Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 42
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Eur J Med Genet ; : 103636, 2019 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-30836150

RESUMO

Copy number variations (CNVs) of the CNTN6 gene - a member of the contactin gene superfamily - have been previously proposed to have an association with neurodevelopmental and autism spectrum disorders. However, no functional evidence has been provided to date and phenotypically normal and mildly affected carriers complicate the interpretation of this aberration. In view of conflicting reports on the pathogenicity of CNVs involving CNTN6 and association with different phenotypes, we, independently, evaluated clinical features of nineteen patients with detected CNV of CNTN6 as part of their clinical microarray analysis at Children's Mercy and Nationwide Children's Hospitals for the period of 2008-2015. The clinical presentations of these patients were variable making it difficult to establish genotype-phenotype correlations. CNVs were inherited in six patients. For thirteen patients, inheritance pattern was not established due to unavailability of parental samples for testing. In three cases CNV was inherited from a healthy parent and in three cases from a parent with neurodevelopmental symptoms. Of the nineteen patients, four had a separate genetic abberation in addition to CNV of the CNTN6 that could independently explain their respective phenotypes. Separately, CNTN6 sequencing was performed on an autism spectrum disorder (ASD) research cohort of 94 children from 80 unrelated families. We found no difference in frequency of rare coding variants between the cohort of patients and controls. We conclude that CNVs involving CNTN6 alone seem to be most likely a neutral variant or a possible modifier rather than a disease-causing variant. Patients with CNVs encompassing CNTN6 could benefit from additional genetic testing since a clinical diagnosis due to a CNV of CNTN6 alone is still questionable.

2.
J Dev Phys Disabil ; 30(3): 355-371, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30197492

RESUMO

Background: Frequent non-pathogenic genetic variants may act as moderators of phenotypic severity for complex disorders such as autism spectrum disorder (ASD). We previously identified polymorphisms affecting mRNA expression of candidate genes, including tryptophan hydroxylase 2 (TPH2), dopamine beta hydroxylase (DBH), and dopamine transporter (DAT, SLC6A3). Method: We compare genotypes and (1) clinical response to atomoxetine, (2) scores from the Autism Diagnostic Interview-Revised (ADI-R), and (3) severity of Attention Deficit Hyperactivity Disorder (ADHD) symptoms in a cohort of patients with ASD from multiple study sites. Results: There was no association between CYP2D6 metabolizer status and atomoxetine response. TPH2 rs7305115 genotype was associated with ADI-R Restrictive/Repetitive Behavior score (p=0.03). DBH rs1611115 genotype was associated with ADI-R Social score (p=0.002) and Restrictive/Repetitive Behavior score (p=0.04). The DAT intron 8 5/6 repeat was associated with ADHD symptoms (ABC Hyperactivity p=0.01 and SNAP ADHD p=0.03), replicating a previous finding. Conclusions: We find associations between ASD phenotypes and regulatory variants in catecholamine biosynthesis genes. This work may help guide future genetics studies related to ASD.

3.
Semin Pediatr Neurol ; 26: 25-27, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29961511

RESUMO

Recent technological advances in exome sequencing or targeted gene sequencing with epilepsy panels have allowed clinicians to better understand the pathogenesis and clinical presentation of children with epilepsy. We present a child with a SLC6A1 mutation with language delay and autistic spectrum disorder and remind the reader that the identification of specific mutations in these conditions increase the likelihood of identification of potential therapeutic targets.


Assuntos
Epilepsia/genética , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Transtornos do Desenvolvimento da Linguagem/genética , Mutação , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Pré-Escolar , Diagnóstico Diferencial , Epilepsia/diagnóstico por imagem , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Feminino , Humanos , Transtornos do Desenvolvimento da Linguagem/diagnóstico por imagem , Transtornos do Desenvolvimento da Linguagem/tratamento farmacológico , Transtornos do Desenvolvimento da Linguagem/fisiopatologia
4.
Hum Mutat ; 39(8): 1126-1138, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29851191

RESUMO

Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans.

