Nature and nurture: understanding phenotypic variation in inborn errors of immunity DOI Creative Commons
Morgan Similuk, Taco W. Kuijpers

Frontiers in Cellular and Infection Microbiology, Journal Year: 2023, Volume and Issue: 13

Published: Sept. 14, 2023

The overall disease burden of pediatric infection is high, with widely varying clinical outcomes including death. Among the most vulnerable children, those inborn errors immunity, reduced penetrance and variable expressivity are common but poorly understood. There several genetic mechanisms that influence phenotypic variation in as well a body knowledge on environmental influences specific pathogen triggers. Critically, recent advances illuminating novel nuances for fundamental concepts penetrance, raising new areas inquiry. last few decades have seen identification almost 500 causes major advancements our ability to characterize somatic events, microbiome, genotypes across large populations. progress has not been linear, yet, these developments accumulated into an enhanced diagnose treat some cases precision therapy. Nonetheless, many questions remain regarding contributions both within among families. purpose this review provide updated summary key conceptualized dynamic, reciprocal interplay factors unfolding dimension time. associated findings, potential gaps, implications research discussed turn each influencing factor. substantial challenge ahead will be organize integrate information such way accommodates heterogeneity immunity arrive at more comprehensive accurate understanding how immune system operates health disease. And, crucially, translate improved patient care millions risk serious other immune-related morbidity.

Language: Английский

Mono- and biallelic variant effects on disease at biobank scale DOI Creative Commons
Henrike Heyne,

Juha Karjalainen,

Konrad J. Karczewski

et al.

Nature, Journal Year: 2023, Volume and Issue: 613(7944), P. 519 - 525

Published: Jan. 18, 2023

Abstract Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics 1 . Population bottleneck events, such as those that occurred the history of Finnish population, enrich some homozygous variants to higher frequencies, which facilitates identification cause with recessive inheritance 2,3 Here we examine heterozygous effects 44,370 coding on 2,444 disease phenotypes using data from nationwide electronic health records 176,899 individuals. We find associations genotypes across a broad spectrum phenotypes, including known retinal dystrophy novel adult-onset cataract female infertility. Of identify, 13 out 20 would have been missed by additive model typically used genome-wide association studies. use these results many whose cannot be adequately described conventional definition dominant or recessive. In particular, are significant phenotypic effects. Similarly, presumed benign Our show how biobanks, particularly founder populations, can broaden our understanding complex dosage disease.

Language: Английский

Citations

59
Mendelian inheritance revisited: dominance and recessiveness in medical genetics DOI
Johannes Zschocke, Peter H. Byers, Andrew O.M. Wilkie

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(7), P. 442 - 463

Published: Feb. 20, 2023

Language: Английский

Citations

54
Practice resource‐focused revision: Standardized pedigree nomenclature update centered on sex and gender inclusivity: A practice resource of the National Society of Genetic Counselors DOI
Robin L. Bennett,

Kathryn Steinhaus French,

Robert G. Resta

et al.

Journal of Genetic Counseling, Journal Year: 2022, Volume and Issue: 31(6), P. 1238 - 1248

Published: Sept. 15, 2022

Abstract This focused revision builds on the expert opinions from original publications of ‘Recommendations for human standardized pedigree nomenclature’ published in 1995 and updated 2008. Our review medical since 2008 did not identify any fundamental systematic alternative nomenclature. These findings attest to relevance most nomenclature with critical exception used denote sex assigned at birth gender. While we are recommending creation new symbols, a major focus this publication is clarification use symbols language description distinction between gender, view ensuring safe inclusive practice people who gender‐diverse or transgender. In addition, recommend modifications way that carrier status depicted. goal respect individual differences identities while maintaining biologically, clinically, genetically meaningful information.

Language: Английский

Citations

41
Influences of rare copy-number variation on human complex traits DOI Creative Commons
Margaux L.A. Hujoel, Maxwell A. Sherman, Alison R. Barton

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(22), P. 4233 - 4248.e27

Published: Oct. 1, 2022

The human genome contains hundreds of thousands regions harboring copy-number variants (CNV). However, the phenotypic effects most such polymorphisms are unknown because only larger CNVs have been ascertainable from SNP-array data generated by large biobanks. We developed a computational approach leveraging haplotype sharing in biobank cohorts to more sensitively detect CNVs. Applied UK Biobank, this accounted for approximately half all rare gene inactivation events produced genomic structural variation. This CNV call set enabled detailed analysis associations between and 56 quantitative traits, identifying 269 independent (p < 5 × 10-8) likely be causally driven Putative target genes were identifiable nearly loci, enabling insights into dosage sensitivity these uncovering several gene-trait relationships. These results demonstrate ability haplotype-informed provide genetic basis complex traits.

Language: Английский

Citations

40
Screening embryos for polygenic disease risk: a review of epidemiological, clinical, and ethical considerations DOI Creative Commons
Antonio Capalbo,

G. de Wert,

Heidi Mertes

et al.

