hypotonia. Risheg et al. [Risheg et al. (2007); Nat Genet 39:451-453] identified an identical mutation (p.R961W) in MED12 in six families with Opitz-Kaveggia syndrome, including a surviving affected man from the family reported in 1974. The previously defined behavior phenotype of hyperactivity, affability, and excessive talkativeness is very frequent in young boys with this mutation, along with socially oriented, attention-seeking behaviors. We present case studies of two older males with FG syndrome and the p.R961W mutation to illustrate how their behavior changes with age. We also characterize the behavior of eight additional individuals with FG syndrome and this recurrent mutation in MED12 using the Vineland Adaptive Behavior Scales 2nd edition, the Reiss Profile of Fundamental Goals and Motivation Sensitivities, and the Achenbach Child Behavior Checklist. Males with this MED12 mutation had deficits in communication skills compared to their socialization and daily living skills. In addition, they were at increased risk for maladaptive behavior, with a propensity towards aggression, anxiety, and inattention. Based on the behavior phenotype in 10 males with this recurrent MED12 mutation, we offer specific recommendations and interventional strategies. Our findings reinforce the importance of testing for the p.R961W MED12 mutation in males who are suspected of having developmental and behavioral problems with a clinical phenotype that is consistent with FG syndrome.
Assuntos
Anormalidades Múltiplas/psicologia , Transtornos do Comportamento Infantil/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/psicologia , Receptores dos Hormônios Tireóideos/genética , Transtornos do Comportamento Social/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Substituição de Aminoácidos , Arginina/genética , Arginina/metabolismo , Criança , Transtornos do Comportamento Infantil/etiologia , Transtornos do Comportamento Infantil/genética , Comunicação , Humanos , Masculino , Complexo Mediador , Deficiência Intelectual Ligada ao Cromossomo X/complicações , Deficiência Intelectual Ligada ao Cromossomo X/genética , Transtornos do Comportamento Social/etiologia , Transtornos do Comportamento Social/genética , Socialização , Síndrome , Triptofano/genética , Triptofano/metabolismo , Adulto JovemRESUMO
All children with an intellectual disability (mental retardation) or global developmental delay should have a comprehensive evaluation to establish the etiology of the disability. A specific etiologic diagnosis offers the opportunity to discuss treatment, prognosis, and genetic recurrence risk. A diagnosis also avoids unnecessary testing and can lead to opportunities for improved health and functional outcomes. The key elements of the diagnostic evaluation are the medical and developmental history, 3-generation family history, dysmorphologic examination, neurologic examination, and judicious use of the laboratory and neuroimaging. All published guidelines for the evaluation of children with intellectual disability acknowledge that there is a substantial percentage of patients who are undiagnosed after a comprehensive evaluation and who deserve ongoing follow-up for the purpose of establishing a diagnosis. Recently, studies of the clinical application of array comparative genomic hybridization (aCGH) to individuals with intellectual disability indicate that this approach provides a diagnosis in as much as 10% of patients and that this technique is replacing the use of fluorescent in situ hybridization for subtelomere imbalances now used for such patients when the standard karyotype is normal. The literature suggests that history and examination by an expert clinician will lead to a diagnosis in 2 of 3 patients in whom a diagnosis is made. Laboratory studies alone, including neuroimaging, provide a diagnosis in the remaining one third. The approach to the evaluation of the patient in whom an etiologic diagnosis is not suspected after the history and physical examinations includes a standard karyotype, Fragile X molecular genetic testing, aCGH, and neuroimaging, based on the evidence to date. One can expect rapid changes in the microarray technology in the near future.
Assuntos
Deficiência Intelectual/genética , Criança , Análise Citogenética , Diagnóstico por Imagem , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/psicologia , Humanos , Hibridização In Situ , Deficiência Intelectual/metabolismo , Deficiência Intelectual/psicologiaRESUMO
Here, we report the neuroimaging findings and neurological changes in 17 unpublished patients with Macrocephaly-Capillary Malformation (M-CM). This syndrome has been traditionally known as Macrocephaly-Cutis Marmorata Telangiectatica Congenita (M-CMTC), but we explain why M-CM is a more accurate term for this overgrowth syndrome. We analyzed the 17 patients with available brain MRI or CT scans and compared their findings with features identified by a comprehensive review of published cases. White matter irregularities with increased signal on T2-weighted images were commonly observed findings. A distinctive feature in more than half the patients was cerebellar tonsillar herniation associated with rapid brain growth and progressive crowding of the posterior fossa during infancy. In four such cases, we confirmed that the tonsillar herniation was an acquired event. Concurrently, with the development of these findings, ventriculomegaly (frequently obstructive) and dilated dural venous sinuses were observed in conjunction with prominent Virchow-Robin spaces in many of those in whom cerebellar tonsil herniation had developed. We postulate that this constellation of unusual features suggests a dynamic process of mechanical compromise in the posterior fossa, perhaps initiated by a rapidly growing cerebellum, which leads to congestion of the venous drainage with subsequently compromised cerebrospinal fluid reabsorption, all of which increases the posterior fossa pressure and leads to acquired tonsillar herniation. We make a distinction between congenital Chiari I malformation and acquired cerebellar tonsil herniation in this syndrome. We also observed numerous examples of abnormal cortical morphogenesis, including focal cortical dysplasia, polymicrogyria which primarily involved the perisylvian and insular regions, and cerebral and/or cerebellar asymmetric overgrowth. Other findings included a high frequency of cavum septum pellucidum or vergae, thickened corpus callosum, prominent optic nerve sheaths and a single case of venous sinus thrombosis. One patient was found to have a frontal perifalcine mass resembling a meningioma at age 5 years. This is the second apparent occurrence of this specific tumor in M-CM.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Craniofaciais/diagnóstico , Imageamento por Ressonância Magnética/métodos , Anormalidades Múltiplas/patologia , Adolescente , Peso ao Nascer , Encéfalo/anormalidades , Capilares/patologia , Criança , Pré-Escolar , Corpo Caloso/patologia , Anormalidades Craniofaciais/patologia , Feminino , Humanos , Lactente , Masculino , Síndrome , Telangiectasia/diagnóstico , Telangiectasia/patologiaRESUMO
Genomic copy-number variations (CNVs) constitute an important cause of epilepsies and other human neurological disorders. Recent advancement of technologies integrating genome-wide CNV mapping and sequencing is rapidly expanding the molecular field of pediatric neurodevelopmental disorders. In a previous study, a novel epilepsy locus was identified on 6q16.3q22.31 by linkage analysis in a large pedigree. Subsequent array comparative genomic hybridization (array CGH) analysis of four unrelated cases narrowed this region to â¼5 Mb on 6q22.1q22.31. We sought to further narrow the critical region on chromosome 6q22. Array CGH analysis was used in genome-wide screen for CNVs of a large cohort of patients with neurological abnormalities. Long-range PCR and DNA sequencing were applied to precisely map chromosomal deletion breakpoints. Finally, real-time qPCR was used to estimate relative expression in the brain of the candidate genes. We identified six unrelated patients with overlapping microdeletions within 6q22.1q22.31 region, three of whom manifested seizures. Deletions were found to be de novo in 5/6 cases, including all subjects presenting with seizures. We sequenced the deletion breakpoints in four patients and narrowed the critical region to a â¼250-kb segment at 6q22.1 that includes NUS1, several expressed sequence tags (ESTs) that are highly expressed in the brain, and putative regulatory sequences of SLC35F1. Our findings indicate that dosage alteration in particular, of NUS1, EST AI858607, or SLC35F1 are important contributors to the neurodevelopmental phenotype associated with 6q22 deletion, including epilepsy and tremors.