5.
Sci Rep ; 7(1): 16812, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29196732

RESUMO

Autism spectrum disorders (ASD) are more common among boys than girls. The mechanisms responsible for ASD symptoms and their sex differences remain mostly unclear. We previously identified collapsin response mediator protein 4 (CRMP4) as a protein exhibiting sex-different expression during sexual differentiation of the hypothalamic sexually dimorphic nucleus. This study investigated the relationship between the sex-different development of autistic features and CRMP4 deficiency. Whole-exome sequencing detected a de novo variant (S541Y) of CRMP4 in a male ASD patient. The expression of mutated mouse CRMP4 S540Y, which is homologous to human CRMP4 S541Y, in cultured hippocampal neurons derived from Crmp4-knockout (KO) mice had increased dendritic branching, compared to those transfected with wild-type (WT) Crmp4, indicating that this mutation results in altered CRMP4 function in neurons. Crmp4-KO mice showed decreased social interaction and several alterations of sensory responses. Most of these changes were more severe in male Crmp4-KO mice than in females. The mRNA expression levels of some genes related to neurotransmission and cell adhesion were altered in the brain of Crmp4-KO mice, mostly in a gender-dependent manner. These results indicate a functional link between a case-specific, rare variant of one gene, Crmp4, and several characteristics of ASD, including sexual differences.

6.
Cell ; 169(1): 6-12, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28340351

RESUMO

Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant-phenotype databases, adopting phenotype description standards, and promoting data sharing.


Assuntos
Pesquisa Biomédica , Genômica , Animais , Análise Mutacional de DNA , Bases de Dados Genéticas , Doença/genética , Projeto Genoma Humano , Humanos , Disseminação de Informação , Modelos Animais
7.
Genet Med ; 19(2): 249-255, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27854360

RESUMO

Disclaimer: These recommendations are designed primarily as an educational resource for medical geneticists and other healthcare providers to help them provide quality medical services. Adherence to these recommendations is completely voluntary and does not necessarily assure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.To promote standardized reporting of actionable information from clinical genomic sequencing, in 2013, the American College of Medical Genetics and Genomics (ACMG) published a minimum list of genes to be reported as incidental or secondary findings. The goal was to identify and manage risks for selected highly penetrant genetic disorders through established interventions aimed at preventing or significantly reducing morbidity and mortality. The ACMG subsequently established the Secondary Findings Maintenance Working Group to develop a process for curating and updating the list over time. We describe here the new process for accepting and evaluating nominations for updates to the secondary findings list. We also report outcomes from six nominations received in the initial 15 months after the process was implemented. Applying the new process while upholding the core principles of the original policy statement resulted in the addition of four genes and removal of one gene; one gene did not meet criteria for inclusion. The updated secondary findings minimum list includes 59 medically actionable genes recommended for return in clinical genomic sequencing. We discuss future areas of focus, encourage continued input from the medical community, and call for research on the impact of returning genomic secondary findings.Genet Med 19 2, 249-255.


Assuntos
Testes Genéticos/normas , Genética Médica/normas , Genoma Humano/genética , Sequenciamento Completo do Exoma , Exoma/genética , Genômica , Humanos
8.
Blood Adv ; 1(4): 279-281, 2017 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-29296943

RESUMO

HCT prior to onset of neurologic symptoms in children with OSTM1 osteopetrosis does not halt neurologic progression.

9.
Cell Rep ; 12(11): 1927-38, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26344763

RESUMO

Meiosis-activating sterols (MAS) are substrates of SC4MOL and NSDHL in the cholesterol pathway and are important for normal organismal development. Oncogenic transformation by epidermal growth factor receptor (EGFR) or RAS increases the demand for cholesterol, suggesting a possibility for metabolic interference. To test this idea in vivo, we ablated Nsdhl in adult keratinocytes expressing KRAS(G12D). Strikingly, Nsdhl inactivation antagonized the growth of skin tumors while having little effect on normal skin. Loss of Nsdhl induced the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, reduced the expression of low-density lipoprotein receptor (LDLR), decreased intracellular cholesterol, and was dependent on the liver X receptor (LXR) α. Importantly, EGFR signaling opposed LXRα effects on cholesterol homeostasis, whereas an EGFR inhibitor synergized with LXRα agonists in killing cancer cells. Inhibition of SC4MOL or NSDHL, or activation of LXRα by sterol metabolites, can be an effective strategy against carcinomas with activated EGFR-KRAS signaling.


