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2.
Bioinformatics ; 2024 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-39177091

RESUMEN

MOTIVATION: Circulating-cell free DNA (cfDNA) is widely explored as a non-invasive biomarker for cancer screening and diagnosis. The ability to decode the cells of origin in cfDNA would provide biological insights into pathophysiological mechanisms, aiding in cancer characterization and directing clinical management and follow-up. RESULTS: We developed a DNA methylation signature-based deconvolution algorithm, MetDecode, for cancer tissue origin identification. We built a reference atlas exploiting de novo and published whole-genome methylation sequencing data for colorectal, breast, ovarian and cervical cancer, and blood-cell-derived entities. MetDecode models the contributors absent in the atlas with methylation patterns learnt on-the-fly from the input cfDNA methylation profiles. Additionally, our model accounts for the coverage of each marker region to alleviate potential sources of noise. In-silico experiments showed a limit of detection down to 2.88% of tumour tissue contribution in cfDNA. MetDecode produced Pearson correlation coefficients above 0.95 and outperformed other methods in simulations (p < 0.001; T-test; one-sided). In plasma cfDNA profiles from cancer patients, MetDecode assigned the correct tissue-of-origin in 84.2% of cases. In conclusion, MetDecode can unravel alterations in the cfDNA pool components by accurately estimating the contribution of multiple tissues, while supplied with an imperfect reference atlas. AVAILABILITY: MetDecode is available at https://github.com/JorisVermeeschLab/MetDecode. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

4.
Reprod Biomed Online ; 49(3): 104294, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39024927

RESUMEN

RESEARCH QUESTION: What are the perspectives of preimplantation genetic testing (PGT) patients in Belgium on the ethics of PGT for polygenic risk scoring (PGT-P)? DESIGN: In-depth interviews (18 in total, 10 couples, 8 women, n = 28) were performed with patients who had undergone treatment with PGT for monogenic/single-gene defects (PGT-M) or chromosomal structural rearrangements (PGT-SR) between 2017 and 2019 in Belgium. Participants were asked about their own experiences with PGT-M/SR and about their viewpoints on PGT-P, including their own interest and their ideas on its desirability, scope and consequences. Inductive content analysis was used to analyse the interviews. RESULTS: Participants stated that their experiences with PGT-M/SR had been physically, psychologically and practically difficult. Most participants stated that, partly because of these difficulties, they did not see the added value of knowing the risk scores of embryos via PGT-P. Many participants worried that PGT-P could lead to additional anxieties, responsibilities and complex choices in reproduction and parenthood. They argued that not everything should be controlled and felt that PGT-P, especially non-medical and broad screening, was going too far. With regards to the clinical implementation of PGT-P, participants in general preferred PGT-P to be limited to people with a serious polygenic family history and wanted embryo selection decisions to be made by healthcare professionals. CONCLUSIONS: This study shows that individuals with experience of PGT-M/SR saw PGT-P as different from PGT-M/SR. They had various ethical concerns with regards to PGT-P, especially regarding broadly offering PGT-P. These stakeholder viewpoints need to be considered regarding potential PGT-P implementation and guidelines.


Asunto(s)
Pruebas Genéticas , Diagnóstico Preimplantación , Humanos , Diagnóstico Preimplantación/ética , Diagnóstico Preimplantación/psicología , Femenino , Bélgica , Pruebas Genéticas/ética , Adulto , Masculino , Herencia Multifactorial , Embarazo
5.
JCO Oncol Pract ; 20(8): 1027-1034, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38608208

RESUMEN

In this article, we defined comprehensive recommendations for the clinical follow-up of pregnant women with a malignancy-suspicious NIPT result, on the basis of the vast experience with population-based NIPT screening programs in two European countries complemented with published large data sets. These recommendations provide a tool for classifying NIPT results as malignancy-suspicious, and guide health care professionals in structured clinical decision making for the diagnostic process of pregnant women who receive such a malignancy-suspicious NIPT result.