Human Reproduction Update, Journal Year: 2024, Volume and Issue: 30(5), P. 529 - 557

Published: May 28, 2024

The genetic composition of embryos generated by in vitro fertilization (IVF) can be examined with preimplantation testing (PGT). Until recently, PGT was limited to detecting single-gene, high-risk pathogenic variants, large structural and aneuploidy. Recent advances have made genome-wide genotyping IVF feasible affordable, raising the possibility screening for their risk polygenic diseases such as breast cancer, hypertension, diabetes, or schizophrenia. Despite a heated debate around this new technology, called embryo (PES; also PGT-P), it is already available patients some countries. Several articles studied epidemiological, clinical, ethical perspectives on PES; however, comprehensive, principled review emerging field missing.

Language: Английский

Citations

13
Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits DOI Creative Commons
Nora Scherer, Daniel Fässler, Oleg Borisov

et al.

Nature Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Abstract Genetic studies of the metabolome can uncover enzymatic and transport processes shaping human metabolism. Using rare variant aggregation testing based on whole-exome sequencing data to detect genes associated with levels 1,294 plasma 1,396 urine metabolites, we discovered 235 gene–metabolite associations, many previously unreported. Complementary approaches (genetic, computational (in silico gene knockouts in whole-body models metabolism) one experimental proof principle) provided orthogonal evidence that rare, damaging variants heterozygous state permit inferences concordant those from inborn errors Allelic series functional transporters responsible for transcellular sulfate reabsorption (SLC13A1, SLC26A1) exhibited graded effects height pinpointed alleles increased odds diverse musculoskeletal traits diseases population. This integrative approach identify new players incompletely characterized metabolic reactions reveal readouts informative diseases.

Language: Английский

Citations

1
From genetic variation to precision medicine DOI Creative Commons

Panagiotis I. Sergouniotis,

Tomas Fitzgerald, Ewan Birney

et al.

Cambridge Prisms Precision Medicine, Journal Year: 2023, Volume and Issue: 1

Published: Jan. 1, 2023

Abstract Genetics has been an important tool for discovering new aspects of biology across life. In humans, there is growing momentum behind the application this knowledge to drive innovation in clinical care, most notably through developments precision medicine. Nowhere impact genetics on practice more striking than field rare disorders. For these conditions, individual disease susceptibility influenced by DNA sequence variation a single or small number genes. contrast, common disorders are multifactorial and caused complex interplay multiple genetic, environmental stochastic factors. The longstanding division human into components obscured continuum traits echoes century-old debate between Mendelian biometric views genetics. article, we discuss differences data concepts Opportunities unify two areas noted importance adopting holistic perspective that integrates diverse genetic factors discussed.

Language: Английский

Citations

16
Guidance for estimating penetrance of monogenic disease-causing variants in population cohorts DOI
Caroline F. Wright, Luke N Sharp, Leigh Jackson

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(9), P. 1772 - 1779

Published: July 29, 2024

Language: Английский

Citations

5
Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies DOI Creative Commons
Alex Lipov, Sean J. Jurgens, Francesco Mazzarotto

et al.

Nature Cardiovascular Research, Journal Year: 2023, Volume and Issue: 2(11), P. 1078 - 1094

Published: Oct. 9, 2023

Abstract Discrete categorization of Mendelian disease genes into dominant and recessive models often oversimplifies their underlying genetic architecture. Cardiomyopathies (CMs) are diseases with complex etiologies for which an increasing number associations have recently been proposed. Here, we comprehensively analyze all published evidence pertaining to biallelic variation associated CM phenotypes identify high-confidence explore the spectrum monoallelic variant effects in established genes. We classify 18 robust association CMs, largely characterized by dilated phenotypes, early onset severe outcomes. Several these outcomes cardiac traits UK Biobank, including LMOD2 ALPK3 hypertrophic CM, respectively. Our data provide insights dominance recessiveness heart demonstrate how such approaches enable discovery unexplored associations.

Language: Английский

Citations

13
The effects of pathogenic and likely pathogenic variants for inherited hemostasis disorders in 140 214 UK Biobank participants DOI Creative Commons
Luca Stefanucci, Janine Collins, Matthew C. Sims

et al.

Blood, Journal Year: 2023, Volume and Issue: 142(24), P. 2055 - 2068

Published: Aug. 30, 2023

Abstract Rare genetic diseases affect millions, and identifying causal DNA variants is essential for patient care. Therefore, it imperative to estimate the effect of each independent variant improve their pathogenicity classification. Our study 140 214 unrelated UK Biobank (UKB) participants found that them carries a median 7 previously reported as pathogenic or likely pathogenic. We focused on 967 diagnostic-grade gene (DGG) rare bleeding, thrombotic, platelet disorders (BTPDs) observed in 12 367 UKB participants. By association analysis, subset these variants, we estimated sizes count volume, odds ratios bleeding thrombosis. Variants some autosomal recessive revealed phenotypic consequences carriers. Loss-of-function MPL, which cause chronic amegakaryocytic thrombocytopenia if biallelic, were unexpectedly associated with increased counts also demonstrated common identified by genome-wide studies (GWAS) thrombosis risk may influence penetrance BTPD DGGs hemostasis disorders. Network-propagation analysis applied an interactome 18 410 nodes 571 917 edges showed GWAS large are enriched first-order interactors. Finally, illustrate modifying polygenic scores disease severity carrying TUBB1 PROC PROS1, respectively. findings demonstrate power analyses using population datasets improving classifications variants.

Language: Английский

Citations

11