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PURPOSE: Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease prevalence of the associated condition, leading to a lack of clear segregation between the variant and disease. There is currently substantial variation in the classification of these variants, and no formal classification framework has been widely adopted. The Clinical Genome Resource Low Penetrance/Risk Allele Working Group was formed to address these challenges and promote harmonization within the clinical community. METHODS: The work presented here is the product of internal and community Likert-scaled surveys in combination with expert consensus within the Working Group. RESULTS: We formally recognize risk alleles and low-penetrance variants as distinct variant classes from those causing highly penetrant disease that require special considerations regarding their clinical classification and reporting. First, we provide a preferred terminology for these variants. Second, we focus on risk alleles and detail considerations for reviewing relevant studies and present a framework for the classification these variants. Finally, we discuss considerations for clinical reporting of risk alleles. CONCLUSION: These recommendations support harmonized interpretation, classification, and reporting of variants at the low end of the penetrance spectrum.
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Variación Genética , Humanos , Alelos , Variación Genética/genética , Penetrancia , Frecuencia de los GenesRESUMEN
Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies (IDDFSDA) is an autosomal recessive multisystem disorder caused by compound heterozygous or homozygous variants in the gene OTUD6B. Herein, we describe novel pathogenic compound heterozygous variants in OTUD6B identified via whole-exome sequencing in an index case exhibited the severe IDDFSDA phenotype. The potential pathogenicity of the novel frameshift and missense variants in the index case was investigated using in silico tools. The truncating frameshift variant in one allele was predicted to undergo degradation via nonsense-mediated decay of the mRNA molecule. To predict the severity of the damage to the protein caused by the missense variant in the other allele and its effects on phenotypic severity was further investigated together with a previously reported first homozygous missense variant in the same domain in another patient with a less severe IDDFSDA phenotype using structural modeling and molecular dynamics (MD) simulations for the first time. Based on these analyzes, it is anticipated that Tyr216Cys in the earlier reported case with less severe IDDFSDA will lead to localized destabilization, whereas Ile274Arg in the presented index case with the severe IDDFSDA phenotype will lead to significant distortion in the overall fold of OTUD6B. Our findings suggest that compound LOF and ultrarare missense variants may be contribute to the underlying variability expressivity associated with this disorder. In conclusion, our findings support that the clinical severity could be related with the predicted functional severity of the variations in OTUD6B. However, additional functional studies are required.
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Endopeptidasas , Discapacidad Intelectual , Endopeptidasas/genética , Endopeptidasas/metabolismo , Homocigoto , Humanos , Discapacidad Intelectual/genética , Simulación de Dinámica Molecular , Fenotipo , Secuenciación del ExomaRESUMEN
Autism spectrum disorders (ASD) are neurodevelopmental disorders with an estimated heritability of >60%. Family-based genetic studies of ASD have generally focused on multiple small kindreds, searching for de novo variants of major effect. We hypothesized that molecular genetic analysis of large multiplex families would enable the identification of variants of milder effects. We studied a large multigenerational family of European ancestry with multiple family members affected with ASD or the broader autism phenotype (BAP). We identified a rare heterozygous variant in the gene encoding 1,4-É-glucan branching enzyme 1 (GBE1) that was present in seven of seven individuals with ASD, nine of ten individuals with the BAP, and none of four tested unaffected individuals. We genotyped a community-acquired cohort of 389 individuals with ASD and identified three additional probands. Cascade analysis demonstrated that the variant was present in 11 of 13 individuals with familial ASD/BAP and neither of the two tested unaffected individuals in these three families, also of European ancestry. The variant was not enriched in the combined UK10K ASD cohorts of European ancestry but heterozygous GBE1 deletion was overrepresented in large ASD cohorts, collectively suggesting an association between GBE1 and ASD.
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Enzima Ramificadora de 1,4-alfa-Glucano , Trastorno del Espectro Autista , Sistema de la Enzima Desramificadora del Glucógeno , Enzima Ramificadora de 1,4-alfa-Glucano/genética , Trastorno del Espectro Autista/genética , Exoma , Predisposición Genética a la Enfermedad , Glucanos , Sistema de la Enzima Desramificadora del Glucógeno/genética , HumanosRESUMEN
Autism is a highly heritable complex disorder in which de novo mutation (DNM) variation contributes significantly to risk. Using whole-genome sequencing data from 3,474 families, we investigate another source of large-effect risk variation, ultra-rare variants. We report and replicate a transmission disequilibrium of private, likely gene-disruptive (LGD) variants in probands but find that 95% of this burden resides outside of known DNM-enriched genes. This variant class more strongly affects multiplex family probands and supports a multi-hit model for autism. Candidate genes with private LGD variants preferentially transmitted to probands converge on the E3 ubiquitin-protein ligase complex, intracellular transport and Erb signaling protein networks. We estimate that these variants are approximately 2.5 generations old and significantly younger than other variants of similar type and frequency in siblings. Overall, private LGD variants are under strong purifying selection and appear to act on a distinct set of genes not yet associated with autism.
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Trastorno del Espectro Autista/genética , Predisposición Genética a la Enfermedad , Proteínas/genética , Trastorno Autístico/genética , Evolución Molecular , Dosificación de Gen , Haplotipos , Humanos , Desequilibrio de Ligamiento , Modelos Genéticos , Mutación , Linaje , Polimorfismo de Nucleótido Simple , Mapas de Interacción de Proteínas/genética , Hermanos , Secuenciación Completa del GenomaRESUMEN
Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
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Predisposición Genética a la Enfermedad , Trastornos del Neurodesarrollo/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factor de Unión a CCCTC/genética , Estudios de Casos y Controles , Estudios de Cohortes , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Femenino , Estudios de Asociación Genética , Ribonucleoproteína Heterogénea-Nuclear Grupo U/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Canal de Potasio KCNQ3/genética , Masculino , Mutación , Proteínas de Unión al ARN/genética , Proteínas Represoras/genética , Factores de Transcripción/genéticaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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INTRODUCTION: Congenital clubfoot is a common birth defect that affects at least 0.1% of all births. Nearly 25% cases are familial and the remaining are sporadic in inheritance. Copy number variants (CNVs) involving transcriptional regulators of limb development, including PITX1 and TBX4, have previously been shown to cause familial clubfoot, but much of the heritability remains unexplained. METHODS: Exome sequence data from 816 unrelated clubfoot cases and 2645 in-house controls were analysed using coverage data to identify rare CNVs. The precise size and location of duplications were then determined using high-density Affymetrix Cytoscan chromosomal microarray (CMA). Segregation in families and de novo status were determined using qantitative PCR. RESULTS: Chromosome Xp22.33 duplications involving SHOX were identified in 1.1% of cases (9/816) compared with 0.07% of in-house controls (2/2645) (p=7.98×10-5, OR=14.57) and 0.27% (38/13592) of Atherosclerosis Risk in Communities/the Wellcome Trust Case Control Consortium 2 controls (p=0.001, OR=3.97). CMA validation confirmed an overlapping 180.28 kb duplicated region that included SHOX exons as well as downstream non-coding regions. In four of six sporadic cases where DNA was available for unaffected parents, the duplication was de novo. The probability of four de novo mutations in SHOX by chance in a cohort of 450 sporadic clubfoot cases is 5.4×10-10. CONCLUSIONS: Microduplications of the pseudoautosomal chromosome Xp22.33 region (PAR1) containing SHOX and downstream enhancer elements occur in ~1% of patients with clubfoot. SHOX and regulatory regions have previously been implicated in skeletal dysplasia as well as idiopathic short stature, but have not yet been reported in clubfoot. SHOX duplications likely contribute to clubfoot pathogenesis by altering early limb development.
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Pie Equinovaro/genética , Predisposición Genética a la Enfermedad , Factores de Transcripción Paired Box/genética , Proteína de la Caja Homeótica de Baja Estatura/genética , Proteínas de Dominio T Box/genética , Adolescente , Niño , Preescolar , Duplicación Cromosómica/genética , Pie Equinovaro/patología , Variaciones en el Número de Copia de ADN/genética , Duplicación de Gen/genética , Humanos , Lactante , Análisis por Micromatrices , Persona de Mediana Edad , Linaje , Regiones Pseudoautosómicas/genética , Secuenciación del ExomaRESUMEN
Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10-3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.
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Variaciones en el Número de Copia de ADN , Predisposición Genética a la Enfermedad/genética , Genoma Humano/genética , Población Blanca/genética , Hibridación Genómica Comparativa , Bases de Datos Genéticas , Sitios Genéticos , Predisposición Genética a la Enfermedad/etnología , Estudio de Asociación del Genoma Completo , Humanos , Anotación de Secuencia Molecular , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Hirschsprung's disease, or congenital aganglionosis, is a developmental disorder of the enteric nervous system and is the most common cause of intestinal obstruction in neonates and infants. The disease has more than 80% heritability, including significant associations with rare and common sequence variants in genes related to the enteric nervous system, as well as with monogenic and chromosomal syndromes. METHODS: We genotyped and exome-sequenced samples from 190 patients with Hirschsprung's disease to quantify the genetic burden in patients with this condition. DNA sequence variants, large copy-number variants, and karyotype variants in probands were considered to be pathogenic when they were significantly associated with Hirschsprung's disease or another neurodevelopmental disorder. Novel genes were confirmed by functional studies in the mouse and human embryonic gut and in zebrafish embryos. RESULTS: The presence of five or more variants in four noncoding elements defined a widespread risk of Hirschsprung's disease (48.4% of patients and 17.1% of controls; odds ratio, 4.54; 95% confidence interval [CI], 3.19 to 6.46). Rare coding variants in 24 genes that play roles in enteric neural-crest cell fate, 7 of which were novel, were also common (34.7% of patients and 5.0% of controls) and conferred a much greater risk than noncoding variants (odds ratio, 10.02; 95% CI, 6.45 to 15.58). Large copy-number variants, which were present in fewer patients (11.4%, as compared with 0.2% of controls), conferred the highest risk (odds ratio, 63.07; 95% CI, 36.75 to 108.25). At least one identifiable genetic risk factor was found in 72.1% of the patients, and at least 48.4% of patients had a structural or regulatory deficiency in the gene encoding receptor tyrosine kinase (RET). For individual patients, the estimated risk of Hirschsprung's disease ranged from 5.33 cases per 100,000 live births (approximately 1 per 18,800) to 8.38 per 1000 live births (approximately 1 per 120). CONCLUSIONS: Among the patients in our study, Hirschsprung's disease arose from common noncoding variants, rare coding variants, and copy-number variants affecting genes involved in enteric neural-crest cell fate that exacerbate the widespread genetic susceptibility associated with RET. For individual patients, the genotype-specific odds ratios varied by a factor of approximately 67, which provides a basis for risk stratification and genetic counseling. (Funded by the National Institutes of Health.).
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Variación Genética , Genotipo , Enfermedad de Hirschsprung/genética , Exoma , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Mutación , Oportunidad Relativa , Penetrancia , Análisis de Secuencia de ADN , Secuenciación del ExomaRESUMEN
Human chromosome 15q25 is involved in several disease-associated structural rearrangements, including microdeletions and chromosomal markers with inverted duplications. Using comparative fluorescence in situ hybridization, strand-sequencing, single-molecule, real-time sequencing and Bionano optical mapping analyses, we investigated the organization of the 15q25 region in human and nonhuman primates. We found that two independent inversions occurred in this region after the fission event that gave rise to phylogenetic chromosomes XIV and XV in humans and great apes. One of these inversions is still polymorphic in the human population today and may confer differential susceptibility to 15q25 microdeletions and inverted duplications. The inversion breakpoints map within segmental duplications containing core duplicons of the GOLGA gene family and correspond to the site of an ancestral centromere, which became inactivated about 25 million years ago. The inactivation of this centromere likely released segmental duplications from recombination repression typical of centromeric regions. We hypothesize that this increased the frequency of ectopic recombination creating a hotspot of hominid inversions where dispersed GOLGA core elements now predispose this region to recurrent genomic rearrangements associated with disease.
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Inversión Cromosómica , Cromosomas Humanos Par 15/genética , Duplicaciones Segmentarias en el Genoma , Animales , Autoantígenos/genética , Inestabilidad Cromosómica , Evolución Molecular , Dosificación de Gen , Reordenamiento Génico , Variación Genética , Proteínas de la Matriz de Golgi/genética , Hominidae/genética , Humanos , Familia de Multigenes , Filogenia , Primates/genética , Recombinación Genética , Especificidad de la EspecieRESUMEN
Long noncoding RNAs (lncRNAs) have been shown to act as important cell biological regulators including cell fate decisions but are often ignored in human genetics. Combining differential lncRNA expression during neuronal lineage induction with copy number variation morbidity maps of a cohort of children with autism spectrum disorder/intellectual disability versus healthy controls revealed focal genomic mutations affecting several lncRNA candidate loci. Here we find that a t(5:12) chromosomal translocation in a family manifesting neurodevelopmental symptoms disrupts specifically lnc-NR2F1. We further show that lnc-NR2F1 is an evolutionarily conserved lncRNA functionally enhances induced neuronal cell maturation and directly occupies and regulates transcription of neuronal genes including autism-associated genes. Thus, integrating human genetics and functional testing in neuronal lineage induction is a promising approach for discovering candidate lncRNAs involved in neurodevelopmental diseases.
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Trastorno del Espectro Autista/genética , Diferenciación Celular/genética , Mutación , Trastornos del Neurodesarrollo/genética , Neuronas/metabolismo , ARN Largo no Codificante/genética , Trastorno del Espectro Autista/patología , Niño , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 5/genética , Variaciones en el Número de Copia de ADN , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Masculino , Trastornos del Neurodesarrollo/patología , Neurogénesis/genética , Neuronas/citología , Linaje , Translocación Genética/genéticaRESUMEN
INTRODUCTION: Targeted therapies for lung adenocarcinoma (LUAD) have improved patient outcomes; however, drug resistance remains a major problem. One strategy to achieve durable response is to develop combination-based therapies that target both mutated oncogenes and key modifiers of oncogene-driven tumorigenesis. This is based on the premise that mutated oncogenes, although necessary, are not sufficient for malignant transformation. We aimed to uncover genetic alterations that cooperate with mutant EGFR during LUAD development. METHODS: We performed integrative genomic analyses, combining copy number, gene expression and mutational information for over 500 LUAD tumors. Co-immunoprecipitation and Western blot analysis were performed in LUAD cell lines to confirm candidate interactions while RNA interference and gene overexpression were used for in vitro and in vivo functional assessment. RESULTS: We identified frequent amplifications/deletions of chromosomal regions affecting the activity of genes specifically in the context of EGFR mutation, including amplification of the mutant EGFR allele and deletion of dual specificity phosphatase 4 (DUSP4), which have both previously been reported. In addition, we identified the novel amplification of a segment of chromosome arm 16p in mutant-EGFR tumors corresponding to increased expression of Golgi Associated, Gamma Adaptin Ear Containing, ARF Binding Protein 2 (GGA2), which functions in protein trafficking and sorting. We found that GGA2 interacts with EGFR, increases EGFR protein levels and modifies EGFR degradation after ligand stimulation. Furthermore, we show that overexpression of GGA2 enhances EGFR mediated transformation while GGA2 knockdown reduces the colony and tumor forming ability of EGFR mutant LUAD. CONCLUSIONS: These data suggest that overexpression of GGA2 in LUAD tumors results in the accumulation of EGFR protein and increased EGFR signaling, which helps drive tumor progression. Thus, GGA2 plays a cooperative role with EGFR during LUAD development and is a potential therapeutic target for combination-based strategies in LUAD.
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Proteínas Adaptadoras del Transporte Vesicular/genética , Neoplasias Pulmonares/genética , Células 3T3 , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , Carcinogénesis , Línea Celular Tumoral , Deleción Cromosómica , Receptores ErbB/genética , Receptores ErbB/metabolismo , Amplificación de Genes , Genómica , Células HEK293 , Células HeLa , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Mutación , Transducción de SeñalRESUMEN
PURPOSE: To maximize the discovery of potentially pathogenic variants to better understand the diagnostic utility of genome sequencing (GS) and to assess how the presence of multiple risk events might affect the phenotypic severity in autism spectrum disorders (ASD). METHODS: GS was applied to 180 simplex and multiplex ASD families (578 individuals, 213 patients) with exome sequencing and array comparative genomic hybridization further applied to a subset for validation and cross-platform comparisons. RESULTS: We found that 40.8% of patients carried variants with evidence of disease risk, including a de novo frameshift variant in NR4A2 and two de novo missense variants in SYNCRIP, while 21.1% carried clinically relevant pathogenic or likely pathogenic variants. Patients with more than one risk variant (9.9%) were more severely affected with respect to cognitive ability compared with patients with a single or no-risk variant. We observed no instance among the 27 multiplex families where a pathogenic or likely pathogenic variant was transmitted to all affected members in the family. CONCLUSION: The study demonstrates the diagnostic utility of GS, especially for multiple risk variants that contribute to the phenotypic severity, shows the genetic heterogeneity in multiplex families, and provides evidence for new genes for follow up.
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Trastorno Autístico/genética , Secuenciación del Exoma , Niño , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , FenotipoRESUMEN
We combined de novo mutation (DNM) data from 10,927 individuals with developmental delay and autism to identify 253 candidate neurodevelopmental disease genes with an excess of missense and/or likely gene-disruptive (LGD) mutations. Of these genes, 124 reach exome-wide significance (P < 5 × 10-7) for DNM. Intersecting these results with copy number variation (CNV) morbidity data shows an enrichment for genomic disorder regions (30/253, likelihood ratio (LR) +1.85, P = 0.0017). We identify genes with an excess of missense DNMs overlapping deletion syndromes (for example, KIF1A and the 2q37 deletion) as well as duplication syndromes, such as recurrent MAPK3 missense mutations within the chromosome 16p11.2 duplication, recurrent CHD4 missense DNMs in the 12p13 duplication region, and recurrent WDFY4 missense DNMs in the 10q11.23 duplication region. Network analyses of genes showing an excess of DNMs highlights functional networks, including cell-specific enrichments in the D1+ and D2+ spiny neurons of the striatum.
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Variaciones en el Número de Copia de ADN/genética , Mutación/genética , Trastornos del Neurodesarrollo/genética , Animales , Trastorno Autístico/genética , Aberraciones Cromosómicas , Discapacidades del Desarrollo/genética , Exoma/genética , Humanos , Discapacidad Intelectual/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Ratones , Fenotipo , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Background: We previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype-phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent. Methods: We sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes. Results: We validated recurrent, LGD, de novo mutations (DNMs) in 13 genes. We identified a potential novel risk gene (ZNF292), one novel gene with recurrent LGD DNMs (RALGAPB), as well as genes associated with macrocephaly (GIGYF2 and WDFY3). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes. Conclusions: We identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk.
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Trastorno del Espectro Autista/genética , Modelos Genéticos , Herencia Multifactorial , Mutación , Adulto , Niño , Femenino , Humanos , Masculino , Linaje , Sitios de Carácter CuantitativoRESUMEN
Genotype-first combined with reverse phenotyping has shown to be a powerful tool in human genetics, especially in the era of next generation sequencing. This combines the identification of individuals with mutations in the same gene and linking these to consistent (endo)phenotypes to establish disease causality. We have performed a MIP (molecular inversion probe)-based targeted re-sequencing study in 3,275 individuals with intellectual disability (ID) to facilitate a genotype-first approach for 24 genes previously implicated in ID.Combining our data with data from a publicly available database, we confirmed 11 of these 24 genes to be relevant for ID. Amongst these, PHIP was shown to have an enrichment of disruptive mutations in the individuals with ID (5 out of 3,275). Through international collaboration, we identified a total of 23 individuals with PHIP mutations and elucidated the associated phenotype. Remarkably, all 23 individuals had developmental delay/ID and the majority were overweight or obese. Other features comprised behavioral problems (hyperactivity, aggression, features of autism and/or mood disorder) and dysmorphisms (full eyebrows and/or synophrys, upturned nose, large ears and tapering fingers). Interestingly, PHIP encodes two protein-isoforms, PHIP/DCAF14 and NDRP, each involved in neurodevelopmental processes, including E3 ubiquitination and neuronal differentiation. Detailed genotype-phenotype analysis points towards haploinsufficiency of PHIP/DCAF14, and not NDRP, as the underlying cause of the phenotype.Thus, we demonstrated the use of large scale re-sequencing by MIPs, followed by reverse phenotyping, as a constructive approach to verify candidate disease genes and identify novel syndromes, highlighted by PHIP haploinsufficiency causing an ID-overweight syndrome.
