Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
1.
Am J Hum Genet ; 110(12): 2015-2028, 2023 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-37979581

RESUMEN

We examined more than 97,000 families from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents contributing to neurodevelopmental disease risk in children. We identified within- and cross-disorder correlations between six phenotypes in parents and children, such as obsessive-compulsive disorder (R = 0.32-0.38, p < 10-126). We also found that measures of sub-clinical autism features in parents are associated with several autism severity measures in children, including biparental mean Social Responsiveness Scale scores and proband Repetitive Behaviors Scale scores (regression coefficient = 0.14, p = 3.38 × 10-4). We further describe patterns of phenotypic similarity between spouses, where spouses show correlations for six neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R = 0.24-0.68, p < 0.001) and a cross-disorder correlation between anxiety and bipolar disorder (R = 0.09-0.22, p < 10-92). Using a simulated population, we also found that assortative mating can lead to increases in disease liability over generations and the appearance of "genetic anticipation" in families carrying rare variants. We identified several families in a neurodevelopmental disease cohort where the proband inherited multiple rare variants in disease-associated genes from each of their affected parents. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse relationship with variant pathogenicity and propose that parental relatedness modulates disease risk by increasing genome-wide homozygosity in children (R = 0.05-0.26, p < 0.05). Our results highlight the utility of assessing parent phenotypes and genotypes toward predicting features in children who carry rare variably expressive variants and implicate assortative mating as a risk factor for increased disease severity in these families.


Asunto(s)
Trastorno Autístico , Trastorno Bipolar , Niño , Humanos , Virulencia , Padres , Familia , Trastorno Autístico/genética , Trastorno Bipolar/genética
2.
PLoS Genet ; 17(4): e1009112, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33819264

RESUMEN

We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while "second-hits" in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of "second-hit" genes in Drosophila melanogaster and Xenopus laevis. We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. Compared to genes within the 16p11.2 deletion, which has higher de novo occurrence, 16p12.1 homologs were less likely to interact with each other in Drosophila models or a human brain-specific interaction network, suggesting that interactions with "second-hit" genes may confer higher impact towards neurodevelopmental phenotypes. Assessment of 212 pairwise interactions in Drosophila between 16p12.1 homologs and 76 homologs of patient-specific "second-hit" genes (such as ARID1B and CACNA1A), genes within neurodevelopmental pathways (such as PTEN and UBE3A), and transcriptomic targets (such as DSCAM and TRRAP) identified genetic interactions in 63% of the tested pairs. In 11 out of 15 families, patient-specific "second-hits" enhanced or suppressed the phenotypic effects of one or many 16p12.1 homologs in 32/96 pairwise combinations tested. In fact, homologs of SETD5 synergistically interacted with homologs of MOSMO in both Drosophila and X. laevis, leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the genome towards neurodevelopmental defects, and complex interactions with "second-hit" genes determine the ultimate phenotypic manifestation.


Asunto(s)
Encéfalo/metabolismo , Deleción Cromosómica , Cromosomas Humanos Par 16/genética , Trastornos del Neurodesarrollo/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Encéfalo/patología , Canales de Calcio/genética , Moléculas de Adhesión Celular/genética , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Epistasis Genética/genética , Regulación del Desarrollo de la Expresión Génica , Humanos , Metiltransferasas/genética , Trastornos del Neurodesarrollo/patología , Proteínas Nucleares/genética , Fosfohidrolasa PTEN/genética , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/genética , Proteínas de Xenopus/genética , Xenopus laevis/genética
3.
PLoS Genet ; 16(2): e1008590, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32053595

RESUMEN

The 1.6 Mbp deletion on chromosome 3q29 is associated with a range of neurodevelopmental disorders, including schizophrenia, autism, microcephaly, and intellectual disability. Despite its importance towards neurodevelopment, the role of individual genes, genetic interactions, and disrupted biological mechanisms underlying the deletion have not been thoroughly characterized. Here, we used quantitative methods to assay Drosophila melanogaster and Xenopus laevis models with tissue-specific individual and pairwise knockdown of 14 homologs of genes within the 3q29 region. We identified developmental, cellular, and neuronal phenotypes for multiple homologs of 3q29 genes, potentially due to altered apoptosis and cell cycle mechanisms during development. Using the fly eye, we screened for 314 pairwise knockdowns of homologs of 3q29 genes and identified 44 interactions between pairs of homologs and 34 interactions with other neurodevelopmental genes. Interestingly, NCBP2 homologs in Drosophila (Cbp20) and X. laevis (ncbp2) enhanced the phenotypes of homologs of the other 3q29 genes, leading to significant increases in apoptosis that disrupted cellular organization and brain morphology. These cellular and neuronal defects were rescued with overexpression of the apoptosis inhibitors Diap1 and xiap in both models, suggesting that apoptosis is one of several potential biological mechanisms disrupted by the deletion. NCBP2 was also highly connected to other 3q29 genes in a human brain-specific interaction network, providing support for the relevance of our results towards the human deletion. Overall, our study suggests that NCBP2-mediated genetic interactions within the 3q29 region disrupt apoptosis and cell cycle mechanisms during development.


Asunto(s)
Encéfalo/embriología , Cromosomas Humanos Par 3/genética , Proteínas de Drosophila/genética , Desarrollo Embrionario/genética , Discapacidad Intelectual/genética , Complejo Proteico Nuclear de Unión a la Caperuza/genética , Proteínas de Xenopus/genética , Animales , Apoptosis/genética , Encéfalo/patología , Ciclo Celular/genética , Deleción Cromosómica , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Modelos Animales de Enfermedad , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Embrión no Mamífero , Femenino , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Redes Reguladoras de Genes , Humanos , Discapacidad Intelectual/patología , Complejo Proteico Nuclear de Unión a la Caperuza/metabolismo , Proteínas de Xenopus/metabolismo , Xenopus laevis
4.
Genet Med ; 21(4): 816-825, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30190612

RESUMEN

PURPOSE: To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. METHODS: We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. RESULTS: The number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. CONCLUSION: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.


Asunto(s)
Trastorno Autístico/genética , Moléculas de Adhesión Celular Neuronal/genética , Tamización de Portadores Genéticos , Metiltransferasas/genética , Proteínas del Tejido Nervioso/genética , Proteínas/genética , Trastorno Autístico/fisiopatología , Proteínas de Unión al Calcio , Cromosomas Humanos Par 16/genética , Cognición/fisiología , Proteínas del Citoesqueleto , Variaciones en el Número de Copia de ADN/genética , Femenino , Regulación de la Expresión Génica/genética , Antecedentes Genéticos , Humanos , Masculino , Moléculas de Adhesión de Célula Nerviosa , Padres , Linaje , Fenotipo , Eliminación de Secuencia/genética , Hermanos , Factores de Transcripción
5.
medRxiv ; 2024 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-39252907

RESUMEN

Variable expressivity of disease-associated variants implies a role for secondary variants that modify clinical features. We assessed the effects of modifier variants towards clinical outcomes of 2,252 individuals with primary variants. Among 132 families with the 16p12.1 deletion, distinct rare and common variant classes conferred risk for specific developmental features, including short tandem repeats for neurological defects and SNVs for microcephaly, while additional disease-associated variants conferred multiple genetic diagnoses. Within disease and population cohorts of 773 individuals with the 16p12.1 deletion, we found opposing effects of secondary variants towards clinical features across ascertainments. Additional analysis of 1,479 probands with other primary variants, such as 16p11.2 deletion and CHD8 variants, and 1,084 without primary variants, showed that phenotypic associations differed by primary variant context and were influenced by synergistic interactions between primary and secondary variants. Our study provides a paradigm to dissect the genomic architecture of complex disorders towards personalized treatment.

6.
medRxiv ; 2023 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-37292616

RESUMEN

We examined more than 38,000 spouse pairs from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents associated with neurodevelopmental disease risk in children. We identified correlations between six phenotypes in parents and children, including correlations of clinical diagnoses such as obsessive-compulsive disorder (R=0.31-0.49, p<0.001), and two measures of sub-clinical autism features in parents affecting several autism severity measures in children, such as bi-parental mean Social Responsiveness Scale (SRS) scores affecting proband SRS scores (regression coefficient=0.11, p=0.003). We further describe patterns of phenotypic and genetic similarity between spouses, where spouses show both within- and cross-disorder correlations for seven neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R=0.25-0.72, p<0.001) and a cross-disorder correlation between schizophrenia and personality disorder (R=0.20-0.57, p<0.001). Further, these spouses with similar phenotypes were significantly correlated for rare variant burden (R=0.07-0.57, p<0.0001). We propose that assortative mating on these features may drive the increases in genetic risk over generations and the appearance of "genetic anticipation" associated with many variably expressive variants. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse correlations with burden and pathogenicity of rare variants and propose that parental relatedness drives disease risk by increasing genome-wide homozygosity in children (R=0.09-0.30, p<0.001). Our results highlight the utility of assessing parent phenotypes and genotypes in predicting features in children carrying variably expressive variants and counseling families carrying these variants.