Asunto(s)
Pruebas Prenatales no Invasivas , Humanos , Femenino , Embarazo , Pruebas Prenatales no Invasivas/métodos , Pruebas Prenatales no Invasivas/normas , Complicaciones Neoplásicas del Embarazo/terapia , Complicaciones Neoplásicas del Embarazo/diagnóstico , Guías de Práctica Clínica como Asunto/normas , Neoplasias de la Mama/terapia , Neoplasias de la Mama/diagnóstico
6.
bioRxiv ; 2024 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-38562770

RESUMEN

The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder. Why the incidence of 22q11.2DS is much greater than that of other genomic disorders remains unknown. Short read sequencing cannot resolve the complex segmental duplicon structure to provide direct confirmation of the hypothesis that the rearrangements are caused by non-allelic homologous recombination between the low copy repeats on chromosome 22 (LCR22s). To enable haplotype-specific assembly and rearrangement mapping in LCR22 regions, we combined fiber-FISH optical mapping with whole genome (ultra-)long read sequencing or rearrangement-specific long-range PCR on 24 duos (22q11.2DS patient and parent-of-origin) comprising several different LCR22-mediated rearrangements. Unexpectedly, we demonstrate that not only different paralogous segmental duplicon but also palindromic AT-rich repeats (PATRR) are driving 22q11.2 rearrangements. In addition, we show the existence of two different inversion polymorphisms preceding rearrangement, and somatic mosaicism. The existence of different recombination sites and mechanisms in paralogues and PATRRs which are copy number expanding in the human population are a likely explanation for the high 22q11.2DS incidence.

7.
Am J Obstet Gynecol ; 230(3): 368.e1-368.e12, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37717890

RESUMEN

BACKGROUND: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis. OBJECTIVE: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome. STUDY DESIGN: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site. RESULTS: A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56-11.18; P<.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69-0.89; P<.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06-0.23; P<.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03-0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36-0.91; P=.019). CONCLUSION: Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection.


Asunto(s)
Síndrome de DiGeorge , Cardiopatías Congénitas , Lactante , Recién Nacido , Embarazo , Femenino , Humanos , Masculino , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Estudios Retrospectivos , Diagnóstico Prenatal , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/genética , Atención Prenatal
8.
NPJ Genom Med ; 8(1): 17, 2023 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-37463940

RESUMEN

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD.

10.
Mol Psychiatry ; 28(5): 2071-2080, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36869225

RESUMEN

22q11.2 deletion is one of the strongest known genetic risk factors for schizophrenia. Recent whole-genome sequencing of schizophrenia cases and controls with this deletion provided an unprecedented opportunity to identify risk modifying genetic variants and investigate their contribution to the pathogenesis of schizophrenia in 22q11.2 deletion syndrome. Here, we apply a novel analytic framework that integrates gene network and phenotype data to investigate the aggregate effects of rare coding variants and identified modifier genes in this etiologically homogenous cohort (223 schizophrenia cases and 233 controls of European descent). Our analyses revealed significant additive genetic components of rare nonsynonymous variants in 110 modifier genes (adjusted P = 9.4E-04) that overall accounted for 4.6% of the variance in schizophrenia status in this cohort, of which 4.0% was independent of the common polygenic risk for schizophrenia. The modifier genes affected by rare coding variants were enriched with genes involved in synaptic function and developmental disorders. Spatiotemporal transcriptomic analyses identified an enrichment of coexpression between modifier and 22q11.2 genes in cortical brain regions from late infancy to young adulthood. Corresponding gene coexpression modules are enriched with brain-specific protein-protein interactions of SLC25A1, COMT, and PI4KA in the 22q11.2 deletion region. Overall, our study highlights the contribution of rare coding variants to the SCZ risk. They not only complement common variants in disease genetics but also pinpoint brain regions and developmental stages critical to the etiology of syndromic schizophrenia.


Asunto(s)
Síndrome de DiGeorge , Esquizofrenia , Humanos , Adulto Joven , Adulto , Esquizofrenia/genética , Síndrome de DiGeorge/genética , Encéfalo , Perfilación de la Expresión Génica , Secuenciación Completa del Genoma
11.
Med Genet ; 35(4): 285-295, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38835737

RESUMEN

It is now well-established that non-invasive prenatal testing (NIPT), originally designed to screen cell-free DNA (cfDNA) in maternal blood for the presence of common fetal trisomies, can lead to incidental detection of occult maternal malignancies. Retrospective evaluations have demonstrated that the detection of multiple copy number alterations in cfDNA is particularly suggestive of an incipient tumor and that cancer detection rates not only depend on tumor biology but also on applied NIPT technologies and downstream diagnostic investigations. Since the identification of a maternal cancer in pregnancy has implications for both woman and the unborn child, prospective studies are needed to provide evidence on best clinical practices and on clinical utility in terms of patient outcomes.

12.
Nucleic Acids Res ; 50(11): e63, 2022 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-35212381

RESUMEN

Single-cell whole-genome haplotyping allows simultaneous detection of haplotypes associated with monogenic diseases, chromosome copy-numbering and subsequently, has revealed mosaicism in embryos and embryonic stem cells. Methods, such as karyomapping and haplarithmisis, were deployed as a generic and genome-wide approach for preimplantation genetic testing (PGT) and are replacing traditional PGT methods. While current methods primarily rely on single-nucleotide polymorphism (SNP) array, we envision sequencing-based methods to become more accessible and cost-efficient. Here, we developed a novel sequencing-based methodology to haplotype and copy-number profile single cells. Following DNA amplification, genomic size and complexity is reduced through restriction enzyme digestion and DNA is genotyped through sequencing. This single-cell genotyping-by-sequencing (scGBS) is the input for haplarithmisis, an algorithm we previously developed for SNP array-based single-cell haplotyping. We established technical parameters and developed an analysis pipeline enabling accurate concurrent haplotyping and copy-number profiling of single cells. We demonstrate its value in human blastomere and trophectoderm samples as application for PGT for monogenic disorders. Furthermore, we demonstrate the method to work in other species through analyzing blastomeres of bovine embryos. Our scGBS method opens up the path for single-cell haplotyping of any species with diploid genomes and could make its way into the clinic as a PGT application.


Asunto(s)
Diagnóstico Preimplantación , Animales , Bovinos , Aberraciones Cromosómicas , Femenino , Pruebas Genéticas/métodos , Genotipo , Haplotipos , Humanos , Embarazo , Diagnóstico Preimplantación/métodos
13.
Am J Hematol ; 97(5): 548-561, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35119131

RESUMEN

Acute lymphoblastic leukemia (ALL) is a malignancy that can be subdivided into distinct entities based on clinical, immunophenotypic and genomic features, including mutations, structural variants (SVs), and copy number alterations (CNA). Chromosome banding analysis (CBA) and Fluorescent In-Situ Hybridization (FISH) together with Multiple Ligation-dependent Probe Amplification (MLPA), array and PCR-based methods form the backbone of routine diagnostics. This approach is labor-intensive, time-consuming and costly. New molecular technologies now exist that can detect SVs and CNAs in one test. Here we apply one such technology, optical genome mapping (OGM), to the diagnostic work-up of 41 ALL cases. Compared to our standard testing pathway, OGM identified all recurrent CNAs and SVs as well as additional recurrent SVs and the resulting fusion genes. Based on the genomic profile obtained by OGM, 32 patients could be assigned to one of the major cytogenetic risk groups compared to 23 with the standard approach. The latter identified 24/34 recurrent chromosomal abnormalities, while OGM identified 33/34, misinterpreting only 1 case with low hypodiploidy. The results of MLPA were concordant in 100% of cases. Overall, there was excellent concordance between the results. OGM increased the detection rate and cytogenetic resolution, and abrogated the need for cascade testing, resulting in reduced turnaround times. OGM also provided opportunities for better patient stratification and accurate treatment options. However, for comprehensive cytogenomic testing, OGM still needs to be complemented with CBA or SNP-array to detect ploidy changes and with BCR::ABL1 FISH to assign patients as soon as possible to targeted therapy.


Asunto(s)
Aberraciones Cromosómicas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Mapeo Cromosómico/métodos , Variaciones en el Número de Copia de ADN , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Flujo de Trabajo
14.
Genome Biol ; 22(1): 342, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34911553

RESUMEN

Accurate simulations of structural variation distributions and sequencing data are crucial for the development and benchmarking of new tools. We develop Sim-it, a straightforward tool for the simulation of both structural variation and long-read data. These simulations from Sim-it reveal the strengths and weaknesses for current available structural variation callers and long-read sequencing platforms. With these findings, we develop a new method (combiSV) that can combine the results from structural variation callers into a superior call set with increased recall and precision, which is also observed for the latest structural variation benchmark set developed by the GIAB Consortium.


