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1.
Genet Med ; 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30245513

RESUMO

PURPOSE: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. METHODS: We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review. RESULTS: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. CONCLUSION: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.

2.
Eur J Hum Genet ; 26(12): 1810-1818, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30087448

RESUMO

Approximately 2% of the human genome accounts for protein-coding genes, yet most known Mendelian disease-causing variants lie in exons or splice sites. Individuals who symptomatically present with monogenic disorders but do not possess function-altering variants in the protein-coding regions of causative genes may harbor variants in the surrounding gene regulatory domains. We present such a case: a male of Afghani descent was clinically diagnosed with Wilson Disease-a disorder of systemic copper buildup-but was found to have no function-altering coding variants in ATP7B (ENST00000242839.4), the typically causative gene. Our analysis revealed the homozygous variant chr13:g.52,586,149T>C (NC_000013.10, hg19) 676 bp into the ATP7B promoter, which disrupts a metal regulatory transcription factor 1 (MTF1) binding site and diminishes expression of ATP7B in response to copper intake, likely resulting in Wilson Disease. Our approach to identify the causative variant can be generalized to systematically discover function-altering non-coding variants underlying disease and motivates evaluation of gene regulatory variants.

3.
Am J Hum Genet ; 102(3): 494-504, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29478781

RESUMO

ATP synthase, H+ transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F1FO ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of Drosophila ATPsynδ, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation.

4.
Mol Genet Metab ; 123(3): 297-300, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29396029

RESUMO

PURPOSE OF STUDY: Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor. METHODS USED: Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery. SUMMARY OF RESULTS: Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years. CONCLUSION: Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.

5.
J Inherit Metab Dis ; 40(1): 121-130, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27696117

RESUMO

Mitochondrial diseases collectively represent one of the most heterogeneous group of metabolic disorders. Symptoms can manifest at any age, presenting with isolated or multiple-organ involvement. Advances in next-generation sequencing strategies have greatly enhanced the diagnosis of patients with mitochondrial disease, particularly where a mitochondrial aetiology is strongly suspected yet OXPHOS activities in biopsied tissue samples appear normal. We used whole exome sequencing (WES) to identify the molecular basis of an early-onset mitochondrial syndrome-pathogenic biallelic variants in the HTRA2 gene, encoding a mitochondria-localised serine protease-in five subjects from two unrelated families characterised by seizures, neutropenia, hypotonia and cardio-respiratory problems. A unifying feature in all affected children was 3-methylglutaconic aciduria (3-MGA-uria), a common biochemical marker observed in some patients with mitochondrial dysfunction. Although functional studies of HTRA2 subjects' fibroblasts and skeletal muscle homogenates showed severely decreased levels of mutant HTRA2 protein, the structural subunits and complexes of the mitochondrial respiratory chain appeared normal. We did detect a profound defect in OPA1 processing in HTRA2-deficient fibroblasts, suggesting a role for HTRA2 in the regulation of mitochondrial dynamics and OPA1 proteolysis. In addition, investigated subject fibroblasts were more susceptible to apoptotic insults. Our data support recent studies that described important functions for HTRA2 in programmed cell death and confirm that patients with genetically-unresolved 3-MGA-uria should be screened by WES with pathogenic variants in the HTRA2 gene prioritised for further analysis.


Assuntos
Variação Genética/genética , Serina Peptidase 2 de Requerimento de Alta Temperatura A/genética , Erros Inatos do Metabolismo/genética , Mitocôndrias/genética , Doenças Mitocondriais/genética , Morte Celular/genética , Células Cultivadas , Criança , Exoma/genética , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Proteínas Mitocondriais/genética , Músculo Esquelético/metabolismo , Serina Proteases/genética , Síndrome
6.
Am J Hum Genet ; 98(5): 1001-1010, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-27108799

RESUMO

Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein subunit beta-1, Gß. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p = 7.1 × 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gß binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gßγ interaction (resulting in a constitutively active Gßγ) or through the disruption of residues relevant for interaction between Gßγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.


Assuntos
Deficiências do Desenvolvimento/etiologia , Subunidades beta da Proteína de Ligação ao GTP/genética , Mutação em Linhagem Germinativa/genética , Deficiência Intelectual/etiologia , Hipotonia Muscular/etiologia , Convulsões/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Exoma/genética , Feminino , Subunidades beta da Proteína de Ligação ao GTP/química , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/patologia , Fenótipo , Conformação Proteica , Convulsões/patologia , Transdução de Sinais , Adulto Jovem
7.
Am J Hum Genet ; 98(2): 347-57, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26805781

RESUMO

The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.


Assuntos
Arritmias Cardíacas/genética , Debilidade Muscular/genética , Rabdomiólise/genética , Alelos , Árabes/genética , Arritmias Cardíacas/diagnóstico , Sequência de Bases , Criança , Pré-Escolar , Estresse do Retículo Endoplasmático/genética , Grupo com Ancestrais do Continente Europeu/genética , Exoma , Éxons , Feminino , Deleção de Genes , Complexo de Golgi/genética , Complexo de Golgi/metabolismo , Hispano-Americanos/genética , Homozigoto , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Debilidade Muscular/diagnóstico , Linhagem , Rabdomiólise/diagnóstico
8.
Am J Hum Genet ; 97(6): 862-8, 2015 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-26608784

RESUMO

Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963(∗)] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration.


Assuntos
Proteínas de Transporte/genética , Nanismo/genética , Mutação , Sequência de Aminoácidos , Animais , Encéfalo/anormalidades , Encéfalo/metabolismo , Criança , Pré-Escolar , Consanguinidade , Nanismo/patologia , Exoma , Éxons , Expressão Gênica , Homozigoto , Humanos , Íntrons , Masculino , Microcefalia/genética , Microcefalia/patologia , Dados de Sequência Molecular , Linhagem , Alinhamento de Sequência
9.
Am J Med Genet A ; 167A(1): 142-6, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25402239

RESUMO

The diagnosis of Angelman syndrome (AS) is based on clinical features and genetic testing. Developmental delay, severe speech impairment, ataxia, atypical behavior and microcephaly by two years of age are typical. Feeding difficulties in young infants and obesity in late childhood can also be seen. The NIH Angelman-Rett-Prader-Willi Consortium and others have documented genotype-phenotype associations including an increased body mass index in children with uniparental disomy (UPD) or imprinting center (IC) defects. We recently encountered four cases of infantile obesity in non-deletion AS cases, and therefore examined body mass measures in a cohort of non-deletion AS cases. We report on 16 infants and toddlers (ages 6 to 44 months; 6 female, and 10 male) with severe developmental delay. Birth weights were appropriate for gestational age in most cases, >97th% in one case and not available in four cases. The molecular subclass case distribution consisted of: UPD (n = 2), IC defect (n = 3), UPD or IC defect (n = 3), and UBE3A mutation (n = 8). Almost all (7 out of 8) UPD, IC and UPD/IC cases went on to exhibit >90th% age- and gender-appropriate weight for height or BMI within the first 44 months. In contrast, no UBE3A mutation cases exhibited obesity or pre-obesity measures (percentiles ranged from <3% to 55%). These findings demonstrate that increased body mass may be evident as early as the first year of life and highlight the utility of considering the diagnosis of AS in the obese infant or toddler with developmental delay, especially when severe. Although a mechanism explaining the association of UPD, and IC defects with obesity has not been identified, recognition of this correlation may inform investigation of imprinting at the PWS/AS locus and obesity.


Assuntos
Síndrome de Angelman/genética , Síndrome de Angelman/patologia , Peso Corporal , Impressão Genômica , Dissomia Uniparental/genética , Dissomia Uniparental/patologia , Cefalometria , Criança , Feminino , Humanos , Lactente , Masculino
10.
J Clin Endocrinol Metab ; 100(2): E333-44, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25383892

RESUMO

CONTEXT: Disorders of sex development (DSD) are clinical conditions where there is a discrepancy between the chromosomal sex and the phenotypic (gonadal or genital) sex of an individual. Such conditions can be stressful for patients and their families and have historically been difficult to diagnose, especially at the genetic level. In particular, for cases of 46,XY gonadal dysgenesis, once variants in SRY and NR5A1 have been ruled out, there are few other single gene tests available. OBJECTIVE: We used exome sequencing followed by analysis with a list of all known human DSD-associated genes to investigate the underlying genetic etiology of 46,XY DSD patients who had not previously received a genetic diagnosis. DESIGN: Samples were either submitted to the research laboratory or submitted as clinical samples to the UCLA Clinical Genomic Center. Sequencing data were filtered using a list of genes known to be involved in DSD. RESULTS: We were able to identify a likely genetic diagnosis in more than a third of cases, including 22.5% with a pathogenic finding, an additional 12.5% with likely pathogenic findings, and 15% with variants of unknown clinical significance. CONCLUSIONS: Early identification of the genetic cause of a DSD will in many cases streamline and direct the clinical management of the patient, with more focused endocrine and imaging studies and better-informed surgical decisions. Exome sequencing proved an efficient method toward such a goal in 46,XY DSD patients.


