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1.
Hepatology ; 71(6): 2067-2079, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31595528

RESUMO

BACKGROUND AND AIMS: The clinical consequences of defective primary cilium (ciliopathies) are characterized by marked phenotypic and genetic heterogeneity. Although fibrocystic liver disease is an established ciliopathy phenotype, severe neonatal cholestasis is rarely recognized as such. APPROACH AND RESULTS: We describe seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one and necessitating liver transplant in two). Positional mapping revealed a single critical locus on chromosome 7. Whole-exome sequencing revealed three different homozygous variants in Tetratricopeptide Repeat Domain 26 (TTC26) that fully segregated with the phenotype. TTC26 (intraflagellar transport [IFT] 56/DYF13) is an atypical component of IFT-B complex, and deficiency of its highly conserved orthologs has been consistently shown to cause defective ciliary function in several model organisms. We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as indicated by dysregulated sonic hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic clustering with cells derived from individuals with closely related ciliopathies. We also demonstrate a strong expression of Ttc26 in the embryonic mouse liver in a pattern consistent with its proposed role in the normal development of the intrahepatic biliary system. CONCLUSIONS: In addition to establishing a TTC26-related ciliopathy phenotype in humans, our results highlight the importance of considering ciliopathies in the differential diagnosis of severe neonatal cholestasis even in the absence of more typical features.


Assuntos
Colestase Intra-Hepática/genética , Doenças do Recém-Nascido/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Repetições de Tetratricopeptídeos/genética , Animais , Ciliopatias , Diagnóstico Diferencial , Proteínas Hedgehog , Humanos , Recém-Nascido , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Mutação , Transporte Proteico/genética , Índice de Gravidade de Doença , Sequenciamento do Exoma/métodos
2.
Am J Hum Genet ; 100(5): 831-836, 2017 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-28475863

RESUMO

Larsen syndrome is characterized by the dislocation of large joints and other less consistent clinical findings. Heterozygous FLNB mutations account for the majority of Larsen syndrome cases, but biallelic mutations in CHST3 and B4GALT7 have been more recently described, thus confirming the existence of recessive forms of the disease. In a multiplex consanguineous Saudi family affected by severe and recurrent large joint dislocation and severe myopia, we identified a homozygous truncating variant in GZF1 through a combined autozygome and exome approach. Independently, the same approach identified a second homozygous truncating GZF1 variant in another multiplex consanguineous family affected by severe myopia, retinal detachment, and milder skeletal involvement. GZF1 encodes GDNF-inducible zinc finger protein 1, a transcription factor of unknown developmental function, which we found to be expressed in the eyes and limbs of developing mice. Global transcriptional profiling of cells from affected individuals revealed a shared pattern of gene dysregulation and significant enrichment of genes encoding matrix proteins, including P3H2, which hints at a potential disease mechanism. Our results suggest that GZF1 mutations cause a phenotype of severe myopia and significant articular involvement not previously described in Larsen syndrome.


Assuntos
Heterogeneidade Genética , Fatores de Transcrição Kruppel-Like/genética , Osteocondrodisplasias/genética , Adolescente , Alelos , Criança , Pré-Escolar , Exoma , Feminino , Regulação da Expressão Gênica , Genes Recessivos , Homozigoto , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Análise de Sequência de DNA , Adulto Jovem
3.
Genet Med ; 21(3): 545-552, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30214071

RESUMO

PURPOSE: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. METHODS: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. RESULTS: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1. CONCLUSION: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.


Assuntos
Microcefalia/genética , Microcefalia/fisiopatologia , Adulto , Criança , Pré-Escolar , Nanismo/genética , Feminino , Genômica/métodos , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Mutação/genética , Linhagem , Fenótipo , Sequenciamento do Exoma/métodos
4.
Clin Genet ; 95(2): 310-319, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30561787

RESUMO

Defects in the peroxisomes biogenesis and/or function result in peroxisomal disorders. In this study, we describe the largest Arab cohort to date (72 families) of clinically, biochemically and molecularly characterized patients with peroxisomal disorders. At the molecular level, we identified 43 disease-causing variants, half of which are novel. The founder nature of many of the variants allowed us to calculate the minimum disease burden for these disorders in our population ~1:30 000, which is much higher than previous estimates in other populations. Clinically, we found an interesting trend toward genotype/phenotype correlation in terms of long-term survival. Nearly half (40/75) of our peroxisomal disorders patients had documented survival beyond 1 year of age. Most unusual among the long-term survivors was a multiplex family in which the affected members presented as adults with non-specific intellectual disability and epilepsy. Other unusual presentations included the very recently described peroxisomal fatty acyl-CoA reductase 1 disorder as well as CRD, spastic paraparesis, white matter (CRSPW) syndrome. We conclude that peroxisomal disorders are highly heterogeneous in their clinical presentation. Our data also confirm the demonstration that milder forms of Zellweger spectrum disorders cannot be ruled out by the "gold standard" very long chain fatty acids assay, which highlights the value of a genomics-first approach in these cases.


Assuntos
Árabes , Transtornos Peroxissômicos/epidemiologia , Transtornos Peroxissômicos/etiologia , Árabes/genética , Biomarcadores , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Estudos de Coortes , Consanguinidade , Efeitos Psicossociais da Doença , Gerenciamento Clínico , Suscetibilidade a Doenças , Fácies , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Imageamento por Ressonância Magnética , Masculino , Mutação , Linhagem , Transtornos Peroxissômicos/diagnóstico , Transtornos Peroxissômicos/terapia , Fenótipo , Vigilância da População , Prognóstico
5.
Ann Neurol ; 81(6): 890-897, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28556411

RESUMO

OBJECTIVE: Congenital hydrocephalus is an important birth defect, the genetics of which remains incompletely understood. To date, only 4 genes are known to cause Mendelian diseases in which congenital hydrocephalus is the main or sole clinical feature, 2 X-linked (L1CAM and AP1S2) and 2 autosomal recessive (CCDC88C and MPDZ). In this study, we aimed to determine the genetic etiology of familial congenital hydrocephalus with the assumption that these cases represent Mendelian forms of the disease. METHODS: Exome sequencing combined, where applicable, with positional mapping. RESULTS: We identified a likely causal mutation in the majority of these families (21 of 27, 78%), spanning 16 genes, none of which is X-linked. Ciliopathies and dystroglycanopathies were the most common etiologies of congenital hydrocephalus in our cohort (19% and 26%, respectively). In 1 family with 4 affected members, we identified a homozygous truncating variant in EML1, which we propose as a novel cause of congenital hydrocephalus in addition to its suggested role in cortical malformation. Similarly, we show that recessive mutations in WDR81, previously linked to cerebellar ataxia, mental retardation, and disequilibrium syndrome 2, cause severe congenital hydrocephalus. Furthermore, we confirm the previously reported candidacy of MPDZ by presenting a phenotypic spectrum of congenital hydrocephalus associated with 5 recessive alleles. INTERPRETATION: Our study highlights the importance of recessive mutations in familial congenital hydrocephalus and expands the locus heterogeneity of this condition. Ann Neurol 2017;81:890-897.


Assuntos
Proteínas de Transporte/genética , Hidrocefalia/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas do Tecido Nervoso/genética , Criança , Pré-Escolar , Estudos de Coortes , Consanguinidade , Exoma , Feminino , Genes Recessivos , Humanos , Hidrocefalia/patologia , Hidrocefalia/fisiopatologia , Lactente , Masculino , Proteínas de Membrana , Mutação , Linhagem , Análise de Sequência de DNA
6.
Hum Mol Genet ; 24(18): 5211-8, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26123494

RESUMO

Meckel-Gruber syndrome (MKS) is a perinatally lethal disorder characterized by the triad of occipital encephalocele, polydactyly and polycystic kidneys. Typical of other disorders related to defective primary cilium (ciliopathies), MKS is genetically heterogeneous with mutations in a dozen genes to date known to cause the disease. In an ongoing effort to characterize MKS clinically and genetically, we implemented a gene panel and next-generation sequencing approach to identify the causal mutation in 25 MKS families. Of the three families that did not harbor an identifiable causal mutation by this approach, two mapped to a novel disease locus in which whole-exome sequencing revealed the likely causal mutation as a homozygous splicing variant in TMEM107, which we confirm leads to aberrant splicing and nonsense-mediated decay. TMEM107 had been independently identified in two mouse models as a cilia-related protein and mutant mice display typical ciliopathy phenotypes. Our analysis of patient fibroblasts shows marked ciliogenesis defect with an accompanying perturbation of sonic hedgehog signaling, highly concordant with the cellular phenotype in Tmem107 mutants. This study shows that known MKS loci account for the overwhelming majority of MKS cases but additional loci exist including MKS13 caused by TMEM107 mutation.


Assuntos
Transtornos da Motilidade Ciliar/genética , Encefalocele/genética , Loci Gênicos , Proteínas de Membrana/genética , Mutação , Doenças Renais Policísticas/genética , Alelos , Cílios/genética , Cílios/metabolismo , Transtornos da Motilidade Ciliar/diagnóstico , Transtornos da Motilidade Ciliar/metabolismo , Consanguinidade , Análise Mutacional de DNA , Encefalocele/diagnóstico , Encefalocele/metabolismo , Feminino , Heterogeneidade Genética , Genótipo , Proteínas Hedgehog/metabolismo , Humanos , Masculino , Linhagem , Doenças Renais Policísticas/diagnóstico , Doenças Renais Policísticas/metabolismo , Retinose Pigmentar , Transdução de Sinais
7.
Genome Res ; 24(2): 291-9, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24389050

RESUMO

Primordial dwarfism (PD) is a disease in which severely impaired fetal growth persists throughout postnatal development and results in stunted adult size. The condition is highly heterogeneous clinically, but the use of certain phenotypic aspects such as head circumference and facial appearance has proven helpful in defining clinical subgroups. In this study, we present the results of clinical and genomic characterization of 16 new patients in whom a broad definition of PD was used (e.g., 3M syndrome was included). We report a novel PD syndrome with distinct facies in two unrelated patients, each with a different homozygous truncating mutation in CRIPT. Our analysis also reveals, in addition to mutations in known PD disease genes, the first instance of biallelic truncating BRCA2 mutation causing PD with normal bone marrow analysis. In addition, we have identified a novel locus for Seckel syndrome based on a consanguineous multiplex family and identified a homozygous truncating mutation in DNA2 as the likely cause. An additional novel PD disease candidate gene XRCC4 was identified by autozygome/exome analysis, and the knockout mouse phenotype is highly compatible with PD. Thus, we add a number of novel genes to the growing list of PD-linked genes, including one which we show to be linked to a novel PD syndrome with a distinct facial appearance. PD is extremely heterogeneous genetically and clinically, and genomic tools are often required to reach a molecular diagnosis.


Assuntos
Nanismo/genética , Microcefalia/genética , Hipotonia Muscular/genética , Mutação/genética , Coluna Vertebral/anormalidades , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteína BRCA2/genética , Medula Óssea/patologia , Proteínas de Ligação a DNA/genética , Nanismo/patologia , Fácies , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Masculino , Microcefalia/patologia , Hipotonia Muscular/patologia , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Coluna Vertebral/patologia
8.
PeerJ Comput Sci ; 8: e840, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35634106

RESUMO

Blockchain technology is accelerating digital transformation across multiple industries, including the pharmaceutical industry. The pharmaceutical industry suffers from a lack of transparency, difficulty tracking products, lack of trust, and the shipment of expired products. Blockchain technology has been applied to solve several of these problems. In this paper, we present a systematic review of the literature focusing on the adoption of blockchain technology in the pharmaceutical industry. We collected, analyzed, qualified, and discussed studies retrieved from seven databases. The initial search yielded 2,185 papers, which were screened, discussed, voted on, critically appraised, and collected by a snowball workflow that finally yielded 38 papers. The blockchain application areas covered in the papers were classified as counterfeit drug prevention, drug distribution, tracking and tracing, and safety and security. The most frequent category was counterfeit drug prevention, which is consistent with the primary objective of the pharmaceutical industry. The newer topics discussed in this study were data governance, data quality, pharmaceutical turnover, and prescription drug monitoring. We discuss issues surrounding each of these topics and research studies, along with their limitations and solutions. We also examine the challenges and future research directions of applying blockchain technology in the pharmaceutical industry.

9.
Genome Biol ; 18(1): 144, 2017 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-28754144

RESUMO

BACKGROUND: Variable expressivity is a well-known phenomenon in which patients with mutations in one gene display varying degrees of clinical severity, potentially displaying only subsets of the clinical manifestations associated with the multisystem disorder linked to the gene. This remains an incompletely understood phenomenon with proposed mechanisms ranging from allele-specific to stochastic. RESULTS: We report three consanguineous families in which an isolated ocular phenotype is linked to a novel 3' UTR mutation in SLC4A4, a gene known to be mutated in a syndromic form of intellectual disability with renal and ocular involvement. Although SLC4A4 is normally devoid of AU-rich elements (AREs), a 3' UTR motif that mediates post-transcriptional control of a subset of genes, the mutation we describe creates a functional ARE. We observe a marked reduction in the transcript level of SLC4A4 in patient cells. Experimental confirmation of the ARE-creating mutation is shown using a post-transcriptional reporter system that reveals consistent reduction in the mRNA-half life and reporter activity. Moreover, the neo-ARE binds and responds to the zinc finger protein ZFP36/TTP, an ARE-mRNA decay-promoting protein. CONCLUSIONS: This novel mutational mechanism for a Mendelian disease expands the potential mechanisms that underlie variable phenotypic expressivity in humans to also include 3' UTR mutations with tissue-specific pathology.


Assuntos
Regiões 3' não Traduzidas , Elementos Ricos em Adenilato e Uridilato , Distrofias Hereditárias da Córnea/genética , Mutação , Fenótipo , Simportadores de Sódio-Bicarbonato/genética , Adulto , Sequência de Bases , Sítios de Ligação , Linhagem Celular Tumoral , Criança , Consanguinidade , Córnea/metabolismo , Córnea/patologia , Distrofias Hereditárias da Córnea/metabolismo , Distrofias Hereditárias da Córnea/patologia , Feminino , Regulação da Expressão Gênica , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Masculino , Análise da Randomização Mendeliana , Linhagem , Estabilidade de RNA , Simportadores de Sódio-Bicarbonato/metabolismo
10.
Genome Biol ; 16: 210, 2015 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-26416026

RESUMO

BACKGROUND: Primordial dwarfism is a state of extreme prenatal and postnatal growth deficiency, and is characterized by marked clinical and genetic heterogeneity. RESULTS: Two presumably unrelated consanguineous families presented with an apparently novel form of primordial dwarfism in which severe growth deficiency is accompanied by distinct facial dysmorphism, brain malformation (microcephaly, agenesis of corpus callosum, and simplified gyration), and severe encephalopathy with seizures. Combined autozygome/exome analysis revealed a novel missense mutation in WDR4 as the likely causal variant. WDR4 is the human ortholog of the yeast Trm82, an essential component of the Trm8/Trm82 holoenzyme that effects a highly conserved and specific (m(7)G46) methylation of tRNA. The human mutation and the corresponding yeast mutation result in a significant reduction of m(7)G46 methylation of specific tRNA species, which provides a potential mechanism for primordial dwarfism associated with this lesion, since reduced m(7)G46 modification causes a growth deficiency phenotype in yeast. CONCLUSION: Our study expands the number of biological pathways underlying primordial dwarfism and adds to a growing list of human diseases linked to abnormal tRNA modification.


Assuntos
Nanismo/genética , Proteínas de Ligação ao GTP/genética , Microcefalia/genética , RNA de Transferência/genética , Nanismo/etiologia , Exoma/genética , Fácies , Humanos , Metilação , Microcefalia/etiologia , Mutação de Sentido Incorreto , Saccharomyces cerevisiae/genética
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