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1.
Hum Mutat ; 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31769566

RESUMO

Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS), and Chronic Intestinal Pseudo-Obstruction (CIPO). The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides, accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2- negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178 > p.Arg257 > p.Arg40 along with other less frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy. This article is protected by copyright. All rights reserved.

3.
J Pediatr Nurs ; 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31027866

RESUMO

PURPOSE: Most of the research in the field of esophageal atresia (EA) is focused on diagnostic problems and surgery. There is scarce literature addressing the impact of EA on the lives of families of patients. The aim of this paper is to investigate whether the presence of underlying associated malformations, disease-specific feeding problems and prematurity would have a significant influence on the family of a child after surgical repair of EA. DESIGN AND METHODS: The study sample consisted of 73 participants who were parents of children after surgery of EA. The impact of EA on families was assessed using an Authors-Designed Questionnaire (ADQ) to collect medical and sociodemographic background data as well as standardized questionnaire: the PedsQL™ Family Impact Module (PedsQL-FIM). RESULTS: The presence of cardiac impairment significantly (p = 0.037) affects the functioning of the family in the emotional domain. The coexistence of skeletal impairment seems to have the greatest impact on the functioning of the family, three statistically significant correlations have been demonstrated: (p = 0.021) - in the social domain, (p = 0.009) - in the cognitive domain and (p = 0.023) - in the domain of communication. The families of patients with tracheoesophageal fistula (TEF) had the statistically lower (p < 0.05) score of functioning in the emotional domain than those with children without TEF. CONCLUSION: Feeding problems and the presence of associated anomalies significantly affect the functioning of the family of the child with EA.

4.
Epigenomics ; 11(7): 767-785, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30873861

RESUMO

Aim: Fetal alcohol spectrum disorder (FASD) involves prenatal growth delay, impaired facial and CNS development and causes severe clinical, social-economic burdens. Here, we aim to detect DNA-methylation aberrations associated with FASD and potential FASD diagnostic and prognostic biomarkers. Patients & methods: The FASD diagnosis was established according to golden-standard protocols in a discovery and independent replication cohort. Genome-wide differential methylation association and replication analyses were performed. Results: We identified several loci that were robustly associated with FASD or one of its sub phenotypes. Our findings were evaluated using previously reported genome-wide surveys. Conclusion: We have detected robust FASD associated differentially methylated positions and differentially methylated regions for FASD in general and for FASD subphenotypes, in other words on growth delay, impaired facial and CNS development.

5.
Clin Genet ; 95(4): 462-478, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30677142

RESUMO

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, specific facial features, and marked autonomic nervous system dysfunction, especially with disturbances of regulating respiration and intestinal mobility. It is caused by variants in the transcription factor TCF4. Heterogeneity in the clinical and molecular diagnostic criteria and care practices has prompted a group of international experts to establish guidelines for diagnostics and care. For issues, for which there was limited information available in international literature, we collaborated with national support groups and the participants of a syndrome specific international conference to obtain further information. Here, we discuss the resultant consensus, including the clinical definition of PTHS and a molecular diagnostic pathway. Recommendations for managing particular health problems such as dysregulated respiration are provided. We emphasize the need for integration of care for physical and behavioral issues. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimization of diagnostics and care.

6.
Am J Hum Genet ; 104(2): 319-330, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639322

RESUMO

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Mutação Puntual , Fatores de Transcrição/genética , Alelos , Animais , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Camundongos , Síndrome , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
7.
J Med Genet ; 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30352868