Assuntos
Colesterol/metabolismo , Receptores ErbB/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Esteróis/metabolismo , 3-Hidroxiesteroide Desidrogenases/genética , 3-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Nucleares Órfãos/agonistas , Papiloma/genética , Papiloma/metabolismo , Papiloma/patologia , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Transfecção
10.
Hum Mol Genet ; 24(10): 2808-25, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25652406

RESUMO

NSDHL is a 3ß-hydroxysterol dehydrogenase that is involved in the removal of two C-4 methyl groups in one of the later steps of cholesterol biosynthesis. Mutations in the gene encoding the enzyme are responsible for the X-linked, male lethal mouse mutations bare patches and striated, as well as most cases of human CHILD syndrome. Rare, hypomorphic NSDHL mutations are also associated with X-linked intellectual disability in males with CK syndrome. Since hemizygous male mice with Nsdhl mutations die by midgestation, we generated a conditional targeted Nsdhl mutation (Nsdhl(tm1.1Hrm)) to investigate the essential role of cholesterol in the early postnatal CNS. Ablation of Nsdhl in radial glia using GFAP-cre resulted in live-born, normal appearing affected male pups. However, the pups develop overt ataxia by postnatal day 8-10 and die shortly thereafter. Histological abnormalities include progressive loss of cortical and hippocampal neurons, as well as deficits in the proliferation and migration of cerebellar granule precursors and subsequent massive apoptosis of the cerebellar cortex. We replicated the granule cell precursor proliferation defect in vitro and demonstrate that it results from defective signaling by SHH. Furthermore, this defect is almost completely rescued by supplementation of the culture media with exogenous cholesterol, while methylsterol accumulation above the enzymatic block appears to be associated with increased cell death. These data support the absolute requirement for cholesterol synthesis in situ once the blood-brain-barrier forms and cholesterol transport to the fetus is abolished. They further emphasize the complex ramifications of cholesterogenic enzyme deficiency on cellular metabolism.


Assuntos
3-Hidroxiesteroide Desidrogenases/genética , Córtex Cerebelar/crescimento & desenvolvimento , Colesterol/fisiologia , Proteínas Hedgehog/fisiologia , Transdução de Sinais , Alelos , Animais , Córtex Cerebelar/fisiopatologia , Colesterol/biossíntese , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Células-Tronco Neurais , Neurônios/fisiologia
11.
Genet Med ; 17(1): 27-35, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25394173

RESUMO

PURPOSE: The aim of this study was to survey American College of Medical Genetics and Genomics members about secondary findings from clinical genome-scale sequencing. METHODS: A Web-based survey was mailed to 1,687 members of the American College of Medical Genetics and Genomics. Exploratory factor analysis identified underlying factors assessed by survey items. Linear regression assessed associations between factor scores and respondent characteristics. RESULTS: The response rate was 29%. Four factors explained 51% of the survey variance: best practices, patient preferences, guidance, and informed consent. Most agreed with "best practice" items describing seeking and reporting of secondary findings as consistent with medical standards, having sufficient evidence, and, for adults, the benefits generally outweighing potential harms. There was lack of agreement regarding benefits versus harms for children and impact on health-care resources. The majority agreed that patient preferences should be considered, including ability to opt out, and that informed consent was feasible and critical. Characteristics significantly associated with factor scores included country of residence, sequencing experience, and years in practice. CONCLUSION: The American College of Medical Genetics and Genomics should update a list of genes to be assessed when clinical genome-scale sequencing is performed. Informed consent is necessary, and reporting of secondary findings should be optional. Research on implementation of secondary findings reporting is needed.


Assuntos
Genômica , Achados Incidentais , Coleta de Dados , Feminino , Genômica/métodos , Pessoal de Saúde , Humanos , Internet , Masculino
12.
Am J Med Genet A ; 164A(11): 2892-900, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25251875

RESUMO

Mutations in ERCC6 are associated with growth failure, intellectual disability, neurological dysfunction and deterioration, premature aging, and photosensitivity. We describe siblings with biallelic ERCC6 mutations (NM_000124.2:c. [543+4delA];[2008C>T]) and brain hypomyelination, microcephaly, cognitive decline, and skill regression but without photosensitivity or progeria. DNA repair assays on cultured skin fibroblasts confirmed a defect of transcription-coupled nucleotide excision repair and increased ultraviolet light sensitivity. This report expands the disease spectrum associated with ERCC6 mutations.


Assuntos
Encéfalo/patologia , Encéfalo/fisiopatologia , DNA Helicases/genética , Enzimas Reparadoras do DNA/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças do Sistema Nervoso/genética , Processamento Alternativo , Biomarcadores/metabolismo , Criança , Pré-Escolar , DNA Helicases/metabolismo , Análise Mutacional de DNA , Enzimas Reparadoras do DNA/metabolismo , Facies , Feminino , Expressão Gênica , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Humanos , Íntrons , Imagem por Ressonância Magnética , Masculino , Mutação , Doenças do Sistema Nervoso/diagnóstico , Linhagem , Fenótipo , Proteínas de Ligação a Poli-ADP-Ribose , Irmãos
13.
Autism Res ; 7(4): 459-67, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24753316

RESUMO

The serotonin 2A receptor gene (HTR2A) harbors two functional single nucleotide polymorphisms (SNPs) that are frequent in populations of African and European descent; rs6311, which affects mRNA expression, and rs6314, which changes the amino acid sequence of the encoded protein and affects the signaling properties of the receptor. Multiple clinical associations support a role for these SNPs in cognitive and neuropsychiatric phenotypes, although studies in autism spectrum disorder (ASD) remain equivocal. Here, we tested transmission disequilibrium of rs6311 and rs6314 in a cohort of 158 ASD trios (simplex and multiplex), observing significant under-transmission of the minor "A" allele of rs6311 to offspring with ASD (permuted P = 0.0004). Consistent with our previous findings in the dorsolateral prefrontal cortex of unaffected individuals, rs6311/A decreases expression of HTR2A mRNA with an extended 5' untranslated region (UTR) in the frontopolar cortex in brain samples from 54 ASD patients and controls. Interpreting the clinical results in the context of our mRNA expression analysis, we speculate that any risk associated with rs6311 is conferred by greater expression of the long 5'UTR mRNA isoform. The current study corroborates earlier associations between rs6311 and ASD in a family study, supporting the hypothesis that rs6311 plays a modulatory role in ASD risk.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Família , Receptor 5-HT2A de Serotonina/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Ohio , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
14.
Am J Med Genet A ; 164A(5): 1188-91, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24664640

RESUMO

Basan syndrome is an extremely rare ectodermal dysplasia with autosomal dominant inheritance and variable expressivity. The etiology of Basan syndrome remains unknown. To identify the Basan syndrome gene, we sequenced keratin 14 (KRT14) and SMARCAD1 in a previously unreported kindred with the disease. Sequencing of the coding regions and splice junctions of KRT14 and SMARCAD1 was performed using PCR-amplified genomic DNA isolated from blood or saliva and standard PCR protocols. In vitro functional studies were performed for a variant identified in SMARCAD1. While direct sequencing of KRT14 failed to reveal any likely pathogenic sequence alterations or splice site variants, a heterozygous splicing variant (c.378+3A>T) that segregated with the disease was identified in the skin-specific isoform of SMARCAD1. In vitro studies failed to demonstrate a splicing defect in SMARCAD1. We screened two candidate genes for Basan syndrome in a 3-generation pedigree. The skin-specific isoform of SMARCAD1 remains a good candidate for this disease.


Assuntos
Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Estudos de Associação Genética , Unhas Malformadas/diagnóstico , Unhas Malformadas/genética , Pré-Escolar , DNA Helicases/genética , Feminino , Genótipo , Humanos , Queratina-14/genética , Masculino , Mutação , Linhagem , Fenótipo , Sítios de Splice de RNA
15.
Cancer Discov ; 3(1): 96-111, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23125191

RESUMO

UNLABELLED: Persistent signaling by the oncogenic EGF receptor (EGFR) is a major source of cancer resistance to EGFR targeting. We established that inactivation of 2 sterol biosynthesis pathway genes, SC4MOL (sterol C4-methyl oxidase-like) and its partner, NSDHL (NADP-dependent steroid dehydrogenase-like), sensitized tumor cells to EGFR inhibitors. Bioinformatics modeling of interactions for the sterol pathway genes in eukaryotes allowed us to hypothesize and then extensively validate an unexpected role for SC4MOL and NSDHL in controlling the signaling, vesicular trafficking, and degradation of EGFR and its dimerization partners, ERBB2 and ERBB3. Metabolic block upstream of SC4MOL with ketoconazole or CYP51A1 siRNA rescued cancer cell viability and EGFR degradation. Inactivation of SC4MOL markedly sensitized A431 xenografts to cetuximab, a therapeutic anti-EGFR antibody. Analysis of Nsdhl-deficient Bpa(1H/+) mice confirmed dramatic and selective loss of internalized platelet-derived growth factor receptor in fibroblasts, and reduced activation of EGFR and its effectors in regions of skin lacking NSDHL. SIGNIFICANCE: This work identifies a critical role for SC4MOL and NSDHL in the regulation of EGFR signaling and endocytic trafficking and suggests novel strategies to increase the potency of EGFR antagonists in tumors.