Asunto(s)
Benchmarking , Simulación por Computador , Genoma Humano , Análisis de Secuencia , Genómica , Humanos , Secuenciación de Nanoporos , Programas Informáticos
15.
Front Genet ; 12: 706641, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34335701

RESUMEN

Segmental duplications or low copy repeats (LCRs) constitute duplicated regions interspersed in the human genome, currently neglected in standard analyses due to their extreme complexity. Recent functional studies have indicated the potential of genes within LCRs in synaptogenesis, neuronal migration, and neocortical expansion in the human lineage. One of the regions with the highest proportion of duplicated sequence is the 22q11.2 locus, carrying eight LCRs (LCR22-A until LCR22-H), and rearrangements between them cause the 22q11.2 deletion syndrome. The LCR22-A block was recently reported to be hypervariable in the human population. It remains unknown whether this variability also exists in non-human primates, since research is strongly hampered by the presence of sequence gaps in the human and non-human primate reference genomes. To chart the LCR22 haplotypes and the associated inter- and intra-species variability, we de novo assembled the region in non-human primates by a combination of optical mapping techniques. A minimal and likely ancient haplotype is present in the chimpanzee, bonobo, and rhesus monkey without intra-species variation. In addition, the optical maps identified assembly errors and closed gaps in the orthologous chromosome 22 reference sequences. These findings indicate the LCR22 expansion to be unique to the human population, which might indicate involvement of the region in human evolution and adaptation. Those maps will enable LCR22-specific functional studies and investigate potential associations with the phenotypic variability in the 22q11.2 deletion syndrome.

16.
Prenat Diagn ; 41(5): 554-563, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33524193

RESUMEN

Ploidy or genome-wide chromosomal anomalies such as triploidy, diploid/triploid mixoploidy, chimerism, and genome-wide uniparental disomy are the cause of molar pregnancies, embryonic lethality, and developmental disorders. While triploidy and genome-wide uniparental disomy can be ascribed to fertilization or meiotic errors, the mechanisms causing mixoploidy and chimerism remain shrouded in mystery. Different models have been proposed, but all remain hypothetical and controversial, are deduced from the developmental persistent genomic constitutions present in the sample studied and lack direct evidence. New single-cell genomic methodologies, such as single-cell genome-wide haplotyping, provide an extended view of the constitution of normal and abnormal embryos and have further pinpointed the existence of mixoploidy in cleavage-stage embryos. Based on those recent findings, we suggest that genome-wide anomalies, which persist in fetuses and patients, can for a large majority be explained by a noncanonical first zygotic cleavage event, during which maternal and paternal genomes in a single zygote, segregate to different blastomeres. This process, termed heterogoneic division, provides an overarching theoretical basis for the different presentations of mixoploidy and chimerism.


Asunto(s)
Aneuploidia , Aberraciones Cromosómicas/embriología , Trastornos de los Cromosomas/genética , Desarrollo Embrionario/genética , Trastornos de los Cromosomas/embriología , Femenino , Humanos , Embarazo , Triploidía
17.
Mol Psychiatry ; 26(8): 4496-4510, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-32015465

RESUMEN

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10-6). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.


Asunto(s)
Síndrome de DiGeorge , Trastornos Psicóticos , Esquizofrenia , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Síndrome de DiGeorge/genética , Humanos , Esquizofrenia/genética
18.
Hum Mol Genet ; 29(21): 3566-3577, 2021 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-33242073

