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1.
Am J Hum Genet ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31708118

RESUMO

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)-96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13-were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), structural chromosomal aberrations (95, 0.16%, PPV 32%,) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up.

2.
Clin Pharmacol Ther ; 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594036

RESUMO

For ~ 80 drugs, widely recognized pharmacogenetics dosing guidelines are available. However, the use of these guidelines in clinical practice remains limited as only a fraction of patients is subjected to pharmacogenetic screening. We investigated the feasibility of repurposing whole exome sequencing (WES) data for a panel of 42 variants in 11 pharmacogenes to provide a pharmacogenomic profile. Existing diagnostic WES-data from child-parent trios totaling 1,583 individuals were used. Results were successfully extracted for 39 variants. No information could be extracted for three variants, located in CYP2C19, UGT1A1, and CYP3A5, and for CYP2D6 copy number. At least one actionable phenotype was present in 86% of the individuals. Haplotype phasing proved relevant for CYP2B6 assignments as 1.5% of the phenotypes were corrected after phasing. In conclusion, repurposing WES-data can yield meaningful pharmacogenetic profiles for 7 of 11 important pharmacogenes, which can be used to guide drug treatment.

3.
Am J Hum Genet ; 105(3): 493-508, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31447100

RESUMO

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.

5.
Genet Med ; 21(10): 2303-2310, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30918357

RESUMO

PURPOSE: Exome sequencing (ES) is an efficient tool to diagnose genetic disorders postnatally. Recent studies show that it may have a considerable diagnostic yield in fetuses with structural anomalies on ultrasound. We report on the clinical impact of the implementation of prenatal ES (pES) for ongoing pregnancies in routine care. METHODS: We retrospectively analyzed the impact of pES on pregnancy outcome and pre- or perinatal management in the first 22 patients counseled for pES because of one or more structural anomalies on fetal ultrasound. RESULTS: In two cases, a diagnosis was made by chromosomal microarray analysis after ES counseling. The remaining 20 cases were divided in three groups: (1) pES to aid parental decision making (n = 12), (2) pES in the context of late pregnancy termination requests (n = 5), and (3) pES to guide pre- or perinatal management (n = 3). pES had a clinical impact in 75% (9/12), 40% (2/5), and 100% (3/3) respectively, showing an overall clinical impact of pES of 70% (14/20). CONCLUSION: We show that clinical implementation of pES is feasible and affects parental decision making or pre- and perinatal management supporting further implementation of ES in the prenatal setting.

6.
Neurobiol Dis ; 121: 187-204, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30296617

RESUMO

Loss-of-function mutations in the recycling endosomal (Na+,K+)/H+ exchanger gene SLC9A6/NHE6 result in overacidification and dysfunction of endosomal-lysosomal compartments, and cause a neurodevelopmental and degenerative form of X-linked intellectual disability called Christianson Syndrome (CS). However, knowledge of the disease heterogeneity of CS is limited. Here, we describe the clinical features and underlying molecular and cellular mechanisms associated with a CS patient carrying a de novo missense variant (p.Gly218Arg; G218R) of a conserved residue in its ion translocation domain that results in a potential gain-of-function. The patient manifested several core symptoms typical of CS, including pronounced cognitive impairment, mutism, epilepsy, ataxia and microcephaly; however, deterioration of motor function often observed after the first decade of life in CS children with total loss of SLC9A6/NHE6 function was not evident. In transfected non-neuronal cells, complex glycosylation and half-life of the G218R were significantly decreased compared to the wild-type transporter. This correlated with elevated ubiquitination and partial proteasomal-mediated proteolysis of G218R. However, a major fraction was delivered to the plasma membrane and endocytic pathways. Compared to wild-type, G218R-containing endosomes were atypically alkaline and showed impaired uptake of recycling endosomal cargo. Moreover, instead of accumulating in recycling endosomes, G218R was redirected to multivesicular bodies/late endosomes and ejected extracellularly in exosomes rather than progressing to lysosomes for degradation. Attenuated acidification and trafficking of G218R-containing endosomes were also observed in transfected hippocampal neurons, and correlated with diminished dendritic branching and density of mature mushroom-shaped spines and increased appearance of filopodia-like protrusions. Collectively, these findings expand our understanding of the genetic diversity of CS and further elucidate a critical role for SLC9A6/NHE6 in fine-tuning recycling endosomal pH and cargo trafficking, processes crucial for the maintenance of neuronal polarity and mature synaptic structures.


Assuntos
Ataxia/genética , Ataxia/patologia , Endossomos/metabolismo , Epilepsia/genética , Epilepsia/patologia , Mutação com Ganho de Função , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Microcefalia/genética , Microcefalia/patologia , Neurônios/patologia , Transtornos da Motilidade Ocular/genética , Transtornos da Motilidade Ocular/patologia , Trocadores de Sódio-Hidrogênio/genética , Adulto , Animais , Atrofia , Cricetulus , Dendritos/patologia , Vesículas Extracelulares/metabolismo , Células HeLa , Hipocampo/patologia , Humanos , Masculino , Mutação de Sentido Incorreto , Trocadores de Sódio-Hidrogênio/química , Adulto Jovem
8.
Genet Med ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30287924

RESUMO

PURPOSE: Several studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population. METHODS: We retrospectively evaluated all genetic NICU consultations in a 2-year period. RESULTS: In 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.4%) were made using standard genetic workup. Most diagnoses (65.6%) were made within 16 days. Diagnostic ES yield was 5/29 (17.2%). Genetic diagnoses had a direct effect on clinical management in 90.6% (29/32) of patients. CONCLUSIONS: Our study shows that exome sequencing has a place in NICU diagnostics, but given the associated costs and the high yield of alternative diagnostic strategies, we recommend to first perform clinical genetic consultation.

9.
Ann Neurol ; 84(5): 788-795, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30269351

RESUMO

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy-like phenotype in a subset of patients. Ann Neurol 2018;84:796-803.

10.
Genet Med ; 20(5): 480-485, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29121006

RESUMO

PurposeNoninvasive prenatal screening (NIPS) using cell-free DNA in maternal blood is highly sensitive for detecting fetal trisomies 21, 18, and 13. Using a genome-wide approach, other chromosome anomalies can also be detected. We report on the origin, frequency, and clinical significance of these other chromosome aberrations found in pregnancies at risk for trisomy 21, 18, or 13.MethodsWhole-genome shallow massively parallel sequencing was used and all autosomes were analyzed.ResultsIn 78 of 2,527 cases (3.1%) NIPS was indicative of trisomy 21, 18, or 13, and in 41 (1.6%) of other chromosome aberrations. The latter were of fetal (n = 10), placental (n = 22), maternal (n = 1) or unknown (n = 7). One case lacked cytogenetic follow-up. Nine of the 10 fetal cases were associated with an abnormal phenotype. Thirteen of the 22 (59%) placental aberrations were associated with fetal congenital anomalies and/or poor fetal growth (

Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Testes Genéticos , Diagnóstico Pré-Natal , Trissomia , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos/métodos , Genômica/métodos , Humanos , Placenta/metabolismo , Gravidez , Resultado da Gravidez , Diagnóstico Pré-Natal/métodos , Sequenciamento Completo do Genoma
12.
Hum Mutat ; 38(11): 1542-1554, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28741757