Assuntos
3-Hidroxiesteroide Desidrogenases/genética , Receptores ErbB/metabolismo , Oxigenases de Função Mista/genética , 3-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cetuximab , Colesterol/metabolismo , Endocitose , Receptores ErbB/antagonistas & inibidores , Humanos , Masculino , Camundongos , Camundongos SCID , Camundongos Transgênicos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Transporte Proteico
16.
Am J Med Genet C Semin Med Genet ; 160C(4): 301-21, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-23042573

RESUMO

Since the discovery in 1993 that Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol biosynthesis, human disorders associated with additional enzymes involved in the conversion of lanosterol to cholesterol have been identified. This review will focus primarily on the clinical aspects of these disorders, highlighting newly described syndromes, such as SC4MOL deficiency and CK syndrome. We will also provide clinical descriptions of additional cases for extremely rare disorders, such as desmosterolosis. We will compare and contrast the findings with those found in SLOS and briefly discuss possible mechanisms of disease pathogenesis.


Assuntos
Lanosterol/biossíntese , Erros Inatos do Metabolismo de Esteroides/fisiopatologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Pré-Escolar , Humanos , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/fisiopatologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/deficiência , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Síndrome de Smith-Lemli-Opitz/genética , Síndrome de Smith-Lemli-Opitz/fisiopatologia , Erros Inatos do Metabolismo de Esteroides/genética
17.
Am J Med Genet A ; 158A(2): 391-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22190277

RESUMO

Basal cell nevus syndrome (BCNS), also known as Gorlin syndrome (OMIM #109400) is a well-described rare autosomal dominant condition due to haploinsufficiency of PTCH1. With the availability of comparative genomic hybridization arrays, increasing numbers of individuals with microdeletions involving this locus are being identified. We present 10 previously unreported individuals with 9q22.3 deletions that include PTCH1. While 7 of the 10 patients (7 females, 3 males) did not meet strict clinical criteria for BCNS at the time of molecular diagnosis, almost all of the patients were too young to exhibit many of the diagnostic features. A number of the patients exhibited metopic craniosynostosis, severe obstructive hydrocephalus, and macrosomia, which are not typically observed in BCNS. All individuals older than a few months of age also had developmental delays and/or intellectual disability. Only facial features typical of BCNS, except in those with prominent midforeheads secondary to metopic craniosynostosis, were shared among the 10 patients. The deletions in these individuals ranged from 352 kb to 20.5 Mb in size, the largest spanning 9q21.33 through 9q31.2. There was significant overlap of the deleted segments among most of the patients. The smallest common regions shared among the deletions were identified in order to localize putative candidate genes that are potentially responsible for each of the non-BCNS features. These were a 929 kb region for metopic craniosynostosis, a 1.08 Mb region for obstructive hydrocephalus, and a 1.84 Mb region for macrosomia. Additional studies are needed to further characterize the candidate genes within these regions.


Assuntos
Síndrome do Nevo Basocelular/diagnóstico , Síndrome do Nevo Basocelular/genética , Síndrome do Nevo Basocelular/patologia , Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Receptores de Superfície Celular/genética , Carcinoma Basocelular/diagnóstico , Carcinoma Basocelular/genética , Carcinoma Basocelular/patologia , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Feminino , Macrossomia Fetal/genética , Estudos de Associação Genética , Haploinsuficiência/genética , Humanos , Hidrocefalia/diagnóstico , Hidrocefalia/genética , Lactente , Recém-Nascido , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Masculino , Receptores Patched , Receptor Patched-1 , Patologia Molecular
18.
Am J Med Genet A ; 155A(4): 706-16, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21438134

RESUMO

Costello syndrome is characterized by severe failure-to-thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto-oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype-phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p.G13C and individuals with p.G12S. The individuals with p.G13C had many typical findings including polyhydramnios, failure-to-thrive, HCM, macrocephaly with posterior fossa crowding, and developmental delay. Subjectively, their facial features were less coarse. Statistically significant differences included the absence of multifocal atrial tachycardia (P-value = 0.033), ulnar deviation of the wrist (P < 0.001) and papillomata (P = 0.003), and fewer neurosurgical procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height below -2 SD) without use of growth hormone (P < 0.001). The noteworthy absence of malignant tumors did not reach statistical significance. Novel ectodermal findings were noted in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, different from the tight curls typical for most Costello syndrome individuals. Unusually long eye lashes requiring trimming are a novel finding we termed dolichocilia. These distinctive ectodermal findings suggest a cell type specific effect of this particular mutation. Additional patients are needed to validate these findings.