RESUMEN

Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG repeat in the DMPK gene, where expansion size and somatic mosaicism correlates with disease severity and age of onset. While it is known that the mismatch repair protein MSH2 contributes to the unstable nature of the repeat, its role on other disease-related features, such as CpG methylation upstream of the repeat, is unknown. In this study, we investigated the effect of an MSH2 knock-down (MSH2KD) on both CTG repeat dynamics and CpG methylation pattern in human embryonic stem cells (hESC) carrying the DM1 mutation. Repeat size in MSH2 wild-type (MSH2WT) and MSH2KD DM1 hESC was determined by PacBio sequencing and CpG methylation by bisulfite massive parallel sequencing. We found stabilization of the CTG repeat concurrent with a gradual loss of methylation upstream of the repeat in MSH2KD cells, while the repeat continued to expand and upstream methylation remained unchanged in MSH2WT control lines. Repeat instability was re-established and biased towards expansions upon MSH2 transgenic re-expression in MSH2KD lines while upstream methylation was not consistently re-established. We hypothesize that the hypermethylation at the mutant DM1 locus is promoted by the MMR machinery and sustained by a constant DNA repair response, establishing a potential mechanistic link between CTG repeat instability and upstream CpG methylation. Our work represents a first step towards understanding how epigenetic alterations and repair pathways connect and contribute to the DM1 pathology.


Asunto(s)
Desmetilación , Inestabilidad Genómica , Células Madre Embrionarias Humanas/patología , Proteína 2 Homóloga a MutS/antagonistas & inhibidores , Distrofia Miotónica/patología , Proteína Quinasa de Distrofia Miotónica/genética , Expansión de Repetición de Trinucleótido , Sistemas CRISPR-Cas , Metilación de ADN , Reparación del ADN , Células Madre Embrionarias Humanas/metabolismo , Humanos , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Distrofia Miotónica/genética
19.
Nat Med ; 26(12): 1912-1918, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33169016

RESUMEN

The 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.


Asunto(s)
Síndrome de DiGeorge/genética , Variación Genética/genética , Discapacidad Intelectual/genética , Esquizofrenia/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/genética , Disfunción Cognitiva/fisiopatología , Estudios de Cohortes , Síndrome de DiGeorge/epidemiología , Síndrome de DiGeorge/fisiopatología , Femenino , Humanos , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/fisiopatología , Masculino , Persona de Mediana Edad , Herencia Multifactorial/genética , Fenotipo , Factores de Riesgo , Esquizofrenia/epidemiología , Esquizofrenia/fisiopatología , Adulto Joven
20.
Am J Hum Genet ; 107(4): 753-762, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32910914

RESUMEN

Lamin B1 plays an important role in the nuclear envelope stability, the regulation of gene expression, and neural development. Duplication of LMNB1, or missense mutations increasing LMNB1 expression, are associated with autosomal-dominant leukodystrophy. On the basis of its role in neurogenesis, it has been postulated that LMNB1 variants could cause microcephaly. Here, we confirm this hypothesis with the identification of de novo mutations in LMNB1 in seven individuals with pronounced primary microcephaly (ranging from -3.6 to -12 SD) associated with relative short stature and variable degree of intellectual disability and neurological features as the core symptoms. Simplified gyral pattern of the cortex and abnormal corpus callosum were noted on MRI of three individuals, and these individuals also presented with a more severe phenotype. Functional analysis of the three missense mutations showed impaired formation of the LMNB1 nuclear lamina. The two variants located within the head group of LMNB1 result in a decrease in the nuclear localization of the protein and an increase in misshapen nuclei. We further demonstrate that another mutation, located in the coil region, leads to increased frequency of condensed nuclei and lower steady-state levels of lamin B1 in proband lymphoblasts. Our findings collectively indicate that de novo mutations in LMNB1 result in a dominant and damaging effect on nuclear envelope formation that correlates with microcephaly in humans. This adds LMNB1 to the growing list of genes implicated in severe autosomal-dominant microcephaly and broadens the phenotypic spectrum of the laminopathies.


Asunto(s)
Enanismo/genética , Discapacidad Intelectual/genética , Lamina Tipo B/genética , Microcefalia/genética , Mutación , Lámina Nuclear/genética , Secuencia de Aminoácidos , Secuencia de Bases , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Preescolar , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/metabolismo , Cuerpo Calloso/patología , Enanismo/diagnóstico por imagen , Enanismo/metabolismo , Enanismo/patología , Femenino , Expresión Génica , Humanos , Lactante , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/patología , Lamina Tipo B/metabolismo , Linfocitos/metabolismo , Linfocitos/patología , Imagen por Resonancia Magnética , Masculino , Microcefalia/diagnóstico por imagen , Microcefalia/metabolismo , Microcefalia/patología , Lámina Nuclear/metabolismo , Lámina Nuclear/patología
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