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1.
Am J Med Genet A ; 194(5): e63522, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38131126

RESUMO

Despite significant advancements in rare genetic disease diagnostics, many patients with rare genetic disease remain without a molecular diagnosis. Novel tools and methods are needed to improve the detection of disease-associated variants and understand the genetic basis of many rare diseases. Long-read genome sequencing provides improved sequencing in highly repetitive, homologous, and low-complexity regions, and improved assessment of structural variation and complex genomic rearrangements compared to short-read genome sequencing. As such, it is a promising method to explore overlooked genetic variants in rare diseases with a high suspicion of a genetic basis. We therefore applied PacBio HiFi sequencing in a large multi-generational family presenting with autosomal dominant 46,XY differences of sexual development (DSD), for whom extensive molecular testing over multiple decades had failed to identify a molecular diagnosis. This revealed a rare SINE-VNTR-Alu retroelement insertion in intron 4 of NR5A1, a gene in which loss-of-function variants are an established cause of 46,XY DSD. The insertion segregated among affected family members and was associated with loss-of-expression of alleles in cis, demonstrating a functional impact on NR5A1. This case highlights the power of long-read genome sequencing to detect genomic variants that have previously been intractable to detection by standard short-read genomic testing.


Assuntos
Transtorno 46,XY do Desenvolvimento Sexual , Retroelementos , Humanos , Mutação , Íntrons/genética , Retroelementos/genética , Transtorno 46,XY do Desenvolvimento Sexual/genética , Doenças Raras/genética , Desenvolvimento Sexual , Fator Esteroidogênico 1/genética
2.
Mol Med ; 27(1): 3, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413077

RESUMO

BACKGROUND: Fetal growth restriction (FGR) is associated with increased risks for complications before, during, and after birth, in addition to risk of disease through to adulthood. Although placental insufficiency, failure to supply the fetus with adequate nutrients, underlies most cases of FGR, its causes are diverse and not fully understood. One of the few diagnosable causes of placental insufficiency in ongoing pregnancies is the presence of large chromosomal imbalances such as trisomy confined to the placenta; however, the impact of smaller copy number variants (CNVs) has not yet been adequately addressed. In this study, we confirm the importance of placental aneuploidy, and assess the potential contribution of CNVs to fetal growth. METHODS: We used molecular-cytogenetic approaches to identify aneuploidy in placentas from 101 infants born small-for-gestational age (SGA), typically used as a surrogate for FGR, and from 173 non-SGA controls from uncomplicated pregnancies. We confirmed aneuploidies and assessed mosaicism by microsatellite genotyping. We then profiled CNVs using high-resolution microarrays in a subset of 53 SGA and 61 control euploid placentas, and compared the load, impact, gene enrichment and clinical relevance of CNVs between groups. Candidate CNVs were confirmed using quantitative PCR. RESULTS: Aneuploidy was over tenfold more frequent in SGA-associated placentas compared to controls (11.9% vs. 1.1%; p = 0.0002, OR = 11.4, 95% CI 2.5-107.4), was confined to the placenta, and typically involved autosomes, whereas only sex chromosome abnormalities were observed in controls. We found no significant difference in CNV load or number of placental-expressed or imprinted genes in CNVs between SGA and controls, however, a rare and likely clinically-relevant germline CNV was identified in 5.7% of SGA cases. These CNVs involved candidate genes INHBB, HSD11B2, CTCF, and CSMD3. CONCLUSIONS: We conclude that placental genomic imbalances at the cytogenetic and submicroscopic level may underlie up to ~ 18% of SGA cases in our population. This work contributes to the understanding of the underlying causes of placental insufficiency and FGR, which is important for counselling and prediction of long term outcomes for affected cases.


Assuntos
Variações do Número de Cópias de DNA , Retardo do Crescimento Fetal/genética , Instabilidade de Microssatélites , Placenta/química , Aneuploidia , Estudos de Casos e Controles , Análise Citogenética/métodos , Feminino , Impressão Genômica , Técnicas de Genotipagem , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Mosaicismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Gravidez
3.
Am J Med Genet A ; 185(6): 1908-1912, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33750025

RESUMO

The presence of multiple large (>1 Mb) copy number variants (CNVs) in non-malignant tissue is rare in human genetics. We present a liveborn male with a birth weight below the first percentile associated with placental mosaicism involving eight 2.4-3.9 Mb de novo duplications. We found that the duplications likely co-localized to the same cells, were mosaic in the placenta, and impacted maternal and paternal chromosomes. In addition, 27.4 Mb and 240 genes were duplicated in affected cells, including candidate placental genes KISS1 and REN. We ruled out involvement of homologous recombination-based mechanisms or an altered epigenome in generating the CNVs. This case highlights the diversity of genetic abnormalities in the human placenta and the gaps in our knowledge of how such errors arise.


Assuntos
Retardo do Crescimento Fetal/genética , Kisspeptinas/genética , Mosaicismo , Renina/genética , Variações do Número de Cópias de DNA/genética , Feminino , Retardo do Crescimento Fetal/patologia , Duplicação Gênica/genética , Humanos , Recém-Nascido , Masculino , Placenta/patologia , Placenta/ultraestrutura , Gravidez
4.
Hum Genet ; 139(9): 1183-1196, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31555906

RESUMO

The placenta is a crucial organ for supporting a healthy pregnancy, and defective development or function of the placenta is implicated in a number of complications of pregnancy that affect both maternal and fetal health, including maternal preeclampsia, fetal growth restriction, and spontaneous preterm birth. In this review, we highlight the role of the placental genome in mediating fetal and maternal health by discussing the impact of a variety of genetic alterations, from large whole-chromosome aneuploidies to single-nucleotide variants, on placental development and function. We also discuss the placental methylome in relation to its potential applications for refining diagnosis, predicting pathology, and identifying genetic variants with potential functional significance. We conclude that understanding the influence of the placental genome on common placental-mediated pathologies is critical to improving perinatal health outcomes.


Assuntos
Epigenoma/genética , Genoma Humano/genética , Saúde Materna , Placenta/fisiopatologia , Complicações na Gravidez/genética , Feminino , Desenvolvimento Fetal/genética , Desenvolvimento Fetal/fisiologia , Retardo do Crescimento Fetal/genética , Feto/fisiologia , Humanos , Recém-Nascido , Placenta/citologia , Pré-Eclâmpsia/genética , Gravidez , Nascimento Prematuro/genética
5.
Hum Mol Genet ; 26(R2): R237-R245, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28595268

RESUMO

The placenta is a multifunctional organ that regulates key aspects of pregnancy maintenance and fetal development. As the placenta is in direct contact with maternal blood, cellular products (DNA, RNA, proteins, etc.) from the placenta can enter maternal circulation by a variety of ways. The application of serum proteins and circulating placental derived DNA has been well demonstrated for the diagnosis of aneuploidy, and there is great interest in exploring the use of placental biomarkers for the prediction of a range of fetal health parameters. In this review, we discuss how placental biomarkers might be used for the diagnosis and early detection of preeclampsia, fetal growth restriction and inflammation associated with preterm birth. We emphasize how increased understanding of the underlying placental biology can aid in the interpretation of such approaches and development of new biomarkers that can help predict the onset of pregnancy and neonatal health concerns before they manifest.


Assuntos
Biomarcadores/sangue , Placenta/metabolismo , Placenta/fisiologia , Animais , Feminino , Desenvolvimento Fetal/genética , Desenvolvimento Fetal/fisiologia , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/diagnóstico , Feto/metabolismo , Humanos/embriologia , Recém-Nascido , Masculino , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Gravidez , Nascimento Prematuro/sangue , Nascimento Prematuro/diagnóstico
6.
BMC Med Genet ; 20(1): 36, 2019 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-30795743