RESUMO

BACKGROUND: Mapping the breakpoints in de novo balanced chromosomal translocations (BCT) in symptomatic individuals provides a unique opportunity to identify in an unbiased way the likely causative genetic defect and thus find novel human disease candidate genes. Our aim was to fine-map breakpoints of de novo BCTs in a case series of nine patients. METHODS: Shallow whole-genome mate pair sequencing (SGMPS) together with long-range PCR and Sanger sequencing. In one case (BCT disrupting BAHD1 and RET) cDNA analysis was used to verify expression of a fusion transcript in cultured fibroblasts. RESULTS: In all nine probands 11 disrupted genes were found, that is, EFNA5, EBF3, LARGE, PPP2R5E, TXNDC5, ZNF423, NIPBL, BAHD1, RET, TRPS1 and SLC4A10. Five subjects had translocations that disrupted genes with so far unknown (EFNA5, BAHD1, PPP2R5E, TXNDC5) or poorly delineated impact on the phenotype (SLC4A10, two previous reports of BCT disrupting the gene). The four genes with no previous disease associations (EFNA5, BAHD1, PPP2R5E, TXNDC5), when compared with all human genes by a bootstrap test, had significantly higher pLI (p<0.017) and DOMINO (p<0.02) scores indicating enrichment in genes likely to be intolerant to single copy damage. Inspection of individual pLI and DOMINO scores, and local topologically associating domain structure suggested that EFNA5, BAHD1 and PPP2R5E were particularly good candidates for novel disease loci. The pathomechanism for BAHD1 may involve deregulation of expression due to fusion with RET promoter. CONCLUSION: SGMPS in symptomatic carriers of BCTs is a powerful approach to delineate novel human gene-disease associations.

8.
Hum Mol Genet ; 27(21): 3669-3674, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30124836

RESUMO

The Neurofascins (NFASCs) are a family of proteins encoded by alternative transcripts of NFASC that cooperate in the assembly of the node of Ranvier in myelinated nerves. Differential expression of NFASC in neurons and glia presents a remarkable example of cell-type specific expression of protein isoforms with a common overall function. In mice there are three NFASC isoforms: Nfasc186 and Nfasc140, located in the axonal membrane at the node of Ranvier, and Nfasc155, a glial component of the paranodal axoglial junction. Nfasc186 and Nfasc155 are the major isoforms at mature nodes and paranodes, respectively. Conditional deletion of the glial isoform Nfasc155 in mice causes severe motor coordination defects and death at 16-17 days after birth. We describe a proband with severe congenital hypotonia, contractures of fingers and toes, and no reaction to touch or pain. Whole exome sequencing revealed a homozygous NFASC variant chr1:204953187-C>T (rs755160624). The variant creates a premature stop codon in 3 out of four NFASC human transcripts and is predicted to specifically eliminate Nfasc155 leaving neuronal Neurofascin intact. The selective absence of Nfasc155 and disruption of the paranodal junction was confirmed by an immunofluorescent study of skin biopsies from the patient versus control. We propose that the disease in our proband is the first reported example of genetic deficiency of glial Neurofascin isoforms in humans and that the severity of the condition reflects the importance of the Nfasc155 in forming paranodal axoglial junctions and in determining the structure and function of the node of Ranvier.

9.
Eur J Hum Genet ; 26(10): 1502-1511, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29899372

RESUMO

PTPN23 encodes a ubiquitously expressed non-receptor type, catalytically inactive protein-tyrosine phosphatase found in all cells including neurons. Recently, we have identified PTPN23 in a cellular screen for the systematic identification of novel regulators of survival motor neuron (SMN) function in the assembly of splicing factors (Uridine-rich small nuclear ribonucleoproteins, UsnRNPs). Based on three families, recessive PTPN23 variants have been associated with human disease tentatively, without functional studies. Here, we describe a pediatric proband with severe developmental delay, epilepsy, cortical blindness, hypomyelination and brain atrophy on MRI. Whole exome sequencing and family study showed two novel PTPN23 variants, c.1902C>G (p.(Asn634Lys)) and c.2974delC (p.(Leu992Tyrfs*168)), in compound heterozygous state, which are predicted in silico to be damaging. When studying patient's fibroblasts we found similar expression of SMN but a dramatic reduction of cells displaying SMN accumulation in Cajal bodies (CB). SMN strongly accumulated in CB in more than 50% of unrelated control cell fibroblasts as well as in fibroblasts from the parent carrying only the c.2974delC (p.(Leu992Tyrfs*168)) variant (predicted to cause loss-of-function). In contrast, only 22% of cells showed respective SMN accumulations in patient fibroblasts (p = 1.9-2.5 × 10-7) while showing a higher level of nucleoplasmic SMN. Furthermore, the remaining accumulations in patient cells displayed weaker SMN signals than control or heterozygous wt/c.2974delC (p.(Leu992Tyrfs*168)) fibroblasts. Our report provides the first description of the clinical phenotype of recessive PTPN23 variants with pathogenicity substantiated by a functional study.

10.
Am J Med Genet A ; 176(7): 1670-1674, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29799162

RESUMO

Cardio-facio-cutaneous syndrome (CFCS), a rare congenital disorder of RASopathies, displays high phenotypic variability. Complications during pregnancy and in the perinatal period are commonly reported. Polyhydramnios is observed in over half of pregnancies and might occur with fetal macrocephaly, macrosomia, and/or heart defects. Premature birth is not uncommon and any complications like respiratory insufficiency, edema, and feeding difficulties are present and might delay accurate clinical diagnosis. Besides neonatal complications, CFCS newborns and later infants have distinctive dysmorphic features usually accompanied by neurological (hypotonia with motor delay, neurocognitive delay) findings. Also, heart defects usually present at birth. Herein, we present the case of a female baby born prematurely from a pregnancy complicated with polyhydramnios, presenting at birth with craniofacial features typical for RASopathies, heart defects, neurological abnormalities, and hyperkeratosis unusual for a neonatal period. Due to the presence of a heart defect and other complications related to premature birth, the course of the disease was severe with a fatal outcome at the age of 9 months. The RASopathy, particularly CFCS, clinical diagnosis was confirmed and de novo p.Phe57Ile mutation in MAP2K2 was identified.

11.
Eur J Pediatr Surg ; 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29635651

RESUMO

INTRODUCTION: Esophageal atresia (EA) is one of the most frequent congenital malformations of the gastrointestinal tract. The aim of the study was to assess surgical treatment results in the context of the quality of life (QoL) of children after correction of EA. MATERIALS AND METHODS: The data were collected among 73 patients after surgery of EA. The work diagnostic survey method was applied using authors' own questionnaire and standardized questionnaire, the PedsQL 4.0 generic core scales. Analysis of children growth was done based on World Health Organization percentile charts for body height and weight. Medical background for each patient, including demographic data, type of EA, type of delivery, the age of gestation, associated anomalies, mode of repair-primary and subsequent, if applicable, was collected from clinical records. Additional anomalies were divided into cardiac, skeletal, respiratory, renal, central nervous system, and other malformations (VACTERL association, CHARGE syndrome, trisomy chromosomes 18 and 21, and others). RESULTS: In this study, 23% of children in the study group weighted below third percentile, 36% were born between 33rd and 37th week of gestation; 56% had at least one associated congenital anomalies. The QoL of children born before 37th week of gestational age was lower (p < 0.034) in social functioning than children born in term. The presence of concomitant anomalies does affect the overall generic QoL. No statistical correlation was found between the type of anomaly (with/without TEF) and patients' QoL. CONCLUSION: It seems to be needed to extend psychological care of premature infants with EA.

13.
J Hum Genet ; 63(4): 517-520, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29410511

RESUMO

Overgrowth, macrocephaly, accelerated osseous maturation, variable intellectual disability, and characteristic facial features are the main symptoms of Weaver syndrome, a rare condition caused by mutations in EZH2 gene. Recently, in four patients with Weaver-like symptoms without mutations in EZH2 gene, pathogenic variants in EED were described. We present another patient clinically diagnosed with Weaver syndrome in whom WES revealed an EED de novo mutation affecting two neighboring aminoacids, NM_003797.3:c.917_919delinsCGG/p.(Arg306_Asn307delinsThrAsp) located in one allele (in cis). Our observation, together with previous reports suggests that EED gene testing is warranted in patients with the overgrowth syndrome features and suspicion of Weaver syndrome with normal results of EZH2 gene sequencing.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Substituição de Aminoácidos , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Mutação , Complexo Repressor Polycomb 2/genética , Alelos , Análise Mutacional de DNA , Facies , Humanos , Lactente , Masculino , Fenótipo , Sequenciamento Completo do Exoma
14.
PLoS Genet ; 13(3): e1006683, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28346496

RESUMO

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Transporte/genética , Anormalidades Craniofaciais/genética , Predisposição Genética para Doença/genética , Deformidades Congênitas da Mão/genética , Neoplasias Hematológicas/genética , Deficiência Intelectual/genética , Mutação , Unhas Malformadas/genética , Proteínas Nucleares/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Western Blotting , Proteínas de Transporte/metabolismo , Linhagem Celular , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Criança , Pré-Escolar , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Células HEK293 , Deformidades Congênitas da Mão/metabolismo , Deformidades Congênitas da Mão/patologia , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Unhas Malformadas/metabolismo , Unhas Malformadas/patologia , Proteínas Nucleares/metabolismo , Fenótipo
15.
Curr Neurol Neurosci Rep ; 17(3): 22, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28283957

