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1.
J Med Genet ; 56(6): 408-412, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30242101

RESUMEN

BACKGROUND: Advances in molecular technologies and in-silico variant prediction tools offer wide-ranging opportunities in diagnostic settings, yet they also present with significant limitations. OBJECTIVE: Here, we contextualise the limitations of next-generation sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA) and in-silico prediction tools routinely used by diagnostic laboratories by reviewing specific experiences from our diagnostic laboratory. METHODS: We investigated discordant annotations and/or incorrect variant 'callings' in exons of 56 genes constituting our cardiomyopathy and connective tissue disorder NGS panels. Discordant variants and segmental duplications (SD) were queried using the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool and the University of California Santa Cruz genome browser, respectively, to identify regions of high homology. Discrepant variant analyses by in-silico models were re-evaluated using updated file entries. RESULTS: We observed a 5% error rate in MYH7 variant 'calling' using MLPA, which resulted from >90% homology of the MYH7 probe-binding site to MYH6. SDs were detected in TTN, PKP2 and MYLK. SDs in MYLK presented the highest risk (15.7%) of incorrect variant 'calling'. The inaccurate 'callings' and discrepant in-silico predictions were resolved following detailed investigation into the source of error. CONCLUSION: Recognising the limitations described here may help avoid incorrect diagnoses and leverage the power of new molecular technologies in diagnostic settings.


Asunto(s)
Técnicas de Diagnóstico Molecular , Medicina Molecular , Alelos , Biología Computacional/métodos , Manejo de la Enfermedad , Duplicación de Gen , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Medicina Molecular/métodos , Medicina Molecular/normas , Anotación de Secuencia Molecular
2.
Genet Med ; 20(3): 365-368, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29240080

RESUMEN

PurposeThe advent of next-generation sequencing resulted in substantial increases in the number of variants detected, interpreted, and reported by molecular genetics diagnostic laboratories. Recent publications have provided standards for the interpretation of sequence variants, but there are currently no standards regarding reinterpretation of these variants. Recognizing that significant changes in variant classification may occur over time, many genetics diagnostic laboratories have independently developed practices for variant reinterpretation. The purpose of this study is to describe our laboratory approach to variant reinterpretation.MethodsWe surveyed eight genetics diagnostic laboratories in Canada and the United States.ResultsEach laboratory had differing protocols, but most felt that clinically relevant changes to variant classifications should be communicated to ordering providers. Based on results of this survey and our experience, we developed a cost-effective and resource-efficient approach to variant reinterpretation.ConclusionOngoing variant reinterpretation is required to maintain the highest standards for delivering genetics laboratory services. Our approach to variant reinterpretation offers an efficient solution that does not compromise accuracy or timely delivery of genetics laboratory services.


Asunto(s)
Variación Genética , Anotación de Secuencia Molecular/normas , Canadá , Comunicación , Estudios de Asociación Genética/métodos , Estudios de Asociación Genética/normas , Predisposición Genética a la Enfermedad , Pruebas Genéticas/normas , Guías como Asunto , Encuestas de Atención de la Salud , Humanos , Laboratorios , Estados Unidos , Flujo de Trabajo
3.
Genet Med ; 20(3): 294-302, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28726806

RESUMEN

PurposeThe purpose of this study was to develop a national program for Canadian diagnostic laboratories to compare DNA-variant interpretations and resolve discordant-variant classifications using the BRCA1 and BRCA2 genes as a case study.MethodsBRCA1 and BRCA2 variant data were uploaded and shared through the Canadian Open Genetics Repository (COGR; http://www.opengenetics.ca). A total of 5,554 variant observations were submitted; classification differences were identified and comparison reports were sent to participating laboratories. Each site had the opportunity to reclassify variants. The data were analyzed before and after the comparison report process to track concordant- or discordant-variant classifications by three different models.ResultsVariant-discordance rates varied by classification model: 38.9% of variants were discordant when using a five-tier model, 26.7% with a three-tier model, and 5.0% with a two-tier model. After the comparison report process, the proportion of discordant variants dropped to 30.7% with the five-tier model, to 14.2% with the three-tier model, and to 0.9% using the two-tier model.ConclusionWe present a Canadian interinstitutional quality improvement program for DNA-variant interpretations. Sharing of variant knowledge by clinical diagnostic laboratories will allow clinicians and patients to make more informed decisions and lead to better patient outcomes.


Asunto(s)
Exactitud de los Datos , Pruebas Genéticas/normas , Difusión de la Información , Mejoramiento de la Calidad , Canadá , Toma de Decisiones Clínicas , Bases de Datos Genéticas , Genes BRCA1 , Genes BRCA2 , Asesoramiento Genético , Pruebas Genéticas/métodos , Variación Genética , Programas de Gobierno , Humanos , Reproducibilidad de los Resultados , Flujo de Trabajo
4.
Hum Mol Genet ; 24(5): 1363-73, 2015 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-25343993

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons. Causative mutations in the global RNA-processing proteins TDP-43 and FUS among others, as well as their aggregation in ALS patients, have identified defects in RNA metabolism as an important feature in this disease. Lethal congenital contracture syndrome 1 and lethal arthrogryposis with anterior horn cell disease are autosomal recessive fetal motor neuron diseases that are caused by mutations in another global RNA-processing protein, hGle1. In this study, we carried out the first screening of GLE1 in ALS patients (173 familial and 760 sporadic) and identified 2 deleterious mutations (1 splice site and 1 nonsense mutation) and 1 missense mutation. Functional analysis of the deleterious mutants revealed them to be unable to rescue motor neuron pathology in zebrafish morphants lacking Gle1. Furthermore, in HeLa cells, both mutations caused a depletion of hGle1 at the nuclear pore where it carries out an essential role in nuclear export of mRNA. These results suggest a haploinsufficiency mechanism and point to a causative role for GLE1 mutations in ALS patients. This further supports the involvement of global defects in RNA metabolism in ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Codón sin Sentido , Mutación Missense , Proteínas de Transporte Nucleocitoplasmático/genética , Esclerosis Amiotrófica Lateral/patología , Animales , Artrogriposis/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Haploinsuficiencia/genética , Células HeLa , Humanos , Microscopía Confocal , Neuronas Motoras/patología , Poro Nuclear/genética , Poro Nuclear/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Linaje , Procesamiento Proteico-Postraduccional , Empalme del ARN , ARN Mensajero/metabolismo , Pez Cebra
5.
J Med Genet ; 53(3): 200-7, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26378117

RESUMEN

BACKGROUND: A homozygous loss-of-function mutation p.(Arg316Gln) in the fat mass and obesity-associated (FTO) gene, which encodes for an iron and 2-oxoglutarate-dependent oxygenase, was previously identified in a large family in which nine affected individuals present with a lethal syndrome characterised by growth retardation and multiple malformations. To date, no other pathogenic mutation in FTO has been identified as a cause of multiple congenital malformations. METHODS: We investigated a 21-month-old girl who presented distinctive facial features, failure to thrive, global developmental delay, left ventricular cardiac hypertrophy, reduced vision and bilateral hearing loss. We performed targeted next-generation sequencing of 4813 clinically relevant genes in the patient and her parents. RESULTS: We identified a novel FTO homozygous missense mutation (c.956C>T; p.(Ser319Phe)) in the affected individual. This mutation affects a highly conserved residue located in the same functional domain as the previously characterised mutation p.(Arg316Gln). Biochemical studies reveal that p.(Ser319Phe) FTO has reduced 2-oxoglutarate turnover and N-methyl-nucleoside demethylase activity. CONCLUSION: Our findings are consistent with previous reports that homozygous mutations in FTO can lead to rare growth retardation and developmental delay syndrome, and further support the proposal that FTO plays an important role in early development of human central nervous and cardiovascular systems.


Asunto(s)
Discapacidades del Desarrollo/genética , Mutación Missense , Proteínas/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Femenino , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante
6.
PLoS Genet ; 10(10): e1004772, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25356899

RESUMEN

Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID.


Asunto(s)
Epilepsia/genética , Discapacidad Intelectual/genética , Codón sin Sentido , Epilepsia/patología , Exoma/genética , Mutación del Sistema de Lectura , Humanos , Discapacidad Intelectual/patología , Mutación Missense , Mutación Puntual , Empalme del ARN/genética , Eliminación de Secuencia
7.
BMC Med Genet ; 17: 15, 2016 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-26922654

RESUMEN

BACKGROUND: Chromosomal deletions encompassing DYRK1A have been associated with intellectual disability for several years. More recently, point mutations in DYRK1A have been shown to be responsible for a recognizable syndrome characterized by microcephaly, developmental delay and intellectual disability (ID) as well as characteristic facial features. Here we present 2 individuals with novel mutations in DYRK1A, and a review of the cases reported to date. CASE PRESENTATION: Both individuals presented with the well-known characteristic features, as well as rarer anomalies seen in a minority of patients. Patient 1 presented shortly after birth with an enlarged cisterna magna, distal contractures, and distinctive facies that included bitemporal narrowing and deep set eyes. A de novo splice site mutation in DYRK1A [c.951 + 4_951 + 7delAGTA; p.Val222Aspfs*22] was identified by next generation sequencing. Patient 2 presented at 7 months of age with microcephaly and dysmorphic features. She went several years without a diagnosis until a de novo DYRK1A nonsense mutation [c.787C>T; p.(Arg263*)] was identified at age 12. These individuals, and the 52 cases reviewed from the literature, show the characteristic features of the DYRK1A-related syndrome including global developmental delay, ID, microcephaly, feeding difficulties, and the facial gestalt. Other common findings include seizures, vision defects, brain abnormalities and skeletal abnormalities of the hands and feet. Less common features include optic nerve defects, contractures, ataxia, and cardiac anomalies. CONCLUSION: DYRK1A testing should be considered in individuals with the facial features, intellectual disability and post-natal microcephaly. Once diagnosed with DYRK1A-related intellectual disability, a cardiac and ophthalmologic assessment would be recommended as would routine surveillance by a pediatrician for psychomotor development, growth, and feeding.


Asunto(s)
Discapacidad Intelectual/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Adolescente , Secuencia de Aminoácidos , Deleción Cromosómica , Codón sin Sentido , Discapacidades del Desarrollo/genética , Exones , Femenino , Reordenamiento Génico , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Masculino , Microcefalia/genética , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Quinasas DyrK
8.
CMAJ ; 188(11): E254-E260, 2016 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-27241786

RESUMEN

BACKGROUND: Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive consultations and traditional genetic or metabolic investigations are costly and often fail to arrive at a final diagnosis when no recognizable syndrome is suspected. For this pilot project, we assessed the feasibility of next-generation sequencing as a tool to improve the diagnosis of rare diseases in newborns in the NICU. METHODS: We retrospectively identified and prospectively recruited newborns and infants admitted to the NICU of the Children's Hospital of Eastern Ontario and the Ottawa Hospital, General Campus, who had been referred to the medical genetics or metabolics inpatient consult service and had features suggesting an underlying genetic or metabolic condition. DNA from the newborns and parents was enriched for a panel of clinically relevant genes and sequenced on a MiSeq sequencing platform (Illumina Inc.). The data were interpreted with a standard informatics pipeline and reported to care providers, who assessed the importance of genotype-phenotype correlations. RESULTS: Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, SCN1A-related encephalopathy syndrome, myotubular myopathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys-Drash syndrome. INTERPRETATION: This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU.


Asunto(s)
Estudios de Asociación Genética/métodos , Pruebas Genéticas/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Unidades de Cuidado Intensivo Neonatal , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Femenino , Humanos , Recién Nacido , Masculino , Mutación , Ontario , Proyectos Piloto , Estudios Prospectivos , Estudios Retrospectivos
9.
Am J Med Genet A ; 167(7): 1654-8, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25899979

RESUMEN

We present the investigation and management of a premature, hypotensive neonate born after a pregnancy complicated by anhydramnios to highlight the impact of early and informed management for rare kidney disease. Vasopressin was used to successfully treat refractory hypotension and anuria in the neonate born at 27 weeks of gestation. Next generation sequencing of a targeted panel of genes was then performed in the neonate and parents. Subsequently, two compound heterozygous deletions leading to frameshift mutations were identified in the angiotensin 1-converting enzyme gene ACE; exon 5:c.820_821delAG (p.Arg274Glyfs*117) and exon24: c.3521delG (p.Gly1174Alafs*12), consistent with a diagnosis of renal tubular dysgenesis. In light of the molecular diagnosis, identification, and treatment of associated low aldosterone level resulted in further improvement in renal function and only mild residual chronic renal failure is present at 14 months of age. Truncating alterations in ACE most often result in fetal demise during gestation or in the first days of life and typically as a result of the Potter sequence. The premature delivery, and serendipitous early treatment with vasopressin, and then later fludrocortisone, resulted in an optimal outcome in an otherwise lethal condition.


Asunto(s)
Anuria/tratamiento farmacológico , Hipotensión/tratamiento farmacológico , Recien Nacido Prematuro/fisiología , Peptidil-Dipeptidasa A/genética , Vasopresinas/uso terapéutico , Adulto , Anuria/genética , Anuria/patología , Secuencia de Bases , Femenino , Fludrocortisona/uso terapéutico , Mutación del Sistema de Lectura/genética , Eliminación de Gen , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hipotensión/genética , Hipotensión/patología , Recién Nacido , Túbulos Renales Proximales/anomalías , Túbulos Renales Proximales/patología , Datos de Secuencia Molecular , Embarazo , Resultado del Tratamiento , Anomalías Urogenitales/genética , Anomalías Urogenitales/patología
10.
Nat Rev Genet ; 10(11): 769-82, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19823194

RESUMEN

The past few years have seen the identification of dozens of genes with causal roles in motor neuron diseases (MNDs), particularly for amyotrophic lateral sclerosis and hereditary spastic paraplegia. Although many additional MND genes remain to be identified, the accumulated genetic evidence has already provided new insights into MND pathogenesis, which adds to the well-established involvement of superoxide dismutase 1 (SOD1) mutations. The pathways that have been recently implicated include those that affect RNA processing, axonal transport and mitochondrial function. The functional classes of MND genes identified so far are likely to aid the selection of high-priority candidate genes for future investigation, including those for so-called sporadic cases.


Asunto(s)
Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/patología , Animales , Humanos
11.
J Med Genet ; 51(6): 419-24, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24706941

RESUMEN

BACKGROUND: The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories. METHODS: The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference. RESULTS: Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9-100%), and the mean specificity was 98.0% (87.5-100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories. CONCLUSIONS: Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.


Asunto(s)
Servicios de Laboratorio Clínico/normas , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Proteínas/genética , Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72 , Femenino , Demencia Frontotemporal/genética , Humanos , Masculino , Reproducibilidad de los Resultados
12.
Am J Hum Genet ; 88(3): 306-16, 2011 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-21376300

RESUMEN

Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.


Asunto(s)
Ácido Glutámico/genética , Discapacidad Intelectual/genética , Mutación/genética , Sustitución de Aminoácidos/genética , Animales , Secuencia de Bases , Canales de Calcio/genética , Canales de Calcio/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Femenino , Células HEK293 , Humanos , Cinesinas/genética , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Mutación Missense/genética , Neuropéptidos/genética , Neuropéptidos/metabolismo , Fenotipo , Unión Proteica/genética , Transporte de Proteínas , Empalme del ARN/genética , Ratas , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Fracciones Subcelulares/metabolismo , Síndrome
13.
Can J Neurol Sci ; 41(6): 759-62, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25377888

RESUMEN

BACKGROUND: A large hexanucleotide repeat expansion in C9orf72 has been identified as the most common genetic cause in familial amyotrophic lateral sclerosis and frontotemporal dementia. Rapid Eye Movement Sleep Behavior Disorder (RBD) is a sleep disorder that has been strongly linked to synuclein-mediated neurodegeneration. The aim of this study was to evaluate the role of the C9orf72 expansions in the pathogenesis of RBD. METHODS: We amplified the C9orf72 repeat expansion in 344 patients with RBD by a repeat-primed polymerase chain reaction assay. RESULTS: We identified two RBD patients carrying the C9orf72 repeat expansion. Most interestingly, these patients have the same C9orf72 associated-risk haplotype identified in 9p21-linked amyotrophic lateral sclerosis and frontotemporal dementia families. CONCLUSIONS: Our study enlarges the phenotypic spectrum associated with the C9orf72 hexanucleotide repeat expansions and suggests that, although rare, this expansion may play a role in the pathogenesis of RBD.


Asunto(s)
Expansión de las Repeticiones de ADN/genética , Proteínas/genética , Trastorno de la Conducta del Sueño REM/diagnóstico , Trastorno de la Conducta del Sueño REM/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteína C9orf72 , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad
14.
J Med Genet ; 50(3): 194-7, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23355746

RESUMEN

BACKGROUND: Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterised by abnormal central nervous system white matter. Mutations in POLR3A and POLR3B genes were recently reported to cause four clinically overlapping hypomyelinating leukodystrophy phenotypes. Our aim was to investigate the presence and frequency of POLR3A and POLR3B mutations in patients with genetically unexplained hypomyelinating leukodystrophies with typical clinical and/or radiologic features of Pol III-related leukodystrophies. METHODS: The entire coding region and the flanking exon/intron boundaries of POLR3A and/or POLR3B genes were amplified and sequenced in 14 patients. RESULTS: Recessive mutations in POLR3A or POLR3B were uncovered in all 14 patients. Eight novel mutations were identified in POLR3A: six missenses, one nonsense, and one frameshift mutation. Seven patients carried compound heterozygous mutations in POLR3B, of whom six shared the common mutation in exon 15 (p.V523E). Seven novel mutations were identified in POLR3B: four missenses, two splice sites, and one intronic mutation. CONCLUSIONS: To date, our group has described 37 patients, of whom 27 have mutations in POLR3A and 10 in POLR3B, respectively. Altogether, our results further support the proposal that POLR3A and POLR3B mutations are a major cause of hypomyelinating leukodystrophies and suggest that POLR3A mutations are more frequent.


Asunto(s)
Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Hipogonadismo/genética , Mutación , ARN Polimerasa III/genética , Anomalías Dentarias/genética , Secuencia de Aminoácidos , Secuencia de Bases , Análisis Mutacional de ADN , Humanos , Datos de Secuencia Molecular
15.
Am J Hum Genet ; 87(5): 671-8, 2010 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-20950788

RESUMEN

Heterozygous mutations in FOXP2, which encodes a forkhead transcription factor, have been shown to cause developmental verbal dyspraxia and language impairment. FOXP2 and its closest homolog, FOXP1, are coexpressed in brain regions that are important for language and cooperatively regulate developmental processes, raising the possibility that FOXP1 may also be involved in developmental conditions that are associated with language impairment. In order to explore this possibility, we searched for mutations in FOXP1 in patients with intellectual disability (ID; mental retardation) and/or autism spectrum disorders (ASD). We first performed array-based genomic hybridization on sporadic nonsyndromic ID (NSID) (n = 30) or ASD (n = 80) cases. We identified a de novo intragenic deletion encompassing exons 4-14 of FOXP1 in a patient with NSID and autistic features. In addition, sequencing of all coding exons of FOXP1 in sporadic NSID (n = 110) or ASD (n = 135) cases, as well as in 570 controls, revealed the presence of a de novo nonsense mutation (c.1573C>T [p.R525X]) in the conserved forkhead DNA-binding domain in a patient with NSID and autism. Luciferase reporter assays showed that the p.R525X alteration disrupts the activity of the protein. Formal assessments revealed that both patients with de novo mutations in FOXP1 also show severe language impairment, mood lability with physical aggressiveness, and specific obsessions and compulsions. In conclusion, both FOXP1 and FOXP2 are associated with language impairment, but decrease of the former has a more global impact on brain development than that of the latter.


Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/genética , Factores de Transcripción Forkhead/genética , Discapacidad Intelectual/genética , Trastornos del Lenguaje/genética , Proteínas Represoras/genética , Adolescente , Secuencia de Aminoácidos , Niño , Preescolar , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Mutación
16.
Am J Hum Genet ; 87(3): 316-24, 2010 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-20797689

RESUMEN

The role of de novo mutations (DNMs) in common diseases remains largely unknown. Nonetheless, the rate of de novo deleterious mutations and the strength of selection against de novo mutations are critical to understanding the genetic architecture of a disease. Discovery of high-impact DNMs requires substantial high-resolution interrogation of partial or complete genomes of families via resequencing. We hypothesized that deleterious DNMs may play a role in cases of autism spectrum disorders (ASD) and schizophrenia (SCZ), two etiologically heterogeneous disorders with significantly reduced reproductive fitness. We present a direct measure of the de novo mutation rate (µ) and selective constraints from DNMs estimated from a deep resequencing data set generated from a large cohort of ASD and SCZ cases (n = 285) and population control individuals (n = 285) with available parental DNA. A survey of ∼430 Mb of DNA from 401 synapse-expressed genes across all cases and 25 Mb of DNA in controls found 28 candidate DNMs, 13 of which were cell line artifacts. Our calculated direct neutral mutation rate (1.36 × 10(-8)) is similar to previous indirect estimates, but we observed a significant excess of potentially deleterious DNMs in ASD and SCZ individuals. Our results emphasize the importance of DNMs as genetic mechanisms in ASD and SCZ and the limitations of using DNA from archived cell lines to identify functional variants.


Asunto(s)
Trastorno Autístico/genética , Análisis Mutacional de ADN/métodos , Mutagénesis/genética , Mutación/genética , Esquizofrenia/genética , Emparejamiento Base/genética , Línea Celular , Segregación Cromosómica/genética , Estudios de Cohortes , Familia , Femenino , Regulación de la Expresión Génica , Humanos , Masculino
18.
Am J Cardiol ; 205: 298-301, 2023 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-37633064

RESUMEN

Our study aimed to explore the national trends in the rates of perioperative complications, in-hospital mortality, and readmissions after pericardiectomy and the impact of center volume on these outcomes. Using the Nationwide Readmission Database, we identified patients who underwent isolated pericardiectomy from 2010 to 2019. In-hospital mortality and readmission rates were assessed using orthogonal polynomial contrasts, with the linear and nonlinear trends evaluated as needed. Multivariable logistic regression models were constructed to identify the independent predictors of mortality and readmission. All analyses accounted for the Nationwide Readmission Database sampling design and were performed using SAS version 9.4 (SAS Institute Inc. Cary, NC.) with p <0.05 used to indicate statistical significance. A total of 26,169 hospitalizations for pericardiectomy were identified during the study period. The median age was 59 years and 44% were female. In-hospital mortality was 5.2%, and the median length of stay was 7 days. Advanced age, higher co-morbidity index, and lower annual facility pericardiectomy volume were independent predictors of in-hospital mortality. The 30- and 90-day readmission rates after pericardiectomy were 18% and 28%, respectively. Previous cardiac surgery, diagnosis of constrictive pericarditis, and greater co-morbidity score were independent predictors of readmission. In conclusion, isolated pericardiectomy rates have remained mostly constant, with relatively small changes in in-hospital mortality and 30- and 90-day readmission rates over the last decade. Advanced age, lower facility pericardiectomy volume, and higher Elixhauser co-morbidity index are independent predictors of surgical mortality.


Asunto(s)
Readmisión del Paciente , Pericardiectomía , Humanos , Femenino , Estados Unidos/epidemiología , Persona de Mediana Edad , Masculino , Mortalidad Hospitalaria , Medios de Contraste , Bases de Datos Factuales
19.
Am J Med Genet A ; 158A(11): 2849-56, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23034868

RESUMEN

Macrosomia, obesity, macrocephaly, and ocular abnormalities syndrome (MOMO syndrome) has been reported in only four patients to date. In these sporadic cases, no chromosomal or molecular abnormality has been identified thus far. Here, we report on the clinical, cytogenetic, and molecular findings in a child of healthy consanguineous parents suffering from MOMO syndrome. Conventional karyotyping revealed an inherited homozygous balanced reciprocal translocation (16;20)(q21;p11.2). Uniparental disomy testing showed bi-parental inheritance for both derivative chromosomes 16 and 20. The patient's oligonucleotide array-comparative genomic hybridization profile revealed no abnormality. From the homozygous balanced reciprocal translocation (16;20)(q21;p11.2), a positional cloning strategy, designed to narrow 16q21 and 20p11.2 breakpoints, revealed the disruption of a novel gene located at 20p11.23. This gene is now named LINC00237, according to the HUGO (Human Genome Organization) nomenclature. The gene apparently leads to the production of a non-coding RNA. We established that LINC00237 was expressed in lymphocytes of control individuals while normal transcripts were absent in lymphocytes of our MOMO patient. LINC00237 was not ubiquitously expressed in control tissues, but it was notably highly expressed in the brain. Our results suggested autosomal recessive inheritance of MOMO syndrome. LINC00237 could play a role in the pathogenesis of this syndrome and could provide new insights into hyperphagia-related obesity and intellectual disability.


Asunto(s)
Anomalías Múltiples/genética , Coloboma/genética , Macrosomía Fetal/genética , Predisposición Genética a la Enfermedad , Homocigoto , Discapacidad Intelectual/genética , Megalencefalia/genética , Obesidad/genética , ARN Largo no Codificante/genética , Translocación Genética , Anomalías Múltiples/diagnóstico , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Puntos de Rotura del Cromosoma , Coloboma/diagnóstico , Macrosomía Fetal/diagnóstico , Perfilación de la Expresión Génica , Cabeza/anomalías , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/diagnóstico , Cariotipo , Masculino , Megalencefalia/diagnóstico , Datos de Secuencia Molecular , Mutación , Obesidad/diagnóstico , Sistemas de Lectura Abierta , Fenotipo
20.
Coron Artery Dis ; 33(2): 69-74, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-34074913

RESUMEN

OBJECTIVE: The principal trend in acute coronary syndrome (ACS) is increasing utilization of percutaneous coronary interventions (PCI) and declining coronary artery bypass graft surgery (CABG) utilization. This study was designed to evaluate whether higher PCI:CABG ratios lead to higher in-hospital PCI or CABG mortality. METHODS: The National Readmission Database for years 2016 was queried for all hospitalized ACS patients who underwent coronary revascularization during their admission. The study population was derived from 355 US hospitals and included 103 021 patients. Hospitals were grouped based on their PCI:CABG ratio into low, intermediate, and high ratio quartiles with a median [interquartile ranges (IQR)] PCI:CABG ratio of 2.9 (2.5-3.2), 5.0 (4.3-5.9) and 8.9 (7.8-10.3), respectively multivariable logistic regression with adjustment for age, demographics and comorbidities were used to identify CABG:PCI ratio related risk for in-hospital CABG and PCI mortality. RESULTS: Higher PCI:CABG ratios correlated with an increased CABG mortality. There was a median (IQR) mortality of 2.5% (1.6-4.3) in the low ratio quartile; 3.1% (1.9-5.3) in the intermediate quartiles; and 5.3% (3.2-9.1) in the high ratio quartile (P < 0.001). On multivariate analysis, the PCI:CABG ratio was associated with an increased risk for CABG mortality with an adjusted odds ratio of 1.38 (95% CI, 1.14-1.67, P < 0.001) and 2.17 (95% CI, 1.70-2.80, P < 0.001) for hospitals with intermediate and high PCI:CABG ratios, respectively. There was no significant association between PCI:CABG ratio and PCI mortality. CONCLUSIONS: The programmatic PCI:CABG ratio is a valid indicator of optimal case selection. The PCI:CABG ratio correlates with in-hospital mortality in ACS.


Asunto(s)
Síndrome Coronario Agudo/terapia , Puente de Arteria Coronaria/rehabilitación , Revascularización Miocárdica/estadística & datos numéricos , Intervención Coronaria Percutánea/rehabilitación , Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/fisiopatología , Anciano , Puente de Arteria Coronaria/métodos , Puente de Arteria Coronaria/estadística & datos numéricos , Femenino , Mortalidad Hospitalaria/tendencias , Humanos , Masculino , Persona de Mediana Edad , Revascularización Miocárdica/métodos , Intervención Coronaria Percutánea/métodos , Intervención Coronaria Percutánea/estadística & datos numéricos
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