Assuntos
Síndrome de Costello/genética , Mutação/genética , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/genética , Adolescente , Adulto , Encéfalo/anormalidades , Criança , Pré-Escolar , Síndrome de Costello/complicações , Síndrome de Costello/diagnóstico , Face/anormalidades , Feminino , Cardiopatias Congênitas/etiologia , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Anormalidades Musculoesqueléticas/etiologia , Neoplasias/etiologia , Gravidez , Adulto Jovem
19.
Autism Res ; 4(3): 189-99, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21308999

RESUMO

Structural and sequence variation have been described in several members of the contactin (CNTN) and contactin-associated protein (CNTNAP) gene families in association with neurodevelopmental disorders, including autism. Using array comparative genome hybridization (CGH), we identified a maternally inherited ∼535 kb deletion at 3p26.3 encompassing the 5' end of the contactin 4 gene (CNTN4) in a patient with autism. Based on this finding and previous reports implicating genomic rearrangements of CNTN4 in autism spectrum disorders (ASDs) and 3p- microdeletion syndrome, we undertook sequencing of the coding regions of the gene in a local ASD cohort in comparison with a set of controls. Unique missense variants were identified in 4 of 75 unrelated individuals with ASD, as well as in 1 of 107 controls. All of the amino acid substitutions were nonsynonomous, occurred at evolutionarily conserved positions, and were, thus, felt likely to be deleterious. However, these data did not reach statistical significance, nor did the variants segregate with disease within all of the ASD families. Finally, there was no detectable difference in binding of two of the variants to the interacting protein PTPRG in vitro. Thus, additional larger studies will be necessary to determine whether CNTN4 functions as an autism susceptibility locus in combination with other genetic and/or environmental factors.


Assuntos
Transtorno Autístico/genética , Contactinas/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Transtorno Autístico/diagnóstico , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Estudos de Coortes , Éxons/genética , Aconselhamento Genético , Genótipo , Humanos , Hibridização in Situ Fluorescente , Masculino , Transtornos Mentais/genética , Análise de Sequência com Séries de Oligonucleotídeos , Análise de Sequência de DNA
20.
J Lipid Res ; 52(1): 6-34, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20929975

RESUMO

Cholesterol homeostasis is critical for normal growth and development. In addition to being a major membrane lipid, cholesterol has multiple biological functions. These roles include being a precursor molecule for the synthesis of steroid hormones, neuroactive steroids, oxysterols, and bile acids. Cholesterol is also essential for the proper maturation and signaling of hedgehog proteins, and thus cholesterol is critical for embryonic development. After birth, most tissues can obtain cholesterol from either endogenous synthesis or exogenous dietary sources, but prior to birth, the human fetal tissues are dependent on endogenous synthesis. Due to the blood-brain barrier, brain tissue cannot utilize dietary or peripherally produced cholesterol. Generally, inborn errors of cholesterol synthesis lead to both a deficiency of cholesterol and increased levels of potentially bioactive or toxic precursor sterols. Over the past couple of decades, a number of human malformation syndromes have been shown to be due to inborn errors of cholesterol synthesis. Herein, we will review clinical and basic science aspects of Smith-Lemli-Opitz syndrome, desmosterolosis, lathosterolosis, HEM dysplasia, X-linked dominant chondrodysplasia punctata, Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects Syndrome, sterol-C-4 methyloxidase-like deficiency, and Antley-Bixler syndrome.


Assuntos
Colesterol/biossíntese , Anormalidades Congênitas/etiologia , Erros Inatos do Metabolismo Lipídico/complicações , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Animais , Condrodisplasia Punctata/etiologia , Condrodisplasia Punctata/genética , Condrodisplasia Punctata/metabolismo , Humanos , Erros Inatos do Metabolismo Lipídico/etiologia , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/deficiência , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Síndrome de Smith-Lemli-Opitz/etiologia , Síndrome de Smith-Lemli-Opitz/genética , Síndrome de Smith-Lemli-Opitz/metabolismo , Erros Inatos do Metabolismo de Esteroides , Síndrome
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA