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1.
Am J Hum Genet ; 110(8): 1229-1248, 2023 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-37541186

RESUMEN

Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order, and emerging technologies, such as optical genome mapping and long-read DNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to research consortia focused on elucidating the underlying cause of rare unsolved genetic disorders.


Asunto(s)
Exoma , Pruebas Genéticas , Humanos , Exoma/genética , Análisis de Secuencia de ADN , Fenotipo , Secuenciación del Exoma , Enfermedades Raras
2.
Prenat Diagn ; 44(4): 454-464, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38242839

RESUMEN

Advances in sequencing and imaging technologies enable enhanced assessment in the prenatal space, with a goal to diagnose and predict the natural history of disease, to direct targeted therapies, and to implement clinical management, including transfer of care, election of supportive care, and selection of surgical interventions. The current lack of standardization and aggregation stymies variant interpretation and gene discovery, which hinders the provision of prenatal precision medicine, leaving clinicians and patients without an accurate diagnosis. With large amounts of data generated, it is imperative to establish standards for data collection, processing, and aggregation. Aggregated and homogeneously processed genetic and phenotypic data permits dissection of the genomic architecture of prenatal presentations of disease and provides a dataset on which data analysis algorithms can be tuned to the prenatal space. Here we discuss the importance of generating aggregate data sets and how the prenatal space is driving the development of interoperable standards and phenotype-driven tools.


Asunto(s)
Medicina de Precisión , Diagnóstico Prenatal , Embarazo , Femenino , Humanos , Fenotipo , Genómica , Algoritmos
3.
Nature ; 536(7615): 205-9, 2016 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-27487209

RESUMEN

Genetic differences that specify unique aspects of human evolution have typically been identified by comparative analyses between the genomes of humans and closely related primates, including more recently the genomes of archaic hominins. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for approximately 1% of cases of autism and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution. Here we reconstruct the evolutionary history of the locus and identify bolA family member 2 (BOLA2) as a gene duplicated exclusively in Homo sapiens. We estimate that a 95-kilobase-pair segment containing BOLA2 duplicated across the critical region approximately 282 thousand years ago (ka), one of the latest among a series of genomic changes that dramatically restructured the locus during hominid evolution. All humans examined carried one or more copies of the duplication, which nearly fixed early in the human lineage--a pattern unlikely to have arisen so rapidly in the absence of selection (P < 0.0097). We show that the duplication of BOLA2 led to a novel, human-specific in-frame fusion transcript and that BOLA2 copy number correlates with both RNA expression (r = 0.36) and protein level (r = 0.65), with the greatest expression difference between human and chimpanzee in experimentally derived stem cells. Analyses of 152 patients carrying a chromosome 16p11. rearrangement show that more than 96% of breakpoints occur within the H. sapiens-specific duplication. In summary, the duplicative transposition of BOLA2 at the root of the H. sapiens lineage about 282 ka simultaneously increased copy number of a gene associated with iron homeostasis and predisposed our species to recurrent rearrangements associated with disease.


Asunto(s)
Cromosomas Humanos Par 16/genética , Variaciones en el Número de Copia de ADN/genética , Evolución Molecular , Predisposición Genética a la Enfermedad , Proteínas/genética , Animales , Trastorno Autístico/genética , Rotura Cromosómica , Duplicación de Gen , Homeostasis/genética , Humanos , Hierro/metabolismo , Pan troglodytes/genética , Pongo/genética , Proteínas/análisis , Recombinación Genética , Especificidad de la Especie , Factores de Tiempo
4.
Am J Hum Genet ; 98(1): 45-57, 2016 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-26749307

RESUMEN

Recurrent deletions and duplications at chromosomal region 16p11.2 are a major genetic contributor to autism but also associate with a wider range of pediatric diagnoses, including intellectual disability, coordination disorder, and language disorder. In order to investigate the potential genetic basis for phenotype variability, we assessed the parent of origin of the 16p11.2 copy-number variant (CNV) and the presence of additional CNVs in 126 families for which detailed phenotype data were available. Among de novo cases, we found a strong maternal bias for the origin of deletions (59/66, 89.4% of cases, p = 2.38 × 10(-11)), the strongest such effect so far observed for a CNV associated with a microdeletion syndrome. In contrast to de novo events, we observed no transmission bias for inherited 16p11.2 CNVs, consistent with a female meiotic hotspot of unequal crossover driving this maternal bias. We analyzed this 16p11.2 CNV cohort for the presence of secondary CNVs and found a significant maternal transmission bias for secondary deletions (32 maternal versus 14 paternal, p = 1.14 × 10(-2)). Of the secondary deletions that disrupted a gene, 82% were either maternally inherited or de novo (p = 4.3 × 10(-3)). Nine probands carry secondary CNVs that disrupt genes associated with autism and/or intellectual disability risk variants. Our findings demonstrate a strong bias toward maternal origin of 16p11.2 de novo deletions as well as a maternal transmission bias for secondary deletions that contribute to the clinical outcome on a background sensitized by the 16p11.2 CNV.


Asunto(s)
Trastorno Autístico/genética , Cromosomas Humanos Par 16 , Impresión Genómica , Estudios de Cohortes , Intercambio Genético , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Recombinación Genética
5.
Am J Hum Genet ; 98(1): 58-74, 2016 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-26749308

RESUMEN

We performed whole-genome sequencing (WGS) of 208 genomes from 53 families affected by simplex autism. For the majority of these families, no copy-number variant (CNV) or candidate de novo gene-disruptive single-nucleotide variant (SNV) had been detected by microarray or whole-exome sequencing (WES). We integrated multiple CNV and SNV analyses and extensive experimental validation to identify additional candidate mutations in eight families. We report that compared to control individuals, probands showed a significant (p = 0.03) enrichment of de novo and private disruptive mutations within fetal CNS DNase I hypersensitive sites (i.e., putative regulatory regions). This effect was only observed within 50 kb of genes that have been previously associated with autism risk, including genes where dosage sensitivity has already been established by recurrent disruptive de novo protein-coding mutations (ARID1B, SCN2A, NR3C2, PRKCA, and DSCAM). In addition, we provide evidence of gene-disruptive CNVs (in DISC1, WNT7A, RBFOX1, and MBD5), as well as smaller de novo CNVs and exon-specific SNVs missed by exome sequencing in neurodevelopmental genes (e.g., CANX, SAE1, and PIK3CA). Our results suggest that the detection of smaller, often multiple CNVs affecting putative regulatory elements might help explain additional risk of simplex autism.


Asunto(s)
Trastorno Autístico/genética , ADN/genética , Genoma Humano , Exoma , Femenino , Humanos , Masculino , Linaje , Polimorfismo de Nucleótido Simple
6.
Genet Med ; 21(7): 1611-1620, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30504930

RESUMEN

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.


Asunto(s)
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 , Fenotipo
7.
Am J Hum Genet ; 94(3): 415-25, 2014 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-24581740

RESUMEN

Increased male prevalence has been repeatedly reported in several neurodevelopmental disorders (NDs), leading to the concept of a "female protective model." We investigated the molecular basis of this sex-based difference in liability and demonstrated an excess of deleterious autosomal copy-number variants (CNVs) in females compared to males (odds ratio [OR] = 1.46, p = 8 × 10(-10)) in a cohort of 15,585 probands ascertained for NDs. In an independent autism spectrum disorder (ASD) cohort of 762 families, we found a 3-fold increase in deleterious autosomal CNVs (p = 7 × 10(-4)) and an excess of private deleterious single-nucleotide variants (SNVs) in female compared to male probands (OR = 1.34, p = 0.03). We also showed that the deleteriousness of autosomal SNVs was significantly higher in female probands (p = 0.0006). A similar bias was observed in parents of probands ascertained for NDs. Deleterious CNVs (>400 kb) were maternally inherited more often (up to 64%, p = 10(-15)) than small CNVs < 400 kb (OR = 1.45, p = 0.0003). In the ASD cohort, increased maternal transmission was also observed for deleterious CNVs and SNVs. Although ASD females showed higher mutational burden and lower cognition, the excess mutational burden remained, even after adjustment for those cognitive differences. These results strongly suggest that females have an increased etiological burden unlinked to rare deleterious variants on the X chromosome. Carefully phenotyped and genotyped cohorts will be required for identifying the symptoms, which show gender-specific liability to mutational burden.


Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/genética , Discapacidades del Desarrollo/genética , Mutación , Adolescente , Adulto , Anciano , Cromosomas Artificiales Bacterianos , Trastornos del Conocimiento/genética , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Bases de Datos Genéticas , Femenino , Eliminación de Gen , Genotipo , Humanos , Masculino , Cadenas de Markov , Persona de Mediana Edad , Oportunidad Relativa , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Polimorfismo de Nucleótido Simple , Factores Sexuales , Adulto Joven
10.
ArXiv ; 2023 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-36713248

RESUMEN

Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order and emerging technologies, such as optical genome mapping and long-read DNA or RNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to a consortium such as GREGoR, which is focused on elucidating the underlying cause of rare unsolved genetic disorders.

11.
Mol Syst Biol ; 7: 555, 2011 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-22146299

RESUMEN

Recruitment of cofactors to specific DNA sites is integral for specificity in gene regulation. As a model system, we examined how targeting and transcriptional control of the sulfur metabolism genes in Saccharomyces cerevisiae is governed by recruitment of the transcriptional co-activator Met4. We developed genome-scale approaches to measure transcription factor (TF) DNA-binding affinities and cofactor recruitment to >1300 genomic binding site sequences. We report that genes responding to the TF Cbf1 and cofactor Met28 contain a novel 'recruitment motif' (RYAAT), adjacent to Cbf1 binding sites, which enhances the binding of a Met4-Met28-Cbf1 regulatory complex, and that abrogation of this motif significantly reduces gene induction under low-sulfur conditions. Furthermore, we show that correct recognition of this composite motif requires both non-DNA-binding cofactors Met4 and Met28. Finally, we demonstrate that the presence of an RYAAT motif next to a Cbf1 site, rather than Cbf1 binding affinity, specifies Cbf1-dependent sulfur metabolism genes. Our results highlight the need to examine TF/cofactor complexes, as novel specificity can result from cofactors that lack intrinsic DNA-binding specificity.


Asunto(s)
ADN de Hongos/metabolismo , Regulación Fúngica de la Expresión Génica , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Factores de Transcripción/metabolismo , Área Bajo la Curva , Secuencia de Bases , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Sitios de Unión , ADN de Hongos/genética , Genoma Fúngico/genética , Datos de Secuencia Molecular , Motivos de Nucleótidos , Unión Proteica , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Sensibilidad y Especificidad , Factores de Transcripción/química , Factores de Transcripción/genética
12.
J Enzyme Inhib Med Chem ; 27(6): 784-94, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22085139

RESUMEN

Trypanothione reductase (TR) is found in the trypanosomatid parasites, where it catalyses the NADPH-dependent reduction of the glutathione analogue, trypanothione, and is a key player in the parasite's defenses against oxidative stress. TR is a promising target for the development of antitrypanosomal drugs; here, we report our synthesis and evaluation of compounds 3-5 as low micromolar Trypanosoma cruzi TR inhibitors. Although 4 and 5 were designed as potential irreversible inhibitors, these compounds, as well as 3, displayed reversible competitive inhibition. Compound 3 proved to be the most potent inhibitor, with a K(i) = 2 µM.


Asunto(s)
Glutatión/análogos & derivados , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , NADP/química , Espermidina/análogos & derivados , Tripanocidas/síntesis química , Trypanosoma cruzi/química , Diseño de Fármacos , Pruebas de Enzimas , Escherichia coli/genética , Glutatión/química , Cinética , Espectroscopía de Resonancia Magnética , Imitación Molecular , Proteínas Recombinantes/antagonistas & inhibidores , Espectroscopía Infrarroja por Transformada de Fourier , Espermidina/química , Especificidad por Sustrato , Tripanocidas/química , Trypanosoma cruzi/enzimología
13.
Clin Case Rep ; 6(1): 147-154, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29375855

RESUMEN

16p11.2 deletions and duplications are commonly associated with autism spectrum disorder and linked to mirrored phenotypes of physical characteristics and higher penetrance for deletions. A male with a rare 16p11.2 triplication demonstrated a similar phenotypic presentation to deletion carriers with neurocognitive and adaptive skill deficits and above-average physical growth.

14.
Genome Biol ; 18(1): 49, 2017 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-28279197

RESUMEN

BACKGROUND: Gene innovation by duplication is a fundamental evolutionary process but is difficult to study in humans due to the large size, high sequence identity, and mosaic nature of segmental duplication blocks. The human-specific gene hydrocephalus-inducing 2, HYDIN2, was generated by a 364 kbp duplication of 79 internal exons of the large ciliary gene HYDIN from chromosome 16q22.2 to chromosome 1q21.1. Because the HYDIN2 locus lacks the ancestral promoter and seven terminal exons of the progenitor gene, we sought to characterize transcription at this locus by coupling reverse transcription polymerase chain reaction and long-read sequencing. RESULTS: 5' RACE indicates a transcription start site for HYDIN2 outside of the duplication and we observe fusion transcripts spanning both the 5' and 3' breakpoints. We observe extensive splicing diversity leading to the formation of altered open reading frames (ORFs) that appear to be under relaxed selection. We show that HYDIN2 adopted a new promoter that drives an altered pattern of expression, with highest levels in neural tissues. We estimate that the HYDIN duplication occurred ~3.2 million years ago and find that it is nearly fixed (99.9%) for diploid copy number in contemporary humans. Examination of 73 chromosome 1q21 rearrangement patients reveals that HYDIN2 is deleted or duplicated in most cases. CONCLUSIONS: Together, these data support a model of rapid gene innovation by fusion of incomplete segmental duplications, altered tissue expression, and potential subfunctionalization or neofunctionalization of HYDIN2 early in the evolution of the Homo lineage.


Asunto(s)
Duplicación de Gen , Fusión Génica , Neuronas/metabolismo , Aberraciones Cromosómicas , Puntos de Rotura del Cromosoma , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 1 , Variaciones en el Número de Copia de ADN , Evolución Molecular , Conversión Génica , Perfilación de la Expresión Génica , Variación Genética , Genética de Población , Genómica/métodos , Humanos , Sistemas de Lectura Abierta , Especificidad de Órganos/genética , Fenotipo , Selección Genética , Transcripción Genética
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