Assuntos
Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Exoma , Testes Genéticos/métodos , Transtorno 46,XY do Desenvolvimento Sexual/genética , Humanos , Masculino , Fenótipo
11.
Genet Med ; 16(9): 717-9, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24525916

RESUMO

BACKGROUND: Clinical laboratories began offering whole-exome sequencing in 2011 at a cost between $4,500 and $9,000. Reported detection rates for deleterious mutations range from 25 to 50%. Based on the experience of our clinical genetics service, actual success rates may be lower than estimated rates. We report results from our own experience along with a survey of clinical geneticists to ascertain (i) current success rates for causal gene detection in a clinical setting; (ii) if there are insurance authorization issues; and (iii) if turnaround times quoted by the clinical laboratories are accurate; we also gauge provider opinions toward clinical whole-exome sequencing. METHODS: We reviewed our results and the results of a survey that was electronically distributed to 47 clinical genetics centers. RESULTS: A total of 35 exome reports were available. If all positive results are collated, we observe a success rate of 22.8%. One result incorrectly identified a known benign variant as pathogenic. Some insurers covered all testing, whereas others denied any insurance coverage. Only three (23.1%) of our reports were available within the laboratory's quoted turnaround times. More than 50% of clinicians queried in our survey had not ordered whole-exome sequencing at the current time, many stating concerns regarding interpretation, insurance coverage, and cost. CONCLUSION: Clinical whole-exome sequencing has proven diagnostic utility; however, currently many clinicians have concerns regarding interpretation of results, insurance coverage, and cost.


Assuntos
Exoma , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Pesquisas sobre Serviços de Saúde , Humanos
12.
J Pediatr ; 154(1): 143-6, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19187739

RESUMO

Microarray-based comparative genomic hybridization can determine genome-wide copy number alterations at the kilobase level. We highlight the clinical utility of microarray-based comparative genomic hybridization in determining tumor susceptibility in 3 patients with dysmorphic features and developmental delay, likely decreasing both morbidity and mortality in these patients.


Assuntos
Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/epidemiologia , Predisposição Genética para Doença/epidemiologia , Síndrome de Li-Fraumeni/epidemiologia , Síndrome de Li-Fraumeni/genética , Síndrome de Peutz-Jeghers/epidemiologia , Síndrome de Peutz-Jeghers/genética , Criança , Pré-Escolar , Genes p53/genética , Humanos , Lactente , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Serina-Treonina Quinases/genética
13.
Am J Med Genet A ; 140(24): 2730-41, 2006 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-17103451

RESUMO

Mowat-Wilson syndrome (MWS) is a relatively newly described multiple congenital anomaly/mental retardation syndrome. Haploinsufficiency of a gene termed ZFHX1B (also known as SIP1) on chromosome 2 is responsible for this condition, and clinical genetic testing for MWS recently became available. The majority of reports in the literature originate from Northern Europe and Australia. Here we report our clinical experience with 12 patients diagnosed with MWS within a 2-year period of time in the United States, with particular emphasis on clinical characteristics and management strategies. Individuals with this condition have characteristic facial features, including microcephaly, hypertelorism, medially flared and broad eyebrows, prominent columella, pointed chin, and uplifted earlobes, which typically prompt the clinician to consider the diagnosis. Medical issues in our cohort of patients included seizures (75%) with no predeliction for any particular seizure type; agenesis of the corpus callosum (60% of our patients studied); congenital heart defects (75%), particularly involving the pulmonary arteries and/or valves; hypospadias (55% of males); severely impaired or absent speech (100% of individuals over 1 year of age) with relatively spared receptive language; and Hirschsprung disease (50%) or chronic constipation (25%). The incidence of MWS is unknown, but based on the number of patients identified in a short period of time within the US, it is likely greatly under recognized. MWS should be considered in any individual with severely impaired or absent speech, especially in the presence of seizures and anomalies involving the pulmonary arteries (particularly pulmonary artery sling) or pulmonary valves.