RESUMO

Migraine and stroke are common, disabling neurologic disorders, with a high socioeconomic burden. A link between them has been proposed years ago, and various theories have been proposed to explain this bidirectional relation. However, the precise causes remain unclear. We briefly summarize existing hypotheses of this correlation seeking for recommendations for stroke prevention in migraineurs, if any exist. Among the strongest suggested theories of migraine-stroke association are cortical spreading depression, endovascular dysfunction, vasoconstriction, neurogenic inflammation, hypercoagulability, increased prevalence of vascular risk factors, shared genetic defects, cervical artery dissection, and patent foramen ovale. There is no evidence that any preventive therapy in migraineurs should be used to decrease stroke risk, even in most predisposed subset of patients. However, a woman with migraine with aura should be encouraged to cease smoking and avoid taking oral contraceptives with high estrogen doses. We need further investigation to better understand the complexity of migraine-stroke association and to make firm recommendations for the future.


Assuntos
Transtornos de Enxaqueca/epidemiologia , Fumar , Acidente Vascular Cerebral/epidemiologia , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Endotélio Vascular/fisiopatologia , Humanos , Transtornos de Enxaqueca/fisiopatologia , Prevalência , Acidente Vascular Cerebral/fisiopatologia
16.
J Appl Genet ; 58(1): 93-98, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27629806

RESUMO

Chromosome 22q11.2 deletion syndrome, one of the most common human genomic syndromes, has highly heterogeneous clinical presentation. Patients usually harbor a 1.5 to 3 Mb hemizygous deletion at chromosome 22q11.2, resulting in pathognomic TBX1, CRKL and/or MAPK1 haploinsufficiency. However, there are some individuals with clinical features resembling the syndrome who are eventually diagnosed with genomic disorders affecting other chromosomal regions. The objective of this study was to evaluate the additive value of high-resolution array-CGH testing in the cohort of 41 patients with clinical features of 22q11.2 deletion syndrome and negative results of standard cytogenetic diagnostic testing (karyotype and FISH for 22q11.2 locus). Array-CGH analysis revealed no aberrations at chromosomes 22 or 10 allegedly related to the syndrome. Five (12.2 %) patients were found to have other genomic imbalances, namely 17q21.31 microdeletion syndrome (MIM#610443), 1p36 deletion syndrome (MIM#607872), NF1 microduplication syndrome (MIM#613675), chromosome 6pter-p24 deletion syndrome (MIM#612582) and a novel interstitial deletion at 3q26.31 of 0.65 Mb encompassing a dosage-dependent gene NAALADL2. Our study demonstrates that the implementation of array-CGH into the panel of classic diagnostic procedures adds significantly to their efficacy. It allows for detection of constitutional genomic imbalances in 12 % of subjects with negative result of karyotype and FISH targeted for 22q11.2 region. Moreover, if used as first-tier genetic test, the method would provide immediate diagnosis in ∼40 % phenotypic 22q11.2 deletion subjects.


Assuntos
Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 6/genética , Hibridização Genômica Comparativa , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Facies , Feminino , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Humanos , Hipertelorismo/diagnóstico , Hipertelorismo/genética , Hibridização in Situ Fluorescente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Cariotipagem , Masculino , Neurofibromatoses/diagnóstico , Neurofibromatoses/genética
17.
Am J Med Genet A ; 173(1): 72-78, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27612309

RESUMO

Defects of 11p15.5 imprinting result in two growth disorders with opposite phenotypes: Beckwith-Wiedemann syndrome (BWS) characterized by overgrowth and Silver-Russell syndrome (SRS) associated with growth retardation. In a small group of patients with BWS and SRS, copy number variations (CNVs) involving the 11p15.5 region are observed; and their effects depend on the localization, size, and the parental mode of transmission. We report a novel IGF2/H19 domain cis-triplication in the 11p15.5 region identified in a girl with BWS and her father with symptoms of SRS. To the best of our knowledge, this is the first report of IGF2/H19 domain triplication associated with BWS or SRS and the second report of an additional copy of this region in an individual with clinical features of SRS. This study shows that paternal IGF2/H19 domain triplication results in BWS, gives additional support to the hypothesis that the maternal amplification of IGF2/H19 domain may lead to the manifestation of SRS and underlines difficulties of genetic counseling in patients with CNVs involving the 11p15.5 region. © 2016 Wiley Periodicals, Inc.


Assuntos
Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Cromossomos Humanos Par 11 , Impressão Genômica , Fator de Crescimento Insulin-Like II/genética , RNA Longo não Codificante/genética , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/genética , Pré-Escolar , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Metilação de DNA , Feminino , Amplificação de Genes , Estudos de Associação Genética , Humanos , Lactente , Masculino , Repetições de Microssatélites , Modelos Genéticos , Linhagem , Fenótipo
18.
Am J Med Genet A ; 170(12): 3265-3270, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27605359

RESUMO

Epileptic encephalopathies (EE) include a range of severe epilepsies in which intractable seizures or severe sub-clinical epileptiform activity are accompanied by impairment of motor and cognitive functions. Mutations in several genes including ion channels and other genes whose function is not completely understood have been associated to some EE. In this report, we provide a detailed clinical description of a sporadic male patient with early-onset epilepsy and epileptic encephalopathy in whom we performed complete exome sequencing (WES) and identified a GRIN2B mutation. The GRIN2B splicing mutation in intron 10 (c.2011-1G>A) was revealed in a WES study. The result was confirmed by Sanger sequencing. No mutation was found in both parents. Our finding confirms that early-onset EE may be caused not only by gain-of-function variants but also by splice site mutations-in particular those affecting the splice acceptor site of the 10th intron of the GRIN2B gene. © 2016 Wiley Periodicals, Inc.


Assuntos
Epilepsia/diagnóstico , Epilepsia/genética , Estudos de Associação Genética , Mutação , Fenótipo , Receptores de N-Metil-D-Aspartato/genética , Biomarcadores , Criança , Deleção Cromossômica , Cromossomos Humanos Par 4 , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Eletroencefalografia , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imagem por Ressonância Magnética , Masculino , Neuroimagem , Exame Físico , Sítios de Splice de RNA
19.
Am J Med Genet A ; 170(12): 3069-3082, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27648933

RESUMO

Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteína de Ligação a CREB/genética , Proteína p300 Associada a E1A/genética , Pré-Eclâmpsia/genética , Síndrome de Rubinstein-Taybi/genética , Adulto , Montagem e Desmontagem da Cromatina/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Pré-Eclâmpsia/fisiopatologia , Gravidez , Síndrome de Rubinstein-Taybi/patologia , Deleção de Sequência
20.
Adv Exp Med Biol ; 912: 1-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26987320

RESUMO

Major congenital anomalies are detectable in 2-3 % of the newborn population. Some of their genetic causes are attributable to copy number variations identified by array comparative genomic hybridization (aCGH). The value of aCGH screening as a first-tier test in children with multiple congenital anomalies has been studied and consensus adopted. However, array resolution has not been agreed upon, specifically in the newborn or infant population. Moreover, most array studies have been focused on mixed populations of intellectual disability/developmental delay with or without multiple congenital anomalies, making it difficult to assess the value of microarrays in newborns. The aim of the study was to determine the optimal quality and clinical sensitivity of high-resolution array comparative genomic hybridization in neonates with multiple congenital anomalies. We investigated a group of 54 newborns with multiple congenital anomalies defined as two or more birth defects from more than one organ system. Cytogenetic studies were performed using OGT CytoSure 8 × 60 K microarray. We found ten rearrangements in ten newborns. Of these, one recurrent syndromic microduplication was observed, whereas all other changes were unique. Six rearrangements were definitely pathogenic, including one submicroscopic and five that could be seen on routine karyotype analysis. Four other copy number variants were likely pathogenic. The candidate genes that may explain the phenotype were discussed. In conclusion, high-resolution array comparative hybridization can be applied successfully in newborns with multiple congenital anomalies as the method detects a significant number of pathogenic changes, resulting in early diagnoses. We hypothesize that small changes previously considered benign or even inherited rearrangements should be classified as potentially pathogenic at least until a subsequent clinical assessment would exclude a developmental delay or dysmorphism.


Assuntos
Anormalidades Múltiplas/genética , Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA , Feminino , Humanos , Recém-Nascido , Masculino
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