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Proceedings of the National Academy of... Feb 2020Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a...
Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencing with deep phenotyping. A cohort of 1,190 adult participants (402 female [33.8%]; mean age, 54 y [range 20 to 89+]; 70.6% European) had whole-genome sequencing, and were deeply phenotyped using metabolomics, advanced imaging, and clinical laboratory tests in addition to family/medical history. Of 1,190 adults, 206 (17.3%) had at least 1 genetic variant with pathogenic (P) or likely pathogenic (LP) assessment that suggests a predisposition of genetic risk. A multidisciplinary clinical team reviewed all reportable findings for the assessment of genotype and phenotype associations, and 137 (11.5%) had genotype and phenotype associations. A high percentage of genotype and phenotype associations (>75%) was observed for dyslipidemia ( = 24), cardiomyopathy, arrhythmia, and other cardiac diseases ( = 42), and diabetes and endocrine diseases ( = 17). A lack of genotype and phenotype associations, a potential burden for patient care, was observed in 69 (5.8%) individuals with P/LP variants. Genomics and metabolomics associations identified 61 (5.1%) heterozygotes with phenotype manifestations affecting serum metabolite levels in amino acid, lipid and cofactor, and vitamin pathways. Our descriptive analysis provides results on the integration of whole-genome sequencing and deep phenotyping for clinical assessments in adults.
Topics: Adult; Aged; Aged, 80 and over; Cohort Studies; Diagnostic Imaging; Female; Genetic Predisposition to Disease; Genotype; Heart Diseases; Humans; Male; Metabolomics; Middle Aged; Phenotype; Precision Medicine; Whole Genome Sequencing; Young Adult
PubMed: 31980526
DOI: 10.1073/pnas.1909378117 -
Journal of the European Academy of... Nov 2017Pustular psoriasis (PP) is a group of inflammatory skin conditions characterized by infiltration of neutrophil granulocytes in the epidermis to such an extent that... (Review)
Review
Pustular psoriasis (PP) is a group of inflammatory skin conditions characterized by infiltration of neutrophil granulocytes in the epidermis to such an extent that clinically visible sterile pustules develop. Because of clinical co-incidence, PP is currently grouped with psoriasis vulgaris (PV). However, PP and PV are phenotypically different, respond differently to treatments and seem to be distinct on the genetic level. In contrast to PV, the phenotypes of PP are not well defined. Descriptions of each form of PP are discordant among standard dermatology textbooks [Saurat Dermatologie 2016, Rook's Dermatology 2016, Fitzpatrick's 2012 and Braun-Falco 2012], encumbering the collection of phenotypically well-matched groups of patients as well as clinical trials. The European Rare and Severe Psoriasis Expert Network (ERASPEN) was founded to define consensus criteria for diagnosis, deeply phenotype large groups of PP patients, analyse the genetics and pathophysiology and prepare for prospective clinical trials. This work reviews historical aspects of these conditions, new genetic findings and presents our initial considerations on the phenotypes of PP and a consensus classification of clinical phenotypes that will be used as a baseline for further, prospective studies of PP. Generalized pustular psoriasis (GPP) is defined as primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulation is restricted to psoriatic plaques). GPP can occur with or without systemic inflammation, with or without PV and can either be a relapsing (>1 episode) or persistent (>3 months) condition. Acrodermatitis continua of Hallopeau (ACH) is characterized by primary, persistent (>3 months), sterile, macroscopically visible pustules affecting the nail apparatus. Palmoplantar pustulosis (PPP) has primary, persistent (>3 months), sterile, macroscopically visible pustules on palms and/or soles and can occur with or without PV.
Topics: Adult; Child; Consensus; Europe; Female; Humans; Male; Phenotype; Psoriasis
PubMed: 28585342
DOI: 10.1111/jdv.14386 -
Circulation Jan 2015Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome in need of improved phenotypic classification. We sought to evaluate whether...
BACKGROUND
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome in need of improved phenotypic classification. We sought to evaluate whether unbiased clustering analysis using dense phenotypic data (phenomapping) could identify phenotypically distinct HFpEF categories.
METHODS AND RESULTS
We prospectively studied 397 patients with HFpEF and performed detailed clinical, laboratory, ECG, and echocardiographic phenotyping of the study participants. We used several statistical learning algorithms, including unbiased hierarchical cluster analysis of phenotypic data (67 continuous variables) and penalized model-based clustering, to define and characterize mutually exclusive groups making up a novel classification of HFpEF. All phenomapping analyses were performed by investigators blinded to clinical outcomes, and Cox regression was used to demonstrate the clinical validity of phenomapping. The mean age was 65±12 years; 62% were female; 39% were black; and comorbidities were common. Although all patients met published criteria for the diagnosis of HFpEF, phenomapping analysis classified study participants into 3 distinct groups that differed markedly in clinical characteristics, cardiac structure/function, invasive hemodynamics, and outcomes (eg, phenogroup 3 had an increased risk of HF hospitalization [hazard ratio, 4.2; 95% confidence interval, 2.0-9.1] even after adjustment for traditional risk factors [P<0.001]). The HFpEF phenogroup classification, including its ability to stratify risk, was successfully replicated in a prospective validation cohort (n=107).
CONCLUSIONS
Phenomapping results in a novel classification of HFpEF. Statistical learning algorithms applied to dense phenotypic data may allow improved classification of heterogeneous clinical syndromes, with the ultimate goal of defining therapeutically homogeneous patient subclasses.
Topics: Aged; Cohort Studies; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Phenotype; Prospective Studies; Stroke Volume
PubMed: 25398313
DOI: 10.1161/CIRCULATIONAHA.114.010637 -
BMC Medical Genomics Mar 2021Distal 8p duplication is rare but clinically significant. Duplication syndrome results in variable phenotypes, such as developmental delay, intellectual disability, and...
BACKGROUND
Distal 8p duplication is rare but clinically significant. Duplication syndrome results in variable phenotypes, such as developmental delay, intellectual disability, and malformation of the heart. We aimed to provide a better understanding of the phenotypes by studying duplication and its effects in a single family.
METHODS
In a family with a previously induced labor (second fetus) at 12 weeks gestation due to increased nuchal translucency (3.5 mm), copy number variation sequencing (CNV-seq) revealed a 16.22 Mb deletion of 8p23.3p22. For their subsequent pregnancy, the family requested a prenatal diagnosis as well as CNV-seq, karyotyping and FISH testing of all family members.
RESULTS
The first and third children were found to have a 16.22 Mb duplication of 8p23.3p22, containing the 8p23.1 duplication syndrome region. The duplication was inherited from their father, a carrier with a translocation of 8p22 and 22q13. We confirmed that the duplication site was located on chromosome 22q13 by combining the results of CNV-seq, karyotype and FISH. The first child is a 7.5-year-old boy. At one month old, he was diagnosed with a ventricular septal defect and treated surgically at age four. His growth and intelligence developed well, and he performed well in school. His primary issue is an inability to distinguish between the blade alveolars and retroflexes in speech. The third fetus had a normal ultrasound index from beginning until birth. The family elected to continue the pregnancy, and the baby was born healthy, providing us the opportunity to evaluate the effects of 8p23.3p22 duplication by comparison with the brother.
CONCLUSION
Our study makes a significant contribution to the literature because this relatively rare condition can have significant phenotypical consequences, and an understanding of the inheritance and variability of phenotypes caused by this mutation is essential to an increased understanding of the condition.
Topics: Chromosomes, Human, Pair 8; DNA Copy Number Variations; Female; Humans; Infant; Karyotyping; Male; Phenotype; Pregnancy; Trisomy
PubMed: 33757501
DOI: 10.1186/s12920-021-00940-z -
Philosophical Transactions of the Royal... Aug 2022Supergenes are involved in adaptation in multiple organisms, but they are little known in humans. Genomic inversions are the most common mechanism of supergene... (Review)
Review
Supergenes are involved in adaptation in multiple organisms, but they are little known in humans. Genomic inversions are the most common mechanism of supergene generation and maintenance. Here, we review the information about two large inversions that are the best examples of potential human supergenes. In addition, we do an integrative analysis of the newest data to understand better their functional effects and underlying genetic changes. We have found that the highly divergent haplotypes of the 17q21.31 inversion of approximately 1.5 Mb have multiple phenotypic associations, with consistent effects in brain-related traits, red and white blood cells, lung function, male and female characteristics and disease risk. By combining gene expression and nucleotide variation data, we also analysed the molecular differences between haplotypes, including gene duplications, amino acid substitutions and regulatory changes, and identify and as good candidates to be responsible for these phenotypes. The situation is more complex for the 8p23.1 inversion, where there is no clear genetic differentiation. However, the inversion is associated with several related phenotypes and gene expression differences that could be linked to haplotypes specific of one orientation. Our work, therefore, contributes to the characterization of both exceptional variants and illustrates the important role of inversions. This article is part of the theme issue 'Genomic architecture of supergenes: causes and evolutionary consequences'.
Topics: Chromosome Inversion; Female; Genomics; Haplotypes; Humans; Male; Phenotype; Polymorphism, Genetic
PubMed: 35694745
DOI: 10.1098/rstb.2021.0209 -
Journal of Evolutionary Biology Jun 2019Sperm function and quality are primary determinants of male reproductive performance and hence fitness. The presence of rival males has been shown to affect ejaculate...
Sperm function and quality are primary determinants of male reproductive performance and hence fitness. The presence of rival males has been shown to affect ejaculate and sperm traits in a wide range of taxa. However, male physiological conditions may not only affect sperm phenotypic traits but also their genetic and epigenetic signatures, affecting the fitness of the resulting offspring. We investigated the effects of male-male competition on sperm quality using TUNEL assays and geometric morphometrics in the zebrafish, Danio rerio. We found that the sperm produced by males exposed to high male-male competition had smaller heads but larger midpiece and flagellum than sperm produced by males under low competition. Head and flagella also appeared less sensitive to the osmotic stress induced by activation with water. In addition, more sperm showed signals of DNA damage in ejaculates of males under high competition. These findings suggest that the presence of a rival male may have positive effects on sperm phenotypic traits but negative effects on sperm DNA integrity. Overall, males facing the presence of rival males may produce faster swimming and more competitive sperm but this may come at a cost for the next generation.
Topics: Animals; Female; Genome; Male; Phenotype; Social Environment; Spermatozoa; Zebrafish
PubMed: 30817032
DOI: 10.1111/jeb.13435 -
Nature Communications Nov 2022Identical genetic variations can have different phenotypic effects depending on their parent of origin. Yet, studies focusing on parent-of-origin effects have been...
Identical genetic variations can have different phenotypic effects depending on their parent of origin. Yet, studies focusing on parent-of-origin effects have been limited in terms of sample size due to the lack of parental genomes or known genealogies. We propose a probabilistic approach to infer the parent-of-origin of individual alleles that does not require parental genomes nor prior knowledge of genealogy. Our model uses Identity-By-Descent sharing with second- and third-degree relatives to assign alleles to parental groups and leverages chromosome X data in males to distinguish maternal from paternal groups. We combine this with robust haplotype inference and haploid imputation to infer the parent-of-origin for 26,393 UK Biobank individuals. We screen 99 phenotypes for parent-of-origin effects and replicate the discoveries of 6 GWAS studies, confirming signals on body mass index, type 2 diabetes, standing height and multiple blood biomarkers, including the known maternal effect at the MEG3/DLK1 locus on platelet phenotypes. We also report a novel maternal effect at the TERT gene on telomere length, thereby providing new insights on the heritability of this phenotype. All our summary statistics are publicly available to help the community to better characterize the molecular mechanisms leading to parent-of-origin effects and their implications for human health.
Topics: Humans; Male; Alleles; Biological Specimen Banks; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Phenotype; Female
PubMed: 36335127
DOI: 10.1038/s41467-022-34383-6 -
Journal of Cardiology Mar 2019Cardiomyopathy, a leading cause of death worldwide, is etiologically and phenotypically heterogeneous and is caused by a combination of genetic and non-genetic factors.... (Review)
Review
Cardiomyopathy, a leading cause of death worldwide, is etiologically and phenotypically heterogeneous and is caused by a combination of genetic and non-genetic factors. Major genomic determinants of dilated cardiomyopathy (DCM) are titin truncating mutations and lamin A/C mutations. Patients with these two genotypes show critically different phenotypes, including penetrance, coexistence with a conduction system abnormality, cardiac prognosis, and treatment response. The transcriptomic and epigenomic characteristics of DCM include activation of the DNA damage response, metabolic reprogramming, and dedifferentiation. The proteomic and metabolomic signatures of the DCM heart include a rigorous dependency for free fatty acids, activation of the stress response, and metabolic reprogramming. Proteomic and metabolomic analyses of blood show a distinct immune response and an unexpected link with pathology-specific microbiota in DCM. The direct integration of multi-omics data will not only elucidate inter-omics associations but also enable omics-based patient stratification, which will lead to a deeper understanding of cardiomyopathy and the development of precision medicine in cardiology.
Topics: Cardiomyopathy, Dilated; Connectin; Epigenome; Female; Genotype; Heart Conduction System; Humans; Lamin Type A; Male; Metabolome; Mutation; Penetrance; Phenotype; Prognosis; Proteomics; Transcriptome
PubMed: 30527532
DOI: 10.1016/j.jjcc.2018.11.001 -
Haematologica May 2008The hemostatic balance is the result of an equilibrium between procoagulant and anticoagulant factors that interact with each other to ensure hemostasis at sites of...
The hemostatic balance is the result of an equilibrium between procoagulant and anticoagulant factors that interact with each other to ensure hemostasis at sites of vascular injury. Abnormalities of hemostatic factors due to defects in the corresponding genes can result in a tendency to hemorrhage or thrombosis. In the last few decades, the progressive identification of the mechanisms underlying coagulation disorders led to the awareness that clinical phenotypes are only rarely the result of single gene defects but are more often influenced by multiple factors. Interactions between different genes or between genes and other acquired factors may account for the phenotypic variability of most coagulation disorders, by improving or worsening their clinical manifestations.1 Examples of interactions between genotype and phenotype in both hemorrhagic and thrombotic disorders are given in this article.
Topics: Blood Coagulation; Family Health; Female; Genetic Predisposition to Disease; Genotype; Hemorrhage; Hemostasis; Heterozygote; Humans; Male; Mutation; Phenotype; Polymorphism, Genetic; Risk; Thrombosis
PubMed: 18450734
DOI: 10.3324/haematol.12356 -
Proceedings. Biological Sciences Mar 2017Ants are important components of most terrestrial habitats, and a better knowledge of the diversity of their life histories is essential to understand many aspects of... (Review)
Review
Ants are important components of most terrestrial habitats, and a better knowledge of the diversity of their life histories is essential to understand many aspects of ecosystem functioning. The myrmicine genus shows a wide range of colony structures, reproductive behaviours, queen and male lifespans, and habitat use. Reconstructing the evolutionary pathways of individual and social phenotypic traits suggests that the ancestral life history of was characterized by the presence of multiple, short-lived queens in small-sized colonies and a male polyphenism with winged dispersers and wingless fighters, which engage in lethal combat over female sexuals within their natal nests. Single queening, queen polyphenism, the loss of winged males and tolerance among wingless males appear to be derived traits that evolved with changes in nesting habits, colony size and the spread from tropical to seasonal environments. The aim of this review is to bring together the information on life-history evolution in and to highlight the suitability of this genus for functional genomic studies of adaptation, phenotypic plasticity, senescence, invasiveness and other key life-history traits of ants.
Topics: Animals; Ants; Biological Evolution; Environment; Female; Male; Phenotype; Wings, Animal
PubMed: 28298341
DOI: 10.1098/rspb.2016.1406