RESUMO

BACKGROUND: Acute chorioamnionitis (aCA), inflammation of the placenta and fetal membranes, is a frequently reported lesion in preterm deliveries. Genetic variants in innate immune system genes such as Interleukin-6 (IL6) may contribute to the placenta's inflammatory response, thus predisposing some pregnancies to aCA. These genetic variants may modulate molecular processes such as DNA methylation and gene expression, and in turn might affect susceptibility to aCA. Currently, there is remarkably little research on the role of fetal (placental) genetic variation in aCA. We aimed to explore the associations between genetic variants in candidate immune-system genes and susceptibility towards inflammatory responses in the placenta, which is linked to a strong inflammatory response in the newborn. METHODS: DNA samples from 269 placentas (72 aCA cases, 197 non-aCA cases) were collected for this study. Samples were genotyped at 55 ancestry informative markers (AIMs) and 16 additional single nucleotide polymorphisms (SNPs) in 12 candidate innate immune system genes using the Sequenom iPLEX Gold Assay. Publicly available datasets were used to obtain DNA methylation (GSE100197, GSE74738, GSE115508, GSE44667, GSE98224) and gene expression data (GSE44711, GSE98224). RESULTS: Differences in IL6 placental allele frequencies were associated with aCA (rs1800796, p = 0.04) with the CC genotype specifically implicated (OR = 3.1; p = 0.02). In a subset of the placental samples (n = 67; chorionic villi), we showed that the IL6 SNP (rs1800796) was associated with differential DNA methylation in five IL6-related CpG sites (cg01770232, cg02335517, cg07998387, cg13104385, and cg0526589), where individuals with a CC genotype showed higher DNA methylation levels than individuals carrying the GG genotype. Using two publicly available datasets, we observed that the DNA methylation levels at cg01770232 negatively correlated with IL6 gene expression in the placenta (r = - 0.67, p < 0.004; r = - 0.56, p < 2.937e-05). CONCLUSIONS: We demonstrated that the minor C allele at the IL6 SNP (rs1800796), which is largely limited to East Asian populations, is associated with the presence of aCA. This SNP was associated with increased DNA methylation at a nearby MEPC2 binding site, which was also associated with decreased expression of IL6 in the placenta. Decreased expression of IL6 may increase vulnerability to microbial infection. Additional studies are required to confirm this association in Asian populations with larger sample sizes.


Assuntos
Corioamnionite/genética , Metilação de DNA , Regulação para Baixo , Interleucina-6/genética , Placenta/química , Polimorfismo de Nucleotídeo Único , Sítios de Ligação , Estudos de Casos e Controles , Ilhas de CpG , Epigênese Genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Interleucina-6/metabolismo , Masculino , Idade Materna , Gravidez
7.
iScience ; 27(2): 109047, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38357671

RESUMO

Molecular quantitative trait loci (QTLs) allow us to understand the biology captured in genome-wide association studies (GWASs). The placenta regulates fetal development and shows sex differences in DNA methylation. We therefore hypothesized that placental methylation QTL (mQTL) explain variation in genetic risk for childhood onset traits, and that effects differ by sex. We analyzed 411 term placentas from two studies and found 49,252 methylation (CpG) sites with mQTL and 2,489 CpG sites with sex-dependent mQTL. All mQTL were enriched in regions that typically affect gene expression in prenatal tissues. All mQTL were also enriched in GWAS results for growth- and immune-related traits, but male- and female-specific mQTL were more enriched than cross-sex mQTL. mQTL colocalized with trait loci at 777 CpG sites, with 216 (28%) specific to males or females. Overall, mQTL specific to male and female placenta capture otherwise overlooked variation in childhood traits.

8.
Nat Genet ; 56(7): 1366-1370, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38937606

RESUMO

The factors driving or preventing pathological expansion of tandem repeats remain largely unknown. Here, we assessed the FGF14 (GAA)·(TTC) repeat locus in 2,530 individuals by long-read and Sanger sequencing and identified a common 5'-flanking variant in 70.34% of alleles analyzed (3,463/4,923) that represents the phylogenetically ancestral allele and is present on all major haplotypes. This common sequence variation is present nearly exclusively on nonpathogenic alleles with fewer than 30 GAA-pure triplets and is associated with enhanced stability of the repeat locus upon intergenerational transmission and increased Fiber-seq chromatin accessibility.


Assuntos
Alelos , Fatores de Crescimento de Fibroblastos , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Haplótipos , Variação Genética , Loci Gênicos
9.
Res Sq ; 2023 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-37461679

RESUMO

Background : Genome-wide DNA methylation (DNAme) profiling of the placenta with Illumina Infinium Methylation bead arrays is often used to explore the connections between in utero exposures, placental pathology, and fetal development. However, many technical and biological factors can lead to signals of DNAme variation between samples and between cohorts, and understanding and accounting for these factors is essential to ensure meaningful and replicable data analysis. Recently, "epiphenotyping" approaches have been developed whereby DNAme data can be used to impute information about phenotypic variables such as gestational age, sex, cell composition, and ancestry. These epiphenotypes offer avenues to compare phenotypic data across cohorts, and to understand how phenotypic variables relate to DNAme variability. However, the relationships between placental epiphenotyping variables and other technical and biological variables, and their application to downstream epigenome analyses, have not been well studied. Results : Using DNAme data from 204 placentas across three cohorts, we applied the PlaNET R package to estimate epiphenotypes gestational age, ancestry, and cell composition in these samples. PlaNET ancestry estimates were highly correlated with independent polymorphic ancestry informative markers, and epigenetic gestational age, on average, was estimated within 4 days of reported gestational age, underscoring the accuracy of these tools. Cell composition estimates varied both within and between cohorts, but reassuringly were robust to placental processing time. Interestingly, the ratio of cytotrophoblast to syncytiotrophoblast proportion decreased with increasing gestational age, and differed slightly by both maternal ethnicity (lower in white vs. non-white) and genetic ancestry (lower in higher probability European ancestry). The cohort of origin and cytotrophoblast proportion were the largest drivers of DNAme variation in this dataset, based on their associations with the first principal component. Conclusions : This work confirms that cohort, array (technical) batch, cell type proportion, self-reported ethnicity, genetic ancestry, and biological sex are important variables to consider in any analyses of Illumina DNAme data. Further, we demonstrate that estimating epiphenotype variables from the DNAme data itself, when possible, provides both an independent check of clinically-obtained data and can provide a robust approach to compare variables across different datasets.

10.
Trends Mol Med ; 27(8): 721-722, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33994120

RESUMO

Mutations arising early in human development are surprisingly common, but most often are confined to the placenta. These mutations provide clues to the normal developmental processes leading to a healthy placenta, despite these features being shared in common with cancer.


Assuntos
Desenvolvimento Embrionário , Mosaicismo , Mutação , Placenta/fisiologia , Dano ao DNA , Desenvolvimento Embrionário/genética , Feminino , Humanos , Placentação , Gravidez , Trofoblastos/metabolismo
11.
Clin Epigenetics ; 10: 34, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29564022

RESUMO

Background: 5,10-Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in one-carbon metabolism that ensures the availability of methyl groups for methylation reactions. Two single-nucleotide polymorphisms (SNPs) in the MTHFR gene, 677C>T and 1298A>C, result in a thermolabile enzyme with reduced function. These variants, in both the maternal and/or fetal genes, have been associated with pregnancy complications including miscarriage, neural tube defects (NTDs), and preeclampsia (PE), perhaps due to altered capacity for DNA methylation (DNAm). In this study, we assessed the association between MTHFR 677TT and 1298CC genotypes and risk of NTDs, PE, or normotensive intrauterine growth restriction (nIUGR). Additionally, we assessed whether these high-risk genotypes are associated with altered DNAm in the placenta. Results: In 303 placentas screened for this study, we observed no significant association between the occurrence of NTDs (N = 55), PE (early-onset: N = 28, late-onset: N = 20), or nIUGR (N = 21) and placental (fetal) MTHFR 677TT or 1298CC genotypes compared to healthy pregnancies (N = 179), though a trend of increased 677TT genotype in PE/IUGR together was observed (OR 2.53, p = 0.048). DNAm was profiled in 10 high-risk 677 (677TT + 1298AA), 10 high-risk 1298 (677CC + 1298CC), and 10 reference (677CC + 1298AA) genotype placentas. Linear modeling identified no significantly differentially methylated sites between high-risk 677 or 1298 and reference placentas at a false discovery rate < 0.05 and Δß ≥ 0.05 using the Illumina Infinium HumanMethylation450 BeadChip. Using a differentially methylated region analysis or separating cytosine-guanine dinucleotides (CpGs) by CpG density to reduce multiple comparisons also did not identify differential methylation. Additionally, there was no consistent evidence for altered methylation of repetitive DNA between high-risk and reference placentas. Conclusions: We conclude that large-scale, genome-wide disruption in DNAm does not occur in placentas with the high-risk MTHFR 677TT or 1298CC genotypes. Furthermore, there was no evidence for an association of the 1298CC genotype and only a tendency to higher 677TT in pregnancy complications of PE/IUGR. This may be due to small sample sizes or folate repletion in our Canadian population attenuating effects of the high-risk MTHFR variants. However, given our results and the conflicting results in the literature, investigations into alternative mechanisms that may explain the link between MTHFR variants and pregnancy complications, or in populations at risk of folate deficiencies, are warranted.


Assuntos
Metilação de DNA , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Placenta/química , Polimorfismo de Nucleotídeo Único , Complicações na Gravidez/genética , Adolescente , Adulto , Canadá , Epigênese Genética , Feminino , Estudos de Associação Genética , Genótipo , Idade Gestacional , Humanos , Idade Materna , Gravidez , Adulto Jovem
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