RESUMO

The closely related paralogues FOXP2 and FOXP1 encode transcription factors with shared functions in the development of many tissues, including the brain. However, while mutations in FOXP2 lead to a speech/language disorder characterized by childhood apraxia of speech (CAS), the clinical profile of FOXP1 variants includes a broader neurodevelopmental phenotype with global developmental delay, intellectual disability, and speech/language impairment. Using clinical whole-exome sequencing, we report an identical de novo missense FOXP1 variant identified in three unrelated patients. The variant, p.R514H, is located in the forkhead-box DNA-binding domain and is equivalent to the well-studied p.R553H FOXP2 variant that cosegregates with CAS in a large UK family. We present here for the first time a direct comparison of the molecular and clinical consequences of the same mutation affecting the equivalent residue in FOXP1 and FOXP2. Detailed functional characterization of the two variants in cell model systems revealed very similar molecular consequences, including aberrant subcellular localization, disruption of transcription factor activity, and deleterious effects on protein interactions. Nonetheless, clinical manifestations were broader and more severe in the three cases carrying the p.R514H FOXP1 variant than in individuals with the p.R553H variant related to CAS, highlighting divergent roles of FOXP2 and FOXP1 in neurodevelopment.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Fatores de Transcrição Forkhead/genética , Mutação de Sentido Incorreto , Fenótipo , Proteínas Repressoras/genética , Substituição de Aminoácidos , Linhagem Celular , Criança , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/química , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica , Genes Reporter , Estudos de Associação Genética , Genótipo , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Mutação com Perda de Função , Imagem por Ressonância Magnética , Masculino , Domínios e Motivos de Interação entre Proteínas , Transporte Proteico , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Sequenciamento Completo do Exoma
13.
Am J Med Genet A ; 170(12): 3289-3293, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27570071

RESUMO

Postaxial polydactyly (PAP) is one of the most common congenital malformations observed in the general population. However, it can also occur as part of a syndrome. Unbiased genetic screening techniques such as exome sequencing are highly appropriate methods to provide a molecular diagnosis in patients with polydactyly due to the large number of mutated genes associated with it. The present study describes a consanguineous family of Pakistani origin with PAP, speech impairment, hearing impairment of variable degree, and proportionate short stature with no prominent intellectual disability or ophthalmological abnormalities. One affected individual of the family was subjected to exome sequencing which resulted in the identification of four homozygous variants including an in-frame deletion (c.1115_1117delCCT; p.(Ser372del) in MKS1, which was later shown to be the only variant segregating with the phenotype. In silico predictions supported the potential pathogenicity of the identified mutation. Additional clinical tests and MRI features of a patient in the family showed a molar tooth sign, which is a hallmark of Joubert syndrome. In conclusion, we have described a pathogenic variant in the MKS1 resulting in a mild Joubert syndrome phenotype, which broadens the spectrum of mutations in the MKS1. © 2016 Wiley Periodicals, Inc.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Ciliopatias/diagnóstico , Ciliopatias/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Mutação , Fenótipo , Proteínas/genética , Retina/anormalidades , Adolescente , Criança , Análise Mutacional de DNA , Exoma , Feminino , Estudos de Associação Genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Paquistão , Linhagem , Locos de Características Quantitativas , Radiografia , Adulto Jovem
14.
Am J Hum Genet ; 99(1): 125-38, 2016 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-27374770

RESUMO

DNA replication precisely duplicates the genome to ensure stable inheritance of genetic information. Impaired licensing of origins of replication during the G1 phase of the cell cycle has been implicated in Meier-Gorlin syndrome (MGS), a disorder defined by the triad of short stature, microtia, and a/hypoplastic patellae. Biallelic partial loss-of-function mutations in multiple components of the pre-replication complex (preRC; ORC1, ORC4, ORC6, CDT1, or CDC6) as well as de novo stabilizing mutations in the licensing inhibitor, GMNN, cause MGS. Here we report the identification of mutations in CDC45 in 15 affected individuals from 12 families with MGS and/or craniosynostosis. CDC45 encodes a component of both the pre-initiation (preIC) and CMG helicase complexes, required for initiation of DNA replication origin firing and ongoing DNA synthesis during S-phase itself, respectively, and hence is functionally distinct from previously identified MGS-associated genes. The phenotypes of affected individuals range from syndromic coronal craniosynostosis to severe growth restriction, fulfilling diagnostic criteria for Meier-Gorlin syndrome. All mutations identified were biallelic and included synonymous mutations altering splicing of physiological CDC45 transcripts, as well as amino acid substitutions expected to result in partial loss of function. Functionally, mutations reduce levels of full-length transcripts and protein in subject cells, consistent with partial loss of CDC45 function and a predicted limited rate of DNA replication and cell proliferation. Our findings therefore implicate the preIC as an additional protein complex involved in the etiology of MGS and connect the core cellular machinery of genome replication with growth, chondrogenesis, and cranial suture homeostasis.


Assuntos
Proteínas de Ciclo Celular/genética , Microtia Congênita/genética , Craniossinostoses/genética , Transtornos do Crescimento/genética , Micrognatismo/genética , Mutação , Patela/anormalidades , Adolescente , Adulto , Alelos , Processamento Alternativo/genética , Sequência de Aminoácidos , Âmnio/citologia , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Células Cultivadas , Criança , Pré-Escolar , Análise Mutacional de DNA , Replicação do DNA , Exoma/genética , Éxons/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Modelos Moleculares , Conformação Proteica , Síndrome , Adulto Jovem
15.
Am J Med Genet A ; 170(10): 2681-93, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27311832

RESUMO

Mutations in CREBBP cause Rubinstein-Taybi syndrome. By using exome sequencing, and by using Sanger in one patient, CREBBP mutations were detected in 11 patients who did not, or only in a very limited manner, resemble Rubinstein-Taybi syndrome. The combined facial signs typical for Rubinstein-Taybi syndrome were absent, none had broad thumbs, and three had only somewhat broad halluces. All had apparent developmental delay (being the reason for molecular analysis); five had short stature and seven had microcephaly. The facial characteristics were variable; main characteristics were short palpebral fissures, telecanthi, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum. Six patients had autistic behavior, and two had self-injurious behavior. Other symptoms were recurrent upper airway infections (n = 5), feeding problems (n = 7) and impaired hearing (n = 7). Major malformations occurred infrequently. All patients had a de novo missense mutation in the last part of exon 30 or beginning of exon 31 of CREBBP, between base pairs 5,128 and 5,614 (codons 1,710 and 1,872). No missense or truncating mutations in this region have been described to be associated with the classical Rubinstein-Taybi syndrome phenotype. No functional studies have (yet) been performed, but we hypothesize that the mutations disturb protein-protein interactions by altering zinc finger function. We conclude that patients with missense mutations in this specific CREBBP region show a phenotype that differs substantially from that in patients with Rubinstein-Taybi syndrome, and may prove to constitute one (or more) separate entities. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteína de Ligação a CREB/genética , Estudos de Associação Genética , Mutação , Fenótipo , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/genética , Adolescente , Adulto , Alelos , Sequência de Aminoácidos , Criança , Pré-Escolar , Exoma , Éxons , Facies , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Adulto Jovem
16.
Neurology ; 86(23): 2171-8, 2016 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-27164704

RESUMO

OBJECTIVE: To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology. METHODS: We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes. RESULTS: We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families. CONCLUSIONS: De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.


Assuntos
Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Estudos de Coortes , Consanguinidade , Heterozigoto , Homozigoto , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/metabolismo , Oócitos , Fenótipo , Convulsões/genética , Convulsões/metabolismo , Xenopus laevis
17.
Prenat Diagn ; 36(2): 177-85, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26716421

RESUMO

OBJECTIVES: To demonstrate the spectrum of copy number variants (CNVs) in fetuses with isolated left-sided congenital heart defects (CHDs), and analyse genetic content. METHODS: Between 2003 and 2012, 200 fetuses were identified with left-sided CHD. Exclusion criteria were chromosomal rearrangements, 22q11.2 microdeletion and/or extra-cardiac malformations (n = 64). We included cases with additional minor anomalies (n = 39), such as single umbilical artery. In 54 of 136 eligible cases, stored material was available for array analysis. CNVs were categorized as either (likely) benign, (likely) pathogenic or of unknown significance. RESULTS: In 18 of the 54 isolated left-sided CHDs we found 28 rare CNVs (prevalence 33%, average 1.6 CNV per person, size 10.6 kb-2.2 Mb). Our interpretation yielded clinically significant CNVs in two of 54 cases (4%) and variants of unknown significance in three other cases (6%). CONCLUSIONS: In left-sided CHDs that appear isolated, with normal chromosome analysis and 22q11.2 FISH analysis, array analysis detects clinically significant CNVs. When counselling parents of a fetus with a left-sided CHD it must be taken into consideration that aside from the cardiac characteristics, the presence of extra-cardiac malformations and chromosomal abnormalities influence the treatment plan and prognosis.


Assuntos
Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , Cardiopatias Congênitas/genética , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/genética , Estenose da Valva Aórtica/congênito , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/genética , Estudos de Coortes , Hibridização Genômica Comparativa , Bases de Dados Factuais , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Humanos , Síndrome do Coração Esquerdo Hipoplásico/diagnóstico por imagem , Síndrome do Coração Esquerdo Hipoplásico/genética , Hibridização in Situ Fluorescente , Gravidez , Ultrassonografia Pré-Natal
18.
Am J Med Genet A ; 167A(8): 1884-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25900458

RESUMO

Copy number variations (CNVs) on the short arm of chromosome 19 are relatively rare. We present a patient with a tandem de novo 3.9 Mb duplication of 19p13.12p13.2 and an adjacent 288 kb deletion of 19p13.12. The CNVs were detected by genome wide SNP-array and confirmed by fluorescence in situ hybridization. Mate-pair sequencing revealed two breakpoint junctions leading to a germline tandem inverted duplication and an adjacent deletion. The patient had a major congenital heart defect and refractory edema leading to metabolic and endocrinological disturbances. Further complications occurred due to refractory chylothorax, severe inflammatory response syndrome, and repeating sepsis. After 2 months, the child died due to intractable respiratory failure. The phenotype of this patient was compared with reported patients with overlapping deletions or duplications. We conclude that the congenital heart defect, respiratory insufficiency, and abnormal neurologic examination are most likely due the contiguous gene deletion/duplication.


Assuntos
Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 19 , Humanos , Recém-Nascido , Masculino
19.
Hum Mutat ; 36(6): 648-55, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25772376

RESUMO

Although the benefits of next-generation sequencing (NGS) for the diagnosis of heterogeneous diseases such as intellectual disability (ID) are undisputed, there is little consensus on the relative merits of targeted enrichment, whole-exome sequencing (WES) or whole-genome sequencing (WGS). To answer this question, WES and WGS data from the same nine samples were compared, and WES was shown not to miss any variants identified by WGS in a gene panel including ∼500 genes linked to ID (500GP). Additionally, deeply sequenced WES data were shown to adequately cover ∼99% of the 500GP; thus, little additional benefit was to be expected from a targeted enrichment approach. To reduce costs, minimal sequencing criteria were determined by investigating the relation between sequenced reads and outcome parameters such as coverage and variant yield. Our analysis indicated that 60 million reads yielded a mean coverage of ∼60×: ∼97% of the 500GP sequences were sufficiently covered to exclude variants, whereas variant yield was ∼99.5% and false-positive and false-negative rates were controlled. Our findings indicate that WES is currently the optimal approach to ID diagnostics. This result depends on the capture kit and sequencing strategy used. The developed framework however is amenable to other sequencing approaches.


Assuntos
Testes Genéticos/métodos , Genômica/métodos , Exoma , Testes Genéticos/normas , Genoma Humano , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/normas , Genômica/normas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
20.
Eur J Med Genet ; 57(4): 163-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24525055

RESUMO

Microdeletions in the 15q22 region have not been well documented. We collected genotype and phenotype data from five patients with microdeletions involving 15q22.2, which were between 0.7 Mb and 6.5 Mb in size; two were of de novo origin and one was of familial origin. Intellectual disability and epilepsy are frequently observed in patients with 15q22.2 deletions. Genotype-phenotype correlation analysis narrowed the critical region for such neurologic symptoms to a genomic region of 654 Kb including the NMDA receptor-regulated 2 gene (NARG2) and the PAR-related orphan receptor A gene (RORA), either of which may be responsible for neurological symptoms commonly observed in patients with deletions in this region. The neighboring regions, including the forkhead box B1 gene (FOXB1), may also be related to the additional neurological features observed in the patients with larger deletions.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Estudos de Associação Genética/métodos , Deficiência Intelectual/genética , Proteínas Nucleares/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Adolescente , Pré-Escolar , Bandeamento Cromossômico , Variações do Número de Cópias de DNA , Feminino , Genótipo , Humanos , Hibridização in Situ Fluorescente , Masculino , Fenótipo , Adulto Jovem
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