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Human diseases are caused by alleles that encompass the full range of variant types, from single-nucleotide changes to copy-number variants, and these variations span a broad frequency spectrum, from the very rare to the common. The picture emerging from analysis of whole-genome sequences, the 1000 Genomes Project pilot studies, and targeted genomic sequencing derived from very large sample sizes reveals an abundance of rare and private variants. One implication of this realization is that recent mutation may have a greater influence on disease susceptibility or protection than is conferred by variations that arose in distant ancestors.
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Predisposição Genética para Doença , Genética Populacional , Genoma Humano , Variação Genética , Genômica , Humanos , Linhagem , Projetos Piloto , Medicina de PrecisãoRESUMO
PURPOSE OF REVIEW: Pathogenic DNA variants underlie many cardiovascular disease phenotypes. The most well-recognized of these include familial dyslipidemias, cardiomyopathies, arrhythmias, and aortopathies. The clinical presentations of monogenic forms of cardiovascular disease are often indistinguishable from those with complex genetic and non-genetic etiologies, making genetic testing an essential aid to precision diagnosis. RECENT FINDINGS: Precision diagnosis enables efficient management, appropriate use of emerging targeted therapies, and follow-up of at-risk family members. Genetic testing for these conditions is widely available but under-utilized. In this review, we summarize the potential benefits of genetic testing, highlighting the specific cardiovascular disease phenotypes in which genetic testing should be considered, and how clinicians can integrate guideline-directed genetic testing into their practice.
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Cardiologia , Cardiomiopatias , Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Testes Genéticos , Cardiomiopatias/genética , FenótipoRESUMO
PURPOSE: To estimate the cost-effectiveness of genome sequencing (GS) for diagnosing critically ill infants and noncritically ill pediatric patients (children) with suspected rare genetic diseases from a United States health sector perspective. METHODS: A decision-analytic model was developed to simulate the diagnostic trajectory of patients. Parameter estimates were derived from a targeted literature review and meta-analysis. The model simulated clinical and economic outcomes associated with 3 diagnostic pathways: (1) standard diagnostic care, (2) GS, and (3) standard diagnostic care followed by GS. RESULTS: For children, costs of GS ($7284) were similar to that of standard care ($7355) and lower than that of standard care followed by GS pathways ($12,030). In critically ill infants, when cost estimates were based on the length of stay in the neonatal intensive care unit, the lowest cost pathway was GS ($209,472). When only diagnostic test costs were included, the cost per diagnosis was $17,940 for standard, $17,019 for GS, and $20,255 for standard care followed by GS. CONCLUSION: The results of this economic model suggest that GS may be cost neutral or possibly cost saving as a first line diagnostic tool for children and critically ill infants.
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Doenças Raras , Doenças não Diagnosticadas , Criança , Mapeamento Cromossômico , Análise Custo-Benefício , Humanos , Lactente , Recém-Nascido , Modelos Econômicos , Doenças Raras/diagnóstico , Doenças Raras/genéticaRESUMO
BACKGROUND: Treatment characteristics such as cranial radiation therapy (CRT) do not fully explain adiposity risk in childhood acute lymphoblastic leukemia (ALL) survivors. This study was aimed at characterizing genetic variation related to adult body mass index (BMI) among survivors of childhood ALL. METHODS: Genetic associations of BMI among 1458 adult survivors of childhood ALL (median time from diagnosis, 20 years) were analyzed by multiple approaches. A 2-stage genome-wide association study in the Childhood Cancer Survivor Study (CCSS) and the St. Jude Lifetime Cohort Study (SJLIFE) was performed. BMI was a highly polygenic trait in the general population. Within the known loci, the BMI percent variance explained was estimated, and additive interactions (chi-square test) with CRT in the CCSS were evaluated. The role of DNA methylation in CRT interaction was further evaluated in a subsample of ALL survivors. RESULTS: In a meta-analysis of the CCSS and SJLIFE, 2 novel loci associated with adult BMI among survivors of childhood ALL (LINC00856 rs575792008 and EMR1 rs62123082; PMeta < 5E-8) were identified. It was estimated that the more than 700 known loci explained 6.2% of the variation in adult BMI in childhood ALL survivors. Within the known loci, significant main effects for 23 loci and statistical interactions with CRT at 9 loci (P < 7.0E-5) were further identified. At 2 CRT-interacting loci, DNA methylation patterns may have differed by age. CONCLUSIONS: Adult survivors of childhood ALL have genetic heritability for BMI similar to that observed in the general population. This study provides evidence that treatment with CRT can modify the effect of genetic variants on adult BMI in childhood ALL survivors.
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Adultos Sobreviventes de Eventos Adversos na Infância , Índice de Massa Corporal , Sobreviventes de Câncer , Irradiação Craniana/efeitos adversos , Obesidade/epidemiologia , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Adiposidade/genética , Adulto , Metilação de DNA/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population. METHODS: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW. RESULTS: A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF ≤ 0.005) with CADD score ≥ 25 in genes linked to AF in cases compared to controls (P = .0023). CONCLUSIONS: Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients.
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Proteínas Quinases Ativadas por AMP/genética , Fibrilação Atrial/genética , Predisposição Genética para Doença , Síndrome de Wolff-Parkinson-White/genética , Adolescente , Adulto , Anquirinas/genética , Fibrilação Atrial/patologia , Proteínas de Transporte/genética , Criança , Estudos de Coortes , Proteínas do Citoesqueleto/genética , Proteínas de Ligação a DNA/genética , Feminino , Estudos de Associação Genética , Átrios do Coração/patologia , Proteínas de Homeodomínio/genética , Humanos , Proteínas com Domínio LIM/genética , Masculino , Mutação/genética , Fatores de Transcrição/genética , Sequenciamento do Exoma , Síndrome de Wolff-Parkinson-White/patologia , Adulto Jovem , Proteína Homeobox PITX2RESUMO
Because survivors of pediatric acute lymphoblastic leukemia (ALL) are more likely to be obese than unaffected contemporaries, we compared DNA methylation profiles between normal-weight and obese survivors at adiposity-associated CpG sites previously-reported by epigenome-wide association studies (EWAS) of body mass index (BMI) in the general population. We selected 96 ALL survivors from the Childhood Cancer Survivor Study: 48 obese and 48 normal weight. The Illumina HumanMethylation450 BeadChip was used to compare DNA methylation at 211 loci identified in EWAS of BMI in the general population. Thirty-nine loci were associated (false discovery rate <0.05) with obesity among survivors who only received chemotherapy (n = 49). No loci were significantly associated with obesity among CRT-exposed survivors (n = 47). Our results suggest that previously identified BMI-DNA methylation loci are associated with obesity in ALL survivors who were spared CRT, while no loci were significantly associated with obesity in survivors who received CRT.
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Metilação de DNA/genética , Obesidade/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Índice de Massa Corporal , Sobreviventes de Câncer , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Proteínas de Neoplasias/genética , Obesidade/complicações , Obesidade/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adulto JovemRESUMO
The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum.
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Atrofia/genética , Deficiências do Desenvolvimento/genética , Variação Genética , Hipotonia Muscular/genética , Proteínas/genética , Escoliose/genética , Adolescente , Alelos , Sequência de Aminoácidos , Atrofia/diagnóstico , Cerebelo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Degradação Associada com o Retículo Endoplasmático , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Proteínas de Membrana , Dados de Sequência Molecular , Hipotonia Muscular/diagnóstico , Mutação , Linhagem , Dobramento de Proteína , Proteínas/metabolismo , Escoliose/diagnósticoRESUMO
Disruption of the establishment of left-right (L-R) asymmetry leads to situs anomalies ranging from situs inversus totalis (SIT) to situs ambiguus (heterotaxy). The genetic causes of laterality defects in humans are highly heterogeneous. Via whole-exome sequencing (WES), we identified homozygous mutations in PKD1L1 from three affected individuals in two unrelated families. PKD1L1 encodes a polycystin-1-like protein and its loss of function is known to cause laterality defects in mouse and medaka fish models. Family 1 had one fetus and one deceased child with heterotaxy and complex congenital heart malformations. WES identified a homozygous splicing mutation, c.6473+2_6473+3delTG, which disrupts the invariant splice donor site in intron 42, in both affected individuals. In the second family, a homozygous c.5072G>C (p.Cys1691Ser) missense mutation was detected in an individual with SIT and congenital heart disease. The p.Cys1691Ser substitution affects a highly conserved cysteine residue and is predicted by molecular modeling to disrupt a disulfide bridge essential for the proper folding of the G protein-coupled receptor proteolytic site (GPS) motif. Damaging effects associated with substitutions of this conserved cysteine residue in the GPS motif have also been reported in other genes, namely GPR56, BAI3, and PKD1 in human and lat-1 in C. elegans, further supporting the likely pathogenicity of p.Cys1691Ser in PKD1L1. The identification of bi-allelic PKD1L1 mutations recapitulates previous findings regarding phenotypic consequences of loss of function of the orthologous genes in mice and medaka fish and further expands our understanding of genetic contributions to laterality defects in humans.
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Alelos , Lateralidade Funcional/genética , Proteínas de Membrana/genética , Mutação , Situs Inversus/genética , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Caenorhabditis elegans/genética , Cisteína/genética , Exoma/genética , Feminino , Doenças Fetais/genética , Cardiopatias Congênitas/genética , Síndrome de Heterotaxia , Homozigoto , Humanos , Recém-Nascido , Íntrons/genética , Masculino , Proteínas de Membrana/química , Camundongos , Pessoa de Meia-Idade , Modelos Moleculares , Mutação de Sentido Incorreto , Oryzias/genética , Linhagem , Splicing de RNA/genéticaRESUMO
Each year in the United States, thousands of cases of sudden and unexpected deaths of infants, children, and young adults are assigned an undetermined cause of death after postmortem investigation and autopsy. Heritable genetic variants have been suggested as the cause of up to a third of sudden death (SD) cases. Elucidation of the genetic variants involved in SD cases is important to not only help establish cause and manner of death of these individuals, but to also aid in determining whether familial genetic testing should be considered. Previously, these types of postmortem screenings have not been a feasible option for most county medical examiners' and coroners' offices. We sequenced full exons of 64 genes associated with SD in the largest known cohort (351) of infant and young SD decedents using massively parallel sequencing at <$600 per sample. Genetic variants were assessed through literature review and clinical evaluation by a multidisciplinary consortium of experts. Thirteen individuals (3.7%), eight infants (2.8% of those <1 yr of age) and five children/young adults (7.0% of those >1 yr of age), were found to have a reportable genetic variant contributing to SD. These percentages represent an estimate lower than those previously reported. Overall yields and results likely vary between studies due to differences in evaluation techniques and reporting. Additionally, we recommend ongoing assessment of data, including nonreported novel variants, as technology and literature continually advance. This study demonstrates a strategy to implement molecular autopsies in medicolegal investigations of young SD decedents.
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Cardiomiopatias/genética , Morte Súbita/epidemiologia , Testes Genéticos , Variação Genética , Adolescente , Adulto , Autopsia , Cardiomiopatias/diagnóstico , Cardiomiopatias/mortalidade , Criança , Pré-Escolar , Morte Súbita/etiologia , Morte Súbita/patologia , Diagnóstico , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estados Unidos , Adulto JovemRESUMO
PURPOSE: To identify the economic impact of pediatric patients with clinical indications of genetic disease (GD) on the US health-care system. METHODS: Using the 2012 Kids' Inpatient Database, we identified pediatric inpatient discharges with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes linked to genetic disease, including well-established genetic disorders, neurological diseases, birth defects, and other physiological or functional abnormalities with a genetic basis. Cohort characteristics and health-care utilization measures were analyzed. Discharges with a GD-associated primary diagnosis were used to estimate the minimum burden; discharges with GD-associated primary or secondary codes established the maximum burden. RESULTS: Of 5.85 million weighted discharges, 2.6-14% included GD-associated ICD-9-CM codes. For these discharges, mean total costs were $16,000-77,000 higher (P < 0.0001) in neonates and $12,000-17,000 higher (P < 0.0001) in pediatric patients compared with background, corresponding to significantly higher total charges and lengths of stay. Aggregate total charges for suspected GD accounted for $14 to $57 billion (11-46%) of the "national bill" for pediatric patients in 2012. CONCLUSION: Pediatric inpatients with diagnostic codes linked to genetic disease have a significant and disproportionate impact on resources and costs in the US health-care system.
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Bases de Dados Factuais , Doenças Genéticas Inatas/epidemiologia , Pediatria , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Doenças Genéticas Inatas/economia , Hospitalização/economia , Humanos , Recém-Nascido , Tempo de Internação/economia , Masculino , Estados Unidos/epidemiologia , Adulto JovemRESUMO
This Article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY-NC-ND 4.0] license. The PDF and HTML versions of the Article have been modified accordingly.
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PURPOSE: Maternal diabetes is a known teratogen that can cause a wide spectrum of birth defects, collectively referred to as diabetic embryopathy (DE). However, the pathogenic mechanisms underlying DE remain uncertain and there are no definitive tests to establish the diagnosis. Here, we explore the potential of DNA methylation as a diagnostic biomarker for DE and to inform disease pathogenesis. METHODS: Bisulfite sequencing was used to identify gene regions with differential methylation between DE neonates and healthy infants born with or without prenatal exposure to maternal diabetes, and to investigate the role of allele-specific methylation at implicated sites. RESULTS: We identified a methylation signature consisting of 237 differentially methylated loci that distinguished infants with DE from control infants. These loci were found proximal to genes associated with Mendelian syndromes that overlap the DE phenotype (e.g., CACNA1C, TRIO, ANKRD11) or genes known to influence embryonic development (e.g., BRAX1, RASA3). Further, we identified allele-specific methylation (ASM) at 11 of these loci, within which 61.5% of ASM single-nucleotide variants are known expression quantitative trait loci (eQTLs). CONCLUSIONS: Our study suggests a role for aberrant DNA methylation and cis-sequence variation in the pathogenesis of DE and highlights the diagnostic potential of DNA methylation for teratogenic birth defects.
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Metilação de DNA/genética , Diabetes Mellitus/embriologia , Doenças Fetais/genética , Alelos , Biomarcadores , Ilhas de CpG/genética , Complicações do Diabetes/genética , Diabetes Mellitus/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Locos de Características Quantitativas/genéticaRESUMO
PURPOSE: Brain malformations caused by 17p13.3 deletions include lissencephaly with deletions of the larger Miller-Dieker syndrome region or smaller deletions of only PAFAH1B1, white matter changes, and a distinct syndrome due to deletions including YWHAE and CRK but sparing PAFAH1B1. We sought to understand the significance of 17p13.3 deletions between the YWHAE/CRK and PAFAH1B1 loci. METHODS: We analyzed the clinical features of six individuals from five families with 17p13.3 deletions between and not including YWHAE/CRK and PAFAH1B1 identified among individuals undergoing clinical chromosomal microarray testing or research genome sequencing. RESULTS: Five individuals from four families had multifocal white matter lesions while a sixth had a normal magnetic resonance image. A combination of our individuals and a review of those in the literature with white matter changes and deletions in this chromosomal region narrows the overlapping region for this brain phenotype to ~345 kb, including 11 RefSeq genes, with RTN4RL1 haploinsufficiency as the best candidate for causing this phenotype. CONCLUSION: While previous literature has hypothesized dysmorphic features and white matter changes related to YWHAE, our cohort contributes evidence to the presence of additional genetic changes within 17p13.3 required for proper brain development.
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Deleção Cromossômica , Cromossomos Humanos Par 17 , Leucoencefalopatias/genética , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Proteínas 14-3-3/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Leucoencefalopatias/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Proteínas Associadas aos Microtúbulos/genéticaRESUMO
Genetic alterations leading to overactivation of mammalian target of rapamycin (mTOR) signaling result in brain overgrowth syndromes such as focal cortical dysplasia (FCD) and megalencephaly. Megalencephaly with cutis tri-color of the Blaschko-linear type pigmentary mosaicism and intellectual disability is a rare neurodevelopmental disorder attributed to the recurrent mosaic c.5930C > T (p.Thr1977Ile) MTOR variant. This variant was previously reported at low to intermediate levels of mosaicism in the peripheral blood of three unrelated individuals with consistent clinical findings. We report a fourth case of a 3-year-old female presenting with megalencephaly, obstructive hydrocephalus due to cerebral aqueductal stenosis, asymmetric polymicrogyria, dysgenesis of the corpus callosum, hypotonia, developmental delay, and cutaneous pigmentary mosaicism. Oligonucleotide and SNP chromosomal microarray (CMA), karyotype, and trio whole exome sequencing (WES) in the peripheral blood, as well as a targeted gene variant panel from fibroblasts derived from hyperpigmented and non-hyperpigmented skin did not detect any abnormalities in MTOR or other genes associated with brain overgrowth syndromes. Unlike the previously reported cases, the de novo c.5930C > T (p.Thr1977Ile) MTOR variant was detected at 32% mosaicism in our patient only after WES was performed on fibroblast-derived DNA from the hyperpigmented skin. This case demonstrates the tissue variability in mosaic expression of the recurrent p.Thr1977Ile MTOR variant, emphasizes the need for skin biopsies in the genetic evaluation of patients with skin pigmentary mosaicism, and expands the clinical phenotype associated with this pathogenic MTOR variant.
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Malformações do Desenvolvimento Cortical/diagnóstico , Malformações do Desenvolvimento Cortical/genética , Megalencefalia/diagnóstico , Megalencefalia/genética , Mutação , Transtornos da Pigmentação/diagnóstico , Transtornos da Pigmentação/genética , Serina-Treonina Quinases TOR/genética , Alelos , Substituição de Aminoácidos , Pré-Escolar , Feminino , Genótipo , Humanos , Imageamento por Ressonância Magnética , Mosaicismo , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We developed an algorithm, HMZDelFinder, that uses whole exome sequencing (WES) data to identify rare and intragenic homozygous and hemizygous (HMZ) deletions that may represent complete loss-of-function of the indicated gene. HMZDelFinder was applied to 4866 samples in the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) cohort and detected 773 HMZ deletion calls (567 homozygous or 206 hemizygous) with an estimated sensitivity of 86.5% (82% for single-exonic and 88% for multi-exonic calls) and precision of 78% (53% single-exonic and 96% for multi-exonic calls). Out of 773 HMZDelFinder-detected deletion calls, 82 were subjected to array comparative genomic hybridization (aCGH) and/or breakpoint PCR and 64 were confirmed. These include 18 single-exon deletions out of which 8 were exclusively detected by HMZDelFinder and not by any of seven other CNV detection tools examined. Further investigation of the 64 validated deletion calls revealed at least 15 pathogenic HMZ deletions. Of those, 7 accounted for 17-50% of pathogenic CNVs in different disease cohorts where 7.1-11% of the molecular diagnosis solved rate was attributed to CNVs. In summary, we present an algorithm to detect rare, intragenic, single-exon deletion CNVs using WES data; this tool can be useful for disease gene discovery efforts and clinical WES analyses.
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Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Exoma , Doenças Genéticas Inatas/genética , Hemizigoto , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Algoritmos , Processamento Alternativo , Estudos de Coortes , Consanguinidade , Conjuntos de Dados como Assunto , Doenças Genéticas Inatas/diagnóstico , Humanos , Padrões de Herança , Modelos Genéticos , Linhagem , Reprodutibilidade dos Testes , Deleção de Sequência , Fluxo de TrabalhoRESUMO
Congenital heart defects involving left-sided lesions (LSLs) are relatively common birth defects with substantial morbidity and mortality. Previous studies have suggested a high heritability with a complex genetic architecture, such that only a few LSL loci have been identified. We performed a genome-wide case-control association study to address the role of common variants using a discovery cohort of 778 cases and 2756 controls. We identified a genome-wide significant association mapping to a 200 kb region on chromosome 20q11 [P= 1.72 × 10-8 for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 × 10-9, odds ratio (OR)= 1.6 for both]. This result was supported by transmission disequilibrium analyses using a subset of 541 case families (lowest P in region= 4.51 × 10-5, OR= 1.5). Replication in a cohort of 367 LSL cases and 5159 controls showed nominal association (P= 0.03 for rs3746446) resulting in P= 9.49 × 10-9 for rs3746446 upon meta-analysis of the combined cohorts. In addition, a group of seven SNPs on chromosome 1q21.3 met threshold for suggestive association (lowest P= 9.35 × 10-7 for rs12045807). Both regions include genes involved in cardiac development-MYH7B/miR499A on chromosome 20 and CTSK, CTSS and ARNT on chromosome 1. Genome-wide heritability analysis using case-control genotyped SNPs suggested that the mean heritability of LSLs attributable to common variants is moderately high ([Formula: see text] range= 0.26-0.34) and consistent with previous assertions. These results provide evidence for the role of common variation in LSLs, proffer new genes as potential biological candidates, and give further insight to the complex genetic architecture of congenital heart disease.
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Cromossomos Humanos Par 20/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias Congênitas/genética , Mapeamento Cromossômico , Estudos de Coortes , Feminino , Genótipo , Cardiopatias Congênitas/fisiopatologia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
In 1995, the American Society of Human Genetics (ASHG) and American College of Medical Genetics and Genomics (ACMG) jointly published a statement on genetic testing in children and adolescents. In the past 20 years, much has changed in the field of genetics, including the development of powerful new technologies, new data from genetic research on children and adolescents, and substantial clinical experience. This statement represents current opinion by the ASHG on the ethical, legal, and social issues concerning genetic testing in children. These recommendations are relevant to families, clinicians, and investigators. After a brief review of the 1995 statement and major changes in genetic technologies in recent years, this statement offers points to consider on a broad range of test technologies and their applications in clinical medicine and research. Recommendations are also made for record and communication issues in this domain and for professional education.
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Testes Genéticos/ética , Testes Genéticos/legislação & jurisprudência , Testes Genéticos/tendências , Genética/história , Genômica/métodos , Consentimento Informado por Menores/psicologia , Adolescente , Criança , Triagem de Portadores Genéticos , Genômica/ética , História do Século XX , História do Século XXI , Humanos , Recém-Nascido , Análise em Microsséries/métodos , Análise em Microsséries/tendências , Farmacogenética/métodosRESUMO
BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. RESULTS: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
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Síndromes de Imunodeficiência/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
To better understand the systemic response to naturally acquired acute respiratory viral infections, we prospectively enrolled 1610 healthy adults in 2009 and 2010. Of these, 142 subjects were followed for detailed evaluation of acute viral respiratory illness. We examined peripheral blood gene expression at 7 timepoints: enrollment, 5 illness visits and the end of each year of the study. 133 completed all study visits and yielded technically adequate peripheral blood microarray gene expression data. Seventy-three (55%) had an influenza virus infection, 64 influenza A and 9 influenza B. The remaining subjects had a rhinovirus infection (N = 32), other viral infections (N = 4), or no viral agent identified (N = 24). The results, which were replicated between two seasons, showed a dramatic upregulation of interferon pathway and innate immunity genes. This persisted for 2-4 days. The data show a recovery phase at days 4 and 6 with differentially expressed transcripts implicated in cell proliferation and repair. By day 21 the gene expression pattern was indistinguishable from baseline (enrollment). Influenza virus infection induced a higher magnitude and longer duration of the shared expression signature of illness compared to the other viral infections. Using lineage and activation state-specific transcripts to produce cell composition scores, patterns of B and T lymphocyte depressions accompanied by a major activation of NK cells were detected in the acute phase of illness. The data also demonstrate multiple dynamic gene modules that are reorganized and strengthened following infection. Finally, we examined pre- and post-infection anti-influenza antibody titers defining novel gene expression correlates.
Assuntos
Influenza Humana/genética , Influenza Humana/imunologia , Infecções Respiratórias/genética , Infecções Respiratórias/imunologia , Adolescente , Adulto , Estudos de Coortes , Resfriado Comum/genética , Resfriado Comum/imunologia , Feminino , Humanos , Vírus da Influenza A/imunologia , Vírus da Influenza B/imunologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Rhinovirus/imunologia , Transcrição Gênica , Transcriptoma , Adulto JovemRESUMO
PURPOSE: To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT). METHODS: WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs). RESULTS: In approximately 5% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development. CONCLUSION: We conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes.Genet Med 19 4, 412-420.