Assuntos
Anormalidades Múltiplas/genética , Deficiência Intelectual/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/terapia , Adolescente , Adulto , Agenesia do Corpo Caloso , Criança , Pré-Escolar , Anormalidades Craniofaciais/genética , Feminino , Doença de Hirschsprung/genética , Proteínas de Homeodomínio/genética , Humanos , Lactente , Recém-Nascido , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Artéria Pulmonar/anormalidades , Proteínas Repressoras/genética , Convulsões/genética , Síndrome , Homeobox 2 de Ligação a E-box com Dedos de Zinco
14.
Eur J Med Genet ; 48(2): 97-111, 2005 Apr-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16053902

RESUMO

Mowat-Wilson Syndrome is a recently delineated mental retardation syndrome usually associated with multiple malformations and a recognizable facial phenotype caused by defects of the transcriptional repressor ZFHX1B. To address the question of clinical and mutational variability, we analysed a large number of patients with suspected Mowat-Wilson Syndrome (MWS). Without prior knowledge of their mutational status, 70 patients were classified into "typical MWS", "ambiguous" and "atypical" groups according to their facial phenotype. Using FISH, qPCR and sequencing, ZFHX1B deletions, splice site or truncating mutations were detected in all 28 patients classified as typical MWS. No ZFHX1B defect was apparent in the remaining 15 cases with ambiguous facial features or in the 27 atypical patients. Genotype-phenotype analysis confirmed that ZFHX1B deletions and stop mutations result in a recognizable facial dysmorphism with associated severe mental retardation and variable malformations such as Hirschsprung disease and congenital heart defects. Our findings indicate that structural eye anomalies such as microphthalmia should be considered as part of the MWS spectrum. We also show that agenesis of the corpus callosum and urogenital anomalies (especially hypospadias) are significant positive predictors of a ZFHX1B defect. Based on our observation of affected siblings and the number of MWS cases previously reported, we suggest a recurrence risk of around 1%. The lack of missense mutations in MWS and MWS-like patients suggests there may be other, as yet unrecognized phenotypes, associated with missense mutations of this transcription factor.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Homeodomínio/genética , Deficiência Intelectual/genética , Mutação , Proteínas Repressoras/genética , Adolescente , Adulto , Sequência de Bases , Criança , Pré-Escolar , Códon de Terminação/genética , DNA/genética , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Fenótipo , Processamento de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Deleção de Sequência , Síndrome , Homeobox 2 de Ligação a E-box com Dedos de Zinco
15.
Am J Med Genet A ; 132A(3): 263-4, 2005 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-15523636

RESUMO

Over the last 20 years, a wide spectrum of congenital anomalies have been described in association with Kabuki syndrome (KS). However, very little information is available on developmental outcome. As more individuals with this syndrome are recognized and reported, it appears that as many as one-sixth may have normal intelligence. The purpose of this report is to describe the developmental outcome in 15 patients with KS, to determine whether a recognizable pattern of disabilities exist, and whether developmental outcome correlates with the presence of malformations. We ascertained 15 patients with KS from three dysmorphology and clinical genetics services in which developmental milestones and formal developmental testing were available. Based on these patients and a review of the literature, in the absence of major structural brain anomalies, the average intelligence quotient (IQ) in patients with this condition fall within the mild mental retardation range, however, specific developmental outcomes are widely variable, ranging from severe MR to normal intelligence. The presence or absence of hearing loss or major malformations, other than those involving the brain, was not predictive of developmental outcome.


Assuntos
Anormalidades Múltiplas/psicologia , Cognição , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Desenvolvimento da Linguagem , Anormalidades Múltiplas/patologia , Adolescente , Criança , Pré-Escolar , Fissura Palatina/patologia , Transtornos do Crescimento/patologia , Humanos , Lactente , Deficiência Intelectual/patologia , Síndrome
16.
Lancet ; 363(9412): 852-9, 2004 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-15031030

RESUMO

BACKGROUND: Juvenile polyposis and hereditary haemorrhagic telangiectasia are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in MADH4 (encoding SMAD4) or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG (endoglin) or ACVRL1 (ALK1). All four genes encode proteins involved in the transforming-growth-factor-beta signalling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic aetiology of this association is unknown. METHODS: Blood samples were collected from seven unrelated families segregating both phenotypes. DNA from the proband of each family was sequenced for the ACVRL1, ENG, and MADH4 genes. Mutations were examined for familial cosegregation with phenotype and presence or absence in population controls. Findings No patient had mutations in the ENG or ACVRL1 genes; all had MADH4 mutations. Three cases of de-novo MADH4 mutations were found. In one, the mutation was passed on to a similarly affected child. Each mutation cosegregated with the syndromic phenotype in other affected family members. INTERPRETATION: Mutations in MADH4 can cause a syndrome consisting of both juvenile polyposis and hereditary haemorrhagic telangiectasia phenotypes. Since patients with these disorders are generally ascertained through distinct medical specialties, genetic testing is recommended for patients presenting with either phenotype to identify those at risk of this syndrome. Patients with juvenile polyposis who have an MADH4 mutation should be screened for the vascular lesions associated with hereditary haemorrhagic telangiectasia, especially occult arteriovenous malformations in visceral organs that may otherwise present suddenly with serious medical consequences.


Assuntos
Polipose Adenomatosa do Colo/genética , Proteínas de Ligação a DNA/genética , Mutação , Transdução de Sinais/genética , Telangiectasia Hemorrágica Hereditária/genética , Transativadores/genética , Polipose Adenomatosa do Colo/epidemiologia , Comorbidade , Expressão Gênica/genética , Expressão Gênica/fisiologia , Humanos , Fenótipo , Transdução de Sinais/fisiologia , Proteína Smad4 , Síndrome , Telangiectasia Hemorrágica Hereditária/epidemiologia
17.
Hum Mutat ; 23(2): 147-59, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14722918

RESUMO

We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.


Assuntos
Regulação da Expressão Gênica/genética , Proteínas de Homeodomínio/genética , Mutação/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Agenesia do Corpo Caloso , Células Cultivadas , Corpo Caloso/patologia , Análise Mutacional de DNA/métodos , Feminino , Ligação Genética/genética , Genitália Feminina/anormalidades , Genitália Feminina/patologia , Genitália Masculina/anormalidades , Genitália Masculina/patologia , Genótipo , Proteínas de Homeodomínio/biossíntese , Humanos , Recém-Nascido , Linfócitos/química , Linfócitos/metabolismo , Linfócitos/patologia , Imagem por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Transtornos dos Cromossomos Sexuais/genética , Fatores de Transcrição/biossíntese
18.
Nat Genet ; 32(4): 661-5, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12415272

RESUMO

Börjeson-Forssman-Lehmann syndrome (BFLS; OMIM 301900) is characterized by moderate to severe mental retardation, epilepsy, hypogonadism, hypometabolism, obesity with marked gynecomastia, swelling of subcutaneous tissue of the face, narrow palpebral fissure and large but not deformed ears. Previously, the gene associated with BFLS was localized to 17 Mb in Xq26-q27 (refs 2-4). We have reduced this interval to roughly 9 Mb containing more than 62 genes. Among these, a novel, widely expressed zinc-finger (plant homeodomain (PHD)-like finger) gene (PHF6) had eight different missense and truncation mutations in seven familial and two sporadic cases of BFLS. Transient transfection studies with PHF6 tagged with green fluorescent protein (GFP) showed diffuse nuclear staining with prominent nucleolar accumulation. Such localization, and the presence of two PHD-like zinc fingers, is suggestive of a role for PHF6 in transcription.


Assuntos
Predisposição Genética para Doença , Deficiência Intelectual/genética , Mutação , Motivos de Aminoácidos , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Nucléolo Celular/metabolismo , Núcleo Celular/metabolismo , Embrião de Mamíferos/metabolismo , Feminino , Proteínas de Fluorescência Verde , Células HeLa , Heterozigoto , Humanos , Proteínas Luminescentes/metabolismo , Masculino , Camundongos , Repetições de Microssatélites , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem , Mapeamento Físico do Cromossomo , Alinhamento de Sequência , Síndrome , Transfecção , Cromossomo X , Dedos de Zinco
19.
Mol Genet Metab ; 75(2): 120-7, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11855930

RESUMO

Tandem mass spectrometry (MS/MS) has been introduced in several newborn screening programs for the detection of a large number of inborn errors of metabolism, including fatty acid oxidation disorders (FAOD). Early identification and treatment of FAOD have the potential to improve outcome and may be life-saving in some cases; an estimated 5% of sudden infant deaths are attributable to undiagnosed disorders of fatty acid oxidation. We report very early neonatal presentations of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (TFP) deficiencies confirmed by molecular analysis. Both patients had cardiorespiratory collapse and hypoglycemia, without a history of maternal pregnancy complications. Retrospective MS/MS analysis of the original newborn screening blood spots revealed characteristic acylcarnitine profiles. These cases are among the earliest reported presentations of LCHAD and TFP deficiencies and further illustrate the potential of MS/MS as a valuable tool for newborn screening of FAOD. However, timely analysis and reporting of results to clinicians are essential, because these disorders can manifest in the first few days of life.


Assuntos
3-Hidroxiacil-CoA Desidrogenases/deficiência , Erros Inatos do Metabolismo/diagnóstico , Complexos Multienzimáticos/deficiência , Adulto , Ácidos Graxos/metabolismo , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/patologia , Proteína Mitocondrial Trifuncional , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Gravidez , Fatores de Tempo
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