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1.
Clin Genet ; 2019 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-31628766

RESUMO

Patients with dystonia are particularly appropriate for diagnostic exome sequencing (DES), due to the complex, diverse features and genetic heterogeneity. Personal and family history data were collected from test requisition forms and medical records from 189 patients with reported dystonia and available family members received for clinical DES. Of them, 20.2% patients had a positive genetic finding associated with dystonia. Detection rates for cases with isolated and combined dystonia were 22.4% and 25.0%, respectively. 71.4% of the cohort had co-occurring non-movement-related findings and a detection rate of 24.4%. Patients with childhood-onset dystonia trended toward higher detection rates (31.8%) compared to infancy (23.6%), adolescence (12.5%), and early-adulthood onset (16%). Uncharacterized gene findings were found in 6.7% (8/119) of cases that underwent analysis for genes without an established disease relationship. Patients with intellectual disability/developmental delay, seizures/epilepsy and/or multifocal dystonia were more likely to have positive findings (P = .0093, .0397, .0006). Four (2.1%) patients had findings in two genes, and seven (3.7%) had reclassification after the original report due to new literature, new clinical information or reanalysis request. Pediatric patients were more likely to have positive findings (P = .0180). Our observations show utility of family-based DES in patients with dystonia and illustrate the complexity of testing.

2.
Genet Med ; 21(10): 2199-2207, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30894705

RESUMO

PURPOSE: We evaluated clinical and genetic features enriched in patients with multiple Mendelian conditions to determine which patients are more likely to have multiple potentially relevant genetic findings (MPRF). METHODS: Results of the first 7698 patients who underwent exome sequencing at Ambry Genetics were reviewed. Clinical and genetic features were examined and degree of phenotypic overlap between the genetic diagnoses was evaluated. RESULTS: Among patients referred for exome sequencing, 2% had MPRF. MPRF were more common in patients from consanguineous families and patients with greater clinical complexity. The difference in average number of organ systems affected is small: 4.3 (multiple findings) vs. 3.9 (single finding) and may not be distinguished in clinic. CONCLUSION: Patients with multiple genetic diagnoses had a slightly higher number of organ systems affected than patients with single genetic diagnoses, largely because the comorbid conditions affected overlapping organ systems. Exome testing may be beneficial for all cases with multiple organ systems affected. The identification of multiple relevant genetic findings in 2% of exome patients highlights the utility of a comprehensive molecular workup and updated interpretation of existing genomic data; a single definitive molecular diagnosis from analysis of a limited number of genes may not be the end of a diagnostic odyssey.

3.
Am J Hum Genet ; 103(4): 553-567, 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30290151

RESUMO

The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.

4.
Nat Genet ; 50(10): 1442-1451, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30224647

RESUMO

The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.

5.
Am J Hum Genet ; 102(6): 1195-1203, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861108

RESUMO

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

6.
Hum Mol Genet ; 27(14): 2454-2465, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29726930

RESUMO

The 17 genes of the T-box family are transcriptional regulators that are involved in all stages of embryonic development, including craniofacial, brain, heart, skeleton and immune system. Malformation syndromes have been linked to many of the T-box genes. For example, haploinsufficiency of TBX1 is responsible for many structural malformations in DiGeorge syndrome caused by a chromosome 22q11.2 deletion. We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome, who are heterozygotes for TBX2 variants. The p.R20Q variant is shared by three affected family members in an autosomal dominant manner; the fourth unrelated individual has a de novo p.R305H mutation. Bioinformatics analyses indicate that these variants are rare and predict them to be damaging. In vitro transcriptional assays in cultured cells show that both variants result in reduced transcriptional repressor activity of TBX2. We also show that the variants result in reduced protein levels of TBX2. Heterologous over-expression studies in Drosophila demonstrate that both p.R20Q and p.R305H function as partial loss-of-function alleles. Hence, these and other data suggest that TBX2 is a novel candidate gene for a new multisystem malformation disorder.

7.
Genet Med ; 20(9): 1099-1102, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29388939

RESUMO

In the published version of this paper, some of the columns in the last three rows of Table 3 were mistakenly transposed. The corrected table appears below. In col. 6 of the row for DNMT3A, "S3" was published in the original article. However, in the revised table for the corrigendum, it has been corrected to "S1". In col. 6 of the row for SON, "S3" was published in the original article. However, in the revised table for the corrigendum, it has been corrected to "S2".

8.
Am J Hum Genet ; 102(1): 188-195, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29304374

RESUMO

Fucosyltransferase 8 (FUT8) encodes a Golgi-localized α1,6 fucosyltransferase that is essential for transferring the monosaccharide fucose into N-linked glycoproteins, a process known as "core fucosylation." Here we describe three unrelated individuals, who presented with intrauterine growth retardation, severe developmental and growth delays with shortened limbs, neurological impairments, and respiratory complications. Each underwent whole-exome sequencing and was found to carry pathogenic variants in FUT8. The first individual (consanguineous family) was homozygous for c.715C>T (p.Arg239∗), while the second (non-consanguineous family) was compound heterozygous for c.1009C>G (p.Arg337Gly) and a splice site variant c.1259+5G>T. The third individual (consanguineous family) was homozygous for a c.943C>T (p.Arg315∗). Splicing analysis confirmed the c.1259+5G>T resulted in expression of an abnormal FUT8 transcript lacking exon 9. Functional studies using primary fibroblasts from two affected individuals revealed a complete lack of FUT8 protein expression that ultimately resulted in substantial deficiencies in total core fucosylated N-glycans. Furthermore, serum samples from all three individuals showed a complete loss of core fucosylation. Here, we show that loss of function mutations in FUT8 cause a congenital disorder of glycosylation (FUT8-CDG) characterized by defective core fucosylation that phenotypically parallels some aspects of the Fut8-/- knockout mouse. Importantly, identification of additional affected individuals can be easily achieved through analysis of core fucosylation of N-glycans.

9.
Hum Mutat ; 38(5): 600-608, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28106320

RESUMO

Ascertaining a diagnosis through exome sequencing can provide potential benefits to patients, insurance companies, and the healthcare system. Yet, as diagnostic sequencing is increasingly employed, vast amounts of human genetic data are produced that need careful curation. We discuss methods for accurately assessing the clinical validity of gene-disease relationships to interpret new research findings in a clinical context and increase the diagnostic rate. The specifics of a gene-disease scoring system adapted for use in a clinical laboratory are described. In turn, clinical validity scoring of gene-disease relationships can inform exome reporting for the identification of new or the upgrade of previous, clinically relevant gene findings. Our retrospective analysis of all reclassification reports from the first 4 years of diagnostic exome sequencing showed that 78% were due to new gene-disease discoveries published in the literature. Among all exome positive/likely positive findings in characterized genes, 32% were in genetic etiologies that were discovered after 2010. Our data underscore the importance and benefits of active and up-to-date curation of a gene-disease database combined with critical clinical validity scoring and proactive reanalysis in the clinical genomics era.


Assuntos
Exoma , Estudos de Associação Genética/métodos , Genômica/métodos , Estudos de Associação Genética/normas , Genômica/normas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Reprodutibilidade dos Testes , Análise de Sequência de DNA
10.
Genet Med ; 19(2): 224-235, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27513193

RESUMO

PURPOSE: Diagnostic exome sequencing (DES) is now a commonly ordered test for individuals with undiagnosed genetic disorders. In addition to providing a diagnosis for characterized diseases, exome sequencing has the capacity to uncover novel candidate genes for disease. METHODS: Family-based DES included analysis of both characterized and novel genetic etiologies. To evaluate candidate genes for disease in the clinical setting, we developed a systematic, rule-based classification schema. RESULTS: Testing identified a candidate gene among 7.7% (72/934) of patients referred for DES; 37 (4.0%) and 35 (3.7%) of the genes received evidence scores of "candidate" and "suspected candidate," respectively. A total of 71 independent candidate genes were reported among the 72 patients, and 38% (27/71) were subsequently corroborated in the peer-reviewed literature. This rate of corroboration increased to 51.9% (27/52) among patients whose gene was reported at least 12 months previously. CONCLUSIONS: Herein, we provide transparent, comprehensive, and standardized scoring criteria for the clinical reporting of candidate genes. These results demonstrate that DES is an integral tool for genetic diagnosis, especially for elucidating the molecular basis for both characterized and novel candidate genetic etiologies. Gene discoveries also advance the understanding of normal human biology and more common diseases.Genet Med 19 2, 224-235.


Assuntos
Estudos de Associação Genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Sequenciamento Completo do Exoma , Bases de Dados Genéticas , Exoma/genética , Doenças Genéticas Inatas/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação
11.
Mol Syst Biol ; 8: 613, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23010996

RESUMO

Morphogens provide positional information for spatial patterns of gene expression during development. However, stochastic effects such as local fluctuations in morphogen concentration and noise in signal transduction make it difficult for cells to respond to their positions accurately enough to generate sharp boundaries between gene expression domains. During development of rhombomeres in the zebrafish hindbrain, the morphogen retinoic acid (RA) induces expression of hoxb1a in rhombomere 4 (r4) and krox20 in r3 and r5. Fluorescent in situ hybridization reveals rough edges around these gene expression domains, in which cells co-express hoxb1a and krox20 on either side of the boundary, and these sharpen within a few hours. Computational analysis of spatial stochastic models shows, surprisingly, that noise in hoxb1a/krox20 expression actually promotes sharpening of boundaries between adjacent segments. In particular, fluctuations in RA initially induce a rough boundary that requires noise in hoxb1a/krox20 expression to sharpen. This finding suggests a novel noise attenuation mechanism that relies on intracellular noise to induce switching and coordinate cellular decisions during developmental patterning.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Rombencéfalo/metabolismo , Transdução de Sinais , Peixe-Zebra/metabolismo , Animais , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Modelos Biológicos , Rombencéfalo/citologia , Rombencéfalo/embriologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tretinoína/farmacologia , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
12.
Development ; 139(12): 2150-5, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22619388

RESUMO

The vitamin A derivative retinoic acid (RA) is a morphogen that patterns the anterior-posterior axis of the vertebrate hindbrain. Cellular retinoic acid-binding proteins (Crabps) transport RA within cells to both its nuclear receptors (RARs) and degrading enzymes (Cyp26s). However, mice lacking Crabps are viable, suggesting that Crabp functions are redundant with those of other fatty acid-binding proteins. Here we show that Crabps in zebrafish are essential for posterior patterning of the hindbrain and that they provide a key feedback mechanism that makes signaling robust as they are able to compensate for changes in RA production. Of the four zebrafish Crabps, Crabp2a is uniquely RA inducible and depletion or overexpression of Crabp2a makes embryos hypersensitive to exogenous RA. Computational models confirm that Crabp2a improves robustness within a narrow concentration range that optimizes a 'robustness index', integrating spatial information along the RA morphogen gradient. Exploration of signaling parameters in our models suggests that the ability of Crabp2a to transport RA to Cyp26 enzymes for degradation is a major factor in promoting robustness. These results demonstrate a previously unrecognized requirement for Crabps in RA signaling and hindbrain development, as well as a novel mechanism for stabilizing morphogen gradients despite genetic or environmental fluctuations in morphogen availability.


Assuntos
Padronização Corporal/genética , Receptores do Ácido Retinoico/metabolismo , Rombencéfalo/embriologia , Transdução de Sinais/genética , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Animais , Padronização Corporal/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Modelos Biológicos , Receptores do Ácido Retinoico/genética , Rombencéfalo/efeitos dos fármacos , Rombencéfalo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tretinoína/farmacologia , Proteínas de Peixe-Zebra/genética
13.
Dev Biol ; 325(1): 60-70, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-18929555

RESUMO

Retinoic acid (RA) signaling regulates multiple aspects of vertebrate embryonic development and tissue patterning, in part through the local availability of nuclear hormone receptors called retinoic acid receptors (RARs) and retinoid receptors (RXRs). RAR/RXR heterodimers transduce the RA signal, and loss-of-function studies in mice have demonstrated requirements for distinct receptor combinations at different stages of embryogenesis. However, the tissue-specific functions of each receptor and their individual contributions to RA signaling in vivo are only partially understood. Here we use morpholino oligonucleotides to deplete the four known zebrafish RARs (raraa, rarab, rarga, and rargb). We show that while all four are required for anterior-posterior patterning of rhombomeres in the hindbrain, there are unique requirements for rarga in the cranial mesoderm for hindbrain patterning, and rarab in lateral plate mesoderm for specification of the pectoral fins. In addition, the alpha subclass (raraa, rarab) is RA inducible, and of these only raraa expression is RA-dependent, suggesting that these receptors establish a region of particularly high RA signaling through positive-feedback. These studies reveal novel tissue-specific roles for RARs in controlling the competence and sensitivity of cells to respond to RA.


Assuntos
Região Branquial/metabolismo , Extremidades/embriologia , Receptores do Ácido Retinoico/metabolismo , Rombencéfalo/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Estruturas Animais/citologia , Estruturas Animais/efeitos dos fármacos , Estruturas Animais/embriologia , Estruturas Animais/metabolismo , Animais , Padronização Corporal/efeitos dos fármacos , Região Branquial/citologia , Região Branquial/efeitos dos fármacos , Região Branquial/embriologia , Embrião não Mamífero/citologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas de Homeodomínio/metabolismo , Modelos Biológicos , Especificidade de Órgãos/efeitos dos fármacos , Receptores do Ácido Retinoico/genética , Rombencéfalo/citologia , Rombencéfalo/efeitos dos fármacos , Rombencéfalo/embriologia , Tretinoína/farmacologia , Peixe-Zebra/genética
14.
Nurs Manage ; 35(6): 18, 22, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15184741
15.
Nurs Manage ; 34(6): 24-6, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12789049

RESUMO

Follow the proper procedure for identifying and reporting sentinel events to the Joint Commission to decrease their incidence.


Assuntos
Erros Médicos/prevenção & controle , Gestão de Riscos/métodos , Vigilância de Evento Sentinela , Humanos , Joint Commission on Accreditation of Healthcare Organizations , Estados Unidos
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