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Pruebas Genéticas/métodos , Genotipo , Discapacidad Intelectual/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Sobrepeso/genética , Adolescente , Adulto , Niño , Femenino , Pruebas Genéticas/normas , Haploinsuficiencia , Humanos , Masculino , Reproducibilidad de los Resultados , Análisis de Secuencia de ADN/métodos , Análisis de Secuencia de ADN/normas , SíndromeRESUMEN
Next-generation sequencing (NGS) is now more accessible to clinicians and researchers. As a result, our understanding of the genetics of neurodevelopmental disorders (NDDs) has rapidly advanced over the past few years. NGS has led to the discovery of new NDD genes with an excess of recurrent de novo mutations (DNMs) when compared to controls. Development of large-scale databases of normal and disease variation has given rise to metrics exploring the relative tolerance of individual genes to human mutation. Genetic etiology and diagnosis rates have improved, which have led to the discovery of new pathways and tissue types relevant to NDDs. In this review, we highlight several key findings based on the discovery of recurrent DNMs ranging from copy number variants to point mutations. We explore biases and patterns of DNM enrichment and the role of mosaicism and secondary mutations in variable expressivity. We discuss the benefit of whole-genome sequencing (WGS) over whole-exome sequencing (WES) to understand more complex, multifactorial cases of NDD and explain how this improved understanding aids diagnosis and management of these disorders. Comprehensive assessment of the DNM landscape across the genome using WGS and other technologies will lead to the development of novel functional and bioinformatics approaches to interpret DNMs and drive new insights into NDD biology.
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Trastornos del Neurodesarrollo/genética , Variaciones en el Número de Copia de ADN , Humanos , Mutación , Secuenciación Completa del GenomaRESUMEN
To further our understanding of the genetic etiology of autism, we generated and analyzed genome sequence data from 516 idiopathic autism families (2,064 individuals). This resource includes >59 million single-nucleotide variants (SNVs) and 9,212 private copy number variants (CNVs), of which 133,992 and 88 are de novo mutations (DNMs), respectively. We estimate a mutation rate of â¼1.5 × 10-8 SNVs per site per generation with a significantly higher mutation rate in repetitive DNA. Comparing probands and unaffected siblings, we observe several DNM trends. Probands carry more gene-disruptive CNVs and SNVs, resulting in severe missense mutations and mapping to predicted fetal brain promoters and embryonic stem cell enhancers. These differences become more pronounced for autism genes (p = 1.8 × 10-3, OR = 2.2). Patients are more likely to carry multiple coding and noncoding DNMs in different genes, which are enriched for expression in striatal neurons (p = 3 × 10-3), suggesting a path forward for genetically characterizing more complex cases of autism.
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Trastorno Autístico/genética , Variaciones en el Número de Copia de ADN , Polimorfismo de Nucleótido Simple , Animales , Análisis Mutacional de ADN , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Mutación INDEL , Masculino , RatonesRESUMEN
Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.
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Secuencia de Aminoácidos/genética , Trastorno Autístico/genética , Exoma/genética , Predisposición Genética a la Enfermedad , Mutación Missense/genética , Femenino , Humanos , Masculino , Receptores AMPA/genética , Receptores de Glutamato/genéticaRESUMEN
Attention-Deficit Hyperactivity Disorder (ADHD) has high heritability; however, studies of common variation account for <5% of ADHD variance. Using data from affected participants without a family history of ADHD, we sought to identify de novo variants that could account for sporadic ADHD. Considering a total of 128 families, two analyses were conducted in parallel: first, in 11 unaffected parent/affected proband trios (or quads with the addition of an unaffected sibling) we completed exome sequencing. Six de novo missense variants at highly conserved bases were identified and validated from four of the 11 families: the brain-expressed genes TBC1D9, DAGLA, QARS, CSMD2, TRPM2, and WDR83. Separately, in 117 unrelated probands with sporadic ADHD, we sequenced a panel of 26 genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD) to evaluate whether variation in ASD/ID-associated genes were also present in participants with ADHD. Only one putative deleterious variant (Gln600STOP) in CHD1L was identified; this was found in a single proband. Notably, no other nonsense, splice, frameshift, or highly conserved missense variants in the 26 gene panel were identified and validated. These data suggest that de novo variant analysis in families with independently adjudicated sporadic ADHD diagnosis can identify novel genes implicated in ADHD pathogenesis. Moreover, that only one of the 128 cases (0.8%, 11 exome, and 117 MIP sequenced participants) had putative deleterious variants within our data in 26 genes related to ID and ASD suggests significant independence in the genetic pathogenesis of ADHD as compared to ASD and ID phenotypes. © 2017 Wiley Periodicals, Inc.