7.
J Am Coll Health ; : 1-4, 2022 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-35997699

RESUMEN

Objective: To examine social connection as a protective factor against exam stress. Participants: 55 undergraduate students at two universities. Methods: Students were evaluated on an exam day for their hardest class and at baseline, a day in a week where they had no exams. Social connection, salivary cortisol, perceived stress, and cognitive control (measured with the Stroop test) were assessed. Exam scores were later reported. Results: Higher social connection was associated with lower perceived stress on exam day. At a small liberal arts school, higher levels of social connection were associated with higher Stroop scores. This correlation with cognitive control was not significant at a large public university. Conclusions: These findings indicate that social connection may be a protective factor in mitigating perceived stress and cognitive control capabilities may help facilitate reduced exam stress in some school environments.

8.
Genome Med ; 13(1): 163, 2021 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-34657631

RESUMEN

BACKGROUND: Recent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in > 90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional "second-hit" variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. METHODS: We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We identified contributions of the 16p12.1 deletion and "second-hit" variants towards a range of expression changes in deletion carriers and their family members, including differential expression, outlier expression, alternative splicing, allele-specific expression, and expression quantitative trait loci analyses. RESULTS: We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed an average of 5323 gene expression changes compared with one or both parents, which matched with 33/39 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of "second-hit" variants in genes with expression changes, where 4/25 variant classes were only enriched when inherited from the noncarrier parent, including loss-of-function SNVs and large duplications. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited "second-hits" in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying "second-hits" and genes with transcriptome alterations in deletion carriers. CONCLUSIONS: Our results suggest a potential mechanism for how "second-hit" variants modulate expressivity of complex disorders such as the 16p12.1 deletion through transcriptomic perturbation of gene networks important for early development. Our work further shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders.


Asunto(s)
Variación Biológica Poblacional , Deleción Cromosómica , Expresión Génica , Ancirinas/genética , Trastorno Autístico/genética , Encéfalo , Familia , Factores de Transcripción Forkhead/genética , Humanos , Fenotipo , Monoéster Fosfórico Hidrolasas/genética , Proteínas Represoras/genética , Factores de Transcripción/genética , Secuenciación del Exoma , Secuenciación Completa del Genoma , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética
10.
Nat Commun ; 9(1): 2548, 2018 06 29.
Artículo en Inglés | MEDLINE | ID: mdl-29959322

RESUMEN

As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive CNVs complicates disease gene discovery and functional evaluation. Here, we propose a complex interaction model for pathogenicity of the autism-associated 16p11.2 deletion, where CNV genes interact with each other in conserved pathways to modulate expression of the phenotype. Using multiple quantitative methods in Drosophila RNAi lines, we identify a range of neurodevelopmental phenotypes for knockdown of individual 16p11.2 homologs in different tissues. We test 565 pairwise knockdowns in the developing eye, and identify 24 interactions between pairs of 16p11.2 homologs and 46 interactions between 16p11.2 homologs and neurodevelopmental genes that suppress or enhance cell proliferation phenotypes compared to one-hit knockdowns. These interactions within cell proliferation pathways are also enriched in a human brain-specific network, providing translational relevance in humans. Our study indicates a role for pervasive genetic interactions within CNVs towards cellular and developmental phenotypes.


Asunto(s)
Trastorno Autístico/genética , Secuencia de Bases , Encéfalo/metabolismo , Drosophila melanogaster/genética , Proteínas del Tejido Nervioso/genética , Eliminación de Secuencia , Animales , Trastorno Autístico/metabolismo , Trastorno Autístico/patología , Encéfalo/patología , Proliferación Celular , Cromosomas Humanos Par 16/química , Cromosomas de Insectos/química , Variaciones en el Número de Copia de ADN , Modelos Animales de Enfermedad , Proteínas de Drosophila/antagonistas & inhibidores , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Masculino , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Neurogénesis/genética , Fenotipo , Mapeo de Interacción de Proteínas , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Homología de Secuencia de Ácido Nucleico
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA