Medical genetics articles within Nature Communications

Featured

• Article
  12 April 2024 | Open Access

  Utility of polygenic scores across diverse diseases in a hospital cohort for predictive modeling

  Here, the authors analyze polygenic scores for 457 phenotypes, finding 49 with robust polygenic score predictive models ( > 0.6 AUC). They find that population diversity and environmental factor integration are key considerations to improving the model’s performance.

  • Ting-Hsuan Sun
  • , Chia-Chun Wang
  •  & Kai-Cheng Hsu

• Article
  04 March 2024 | Open Access

  A humanized mouse model for adeno-associated viral gene therapy

  All natural AAV serotypes transduce murine hepatocytes more efficiently than their human counterparts in human liver chimeric mouse models. Here the authors developed a novel humanized mouse were human transduction of AAV can be studied.

  • Mercedes Barzi
  • , Tong Chen
  •  & Karl-Dimiter Bissig

• Article
  14 December 2023 | Open Access

  Prediction and stratification of longitudinal risk for chronic obstructive pulmonary disease across smoking behaviors

  Many people who never smoke develop COPD. Here, the authors derive and validate the Socioeconomic and Environmental Risk Score (SERS) which captures cumulative exposure risks beyond tobacco smoking to predict and stratify risk of COPD.

  • Yixuan He
  • , David C. Qian
  •  & Chirag J. Patel

• Article
  17 November 2023 | Open Access

  Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations

  Vein of Galen malformations (VOGMs) are severe congenital brain arteriovenous malformations. Here the authors work to elucidate the pathogenesis of VOGMs by performing an integrated analysis of 310 VOGM proband family exomes and 336,326 human cerebrovasculature single-cell transcriptomes to identify mutations of key signaling regulators.

  • Shujuan Zhao
  • , Kedous Y. Mekbib
  •  & Kristopher T. Kahle

• Article
  11 November 2023 | Open Access

  A large meta-analysis identifies genes associated with anterior uveitis

  Anterior Uveitis is a common inflammatory eye disease that can result in vision loss. Here, the authors perform GWAS and whole-exome analyses of Anterior Uveitis to identify the underlying genetics of HLA-B*27 positive and negative forms of the disease.

  • Sahar Gelfman
  • , Arden Moscati
  •  & Giovanni Coppola

• Article
  02 November 2023 | Open Access

  Single-nucleus DNA sequencing reveals hidden somatic loss-of-heterozygosity in Cerebral Cavernous Malformations

  Here the authors establish somatic loss-of-heterozygosity as a genetic underpinning of Cerebral Cavernous Malformations (CCMs): using single-nucleus DNA sequencing, they show homozygosity of chromosomes 7p and/or 7q leads to biallelic inactivation of CCM genes in resected lesions.

  • Andrew K. Ressler
  • , Daniel A. Snellings
  •  & Douglas A. Marchuk

• Article
  09 September 2023 | Open Access

  Dominance vs epistasis: the biophysical origins and plasticity of genetic interactions within and between alleles

  The authors examine how mutations combine to alter phenotypes in biophysical models of proteins and conclude that non-additive interactions (epistasis and dominance) are frequent, context-dependent and so challenging to predict in even the simplest of biological systems.

  • Xuan Xie
  • , Xia Sun
  •  & Xianghua Li

• Article
  19 August 2023 | Open Access

  APOGEE 2: multi-layer machine-learning model for the interpretable prediction of mitochondrial missense variants

  APOGEE 2 is a machine-learning tool for assessing the fragility of the mitochondrial genome, evaluating genetic variant pathogenicity and ultimately enhancing our understanding of the clinical heterogeneity of mitochondrial genetic diseases.

  • Salvatore Daniele Bianco
  • , Luca Parca
  •  & Tommaso Mazza

• Article
  22 June 2023 | Open Access

  Striated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy

  Dilated cardiomyopathy is the second most common cause for heart failure. Here the authors combine CRISPR base editors with the muscle-targeting viral vector AAVMYO to repair patient mutations in the cardiac splice factor Rbm20 in two mouse models.

  • Markus Grosch
  • , Laura Schraft
  •  & Lars M. Steinmetz

• Article
  08 May 2023 | Open Access

  Genetics implicates overactive osteogenesis in the development of diffuse idiopathic skeletal hyperostosis

  The genetic contribution to risk of Diffuse Idiopathic Skeletal Hyperostosis has been unclear. Here, the authors find genetic variation associated with Diffuse Idiopathic Skeletal Hyperostosis, finding phenotypic and genetic association with increased bone mass throughout the skeletal system.

  • Anurag Sethi
  • , J. Graham Ruby
  •  & Eugene Melamud

• Article
  12 November 2022 | Open Access

  The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration

  Analysis of age of onset and disease duration in a large, international cohort of people with SOD1-ALS shows that there is a distinct phenotype and that onset and progression are decoupled.

  • Sarah Opie-Martin
  • , Alfredo Iacoangeli
  •  & Christopher E. Shaw

• Article
  03 November 2022 | Open Access

  The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision

  Motile and non-motile cilia have distinct functions and protein complexes associated with them. Here, the authors show the conserved protein CFAP20 is important for both motile and non-motile cilia and is distinct from other ciliopathy-associated domains or macromolecular complexes.

  • Paul W. Chrystal
  • , Nils J. Lambacher
  •  & Michel R. Leroux

• Article
  29 October 2022 | Open Access

  Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder

  Morphological subtypes of autism spectrum disorder (ASD) may differ in their genetic bases. Chan et al. develop a method for calculating a patient-level, genome-wide rare variant score and find significant differences in rare and common variant associations between dysmorphic and nondysmorphic ASD groups.

  • Ada J. S. Chan
  • , Worrawat Engchuan
  •  & Stephen W. Scherer

• Article
  09 August 2022 | Open Access

  Transferability of genetic loci and polygenic scores for cardiometabolic traits in British Pakistani and Bangladeshi individuals

  Most genetic studies of disease have been done in European ancestry cohorts, and the relevance to other populations is not guaranteed. Here, the authors use data from 22,000 British South Asian individuals and find that the transferability of polygenic scores was high for lipids and blood pressure, and lower for BMI and coronary artery disease.

  • Qin Qin Huang
  • , Neneh Sallah
  •  & Karoline Kuchenbaecker

• Article
  26 July 2022 | Open Access

  An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases

  Rapid diagnosis and implementation of treatments is crucial in many genetic conditions. Here the authors describe Genome-to-Treatment, a virtual disease management system that can achieve a rapid diagnosis by expedited whole genome sequencing in 13.5 hours and provide guidance to clinicians for possible therapies.

  • Mallory J. Owen
  • , Sebastien Lefebvre
  •  & Stephen F. Kingsmore

• Article
  08 July 2022 | Open Access

  The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism

  Albinism is a rare disorder often caused by high-effect rare variants in the TYR gene. Here, the authors study a large albinism cohort and find that a common variant in the TYR promoter contributes to albinism by modifying the penetrance of other common variants, demonstrating a complex genetic architecture.

  • Vincent Michaud
  • , Eulalie Lasseaux
  •  & Panagiotis I. Sergouniotis

• Article
  30 June 2022 | Open Access

  Inherited basis of visceral, abdominal subcutaneous and gluteofemoral fat depots

  The inherited basis of body fat distribution is not fully understood. Here, the authors use genetic data and MRI-derived measures of local adiposity to highlight fat depot-specific genetic architecture with implications for cardiometabolic health.

  • Saaket Agrawal
  • , Minxian Wang
  •  & Amit V. Khera

• Article
  27 June 2022 | Open Access

  Common genetic variation associated with Mendelian disease severity revealed through cryptic phenotype analysis

  The severity of rare genetic diseases often varies between individuals, but small sample sizes make it difficult to identify contributing factors. Here, the authors use biobank-scale clinical and genetic data to investigate a role for common genetic variation.

  • David R. Blair
  • , Thomas J. Hoffmann
  •  & Joseph T. Shieh

• Article
  23 November 2021 | Open Access

  Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis

  Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease with a complex underlying genetic etiology. Here, the authors identify a series of rare variants in DSP and PPL in multiplex families with EoE and uncover a pathogenic role for desmosomal dysfunction in EoE.

  • Tetsuo Shoda
  • , Kenneth M. Kaufman
  •  & Marc E. Rothenberg

• Article
  18 August 2021 | Open Access

  Human MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging

  Proper meiotic chromosome segregation requires mismatch repair genes MLH1 and MLH3, of which variants occur in the human population. Here, the authors use computational predictions and yeast assays to select human MLH1/3 variants for modelling in mice, observing reproductive defects from abnormal levels of crossing over.

  • Priti Singh
  • , Robert Fragoza
  •  & John C. Schimenti

• Article
  18 June 2021 | Open Access

  Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder

  The significance of rare and de novo variants in bipolar disorder is not well understood. Here, the authors have analyzed whole exome/genome data from trios to identify deleterious de novo variants associated with bipolar disorder.

  • Masaki Nishioka
  • , An-a Kazuno
  •  & Atsushi Takata

• Article
  17 February 2021 | Open Access

  Population-specific causal disease effect sizes in functionally important regions impacted by selection

  Trans-ethnic genetic correlation is significantly less than 1 for many diseases. Here, the authors stratify this correlation by genomic annotations, finding that loci whose causal disease effect sizes differ between ethnicities are likely impacted by selection, particularly positive selection.

  • Huwenbo Shi
  • , Steven Gazal
  •  & Alkes L. Price

• Article
  27 January 2021 | Open Access

  The contribution of X-linked coding variation to severe developmental disorders

  Developmental disorders (DDs) are more prevalent in males, thought to be due to X-linked genetic variation. Here, the authors investigate the burden of X-linked coding variants in 11,044 DD patients, showing that this contributes to ~6% of both male and female cases and therefore does not solely explain male bias in DDs.

  • Hilary C. Martin
  • , Eugene J. Gardner
  •  & Matthew E. Hurles

• Article
  21 February 2020 | Open Access

  Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

  Adult forms of inflammatory bowel disease (IBD) are of a polygenic nature, but paediatric and very early onset (VEO) IBD also occur as monogenic forms. Here, using whole exome sequencing, the authors explore both the monogenic and polygenic contribution to VEO-IBD and characterize a rare somatic mosaic VEO-IBD patient.

  • Eva Gonçalves Serra
  • , Tobias Schwerd
  •  & Carl A. Anderson

• Article
  10 January 2020 | Open Access

  Cold-induced urticarial autoinflammatory syndrome related to factor XII activation

  Systemic autoinflammatory syndromes such as cryopyrin-associated periodic syndrome (CAPS) are rare and often involve genes related to the inflammasome. Here, the authors report a syndrome characterised by systemic inflammation and cold-induced urticarial rash associated with a Factor XII-activating mutation.

  • Jörg Scheffel
  • , Niklas A. Mahnke
  •  & Karoline Krause

• Article
  25 October 2019 | Open Access

  Quantifying the polygenic contribution to variable expressivity in eleven rare genetic disorders

  Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals. Here, Oetjens et al. systematically study the contribution of common genetic variation to variable expressivity of RGDs and find it is frequently influenced by polygenic factors identified in genome-wide association studies of relevant traits.

  • M. T. Oetjens
  • , M. A. Kelly
  •  & D. H. Ledbetter

• Article
  21 October 2019 | Open Access

  Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia

  Disturbances in IP3 receptor-mediated release of Ca²+ from the endoplasmatic reticulum are associated with neurodegenerative disease. Here, the authors identify in four families with hereditary spastic paraplegia biallelic mutations in RNF170 that associate with increased basal levels of IP3 receptors.

  • Matias Wagner
  • , Daniel P. S. Osborn
  •  & Rebecca Schüle

• Article
  01 October 2019 | Open Access

  ABCC9-related Intellectual disability Myopathy Syndrome is a K_ATP channelopathy with loss-of-function mutations in ABCC9

  ABCC9 encodes the SUR2 subunit of K_ATP channels and dominant genetic variants in ABCC9 have been associated with cardiac phenotypes. Here, the authors report recessive ABCC9 mutations in individuals with mild intellectual disability, myopathy and cardiac systolic dysfunction which is associated with loss of K_ATP channel function.

  • Marie F. Smeland
  • , Conor McClenaghan
  •  & Gijs van Haaften

• Article
  25 September 2019 | Open Access

  Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology

  Causally linking a mutation to clinical phenotypes in rare hereditary diseases is both challenging and illuminating. Here the authors identify PI3Kɣ mutations in a patient with immune dysregulation, and recapitulate the phenotypes in PI3Kɣ-deficient mice by exposing them to natural microbiota from pet-shop mice.

  • Andrew J. Takeda
  • , Timothy J. Maher
  •  & Carrie L. Lucas

• Article
  06 September 2019 | Open Access

  Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model

  The molecular role of ciliary Polycystin-2 (PC2) in cyst formation and polycystic kidney disease (ADKPD) is unclear. Here, the authors identify a PC2 mutant lacking ciliary localisation but with active Ca2+ channel function in mice, that is sufficient to generate an ADPKD phenotype.

  • Rebecca V. Walker
  • , Jennifer L. Keynton
  •  & Dominic P. Norris

• Article
  03 September 2019 | Open Access

  Defects in t⁶A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome

  The biosynthesis of N⁶-threonylcarbamoylated adenosine 37 in tRNA (t⁶A) involves the YRDC enzyme and the KEOPS complex. Here, the authors report mutations in YRDC and the KEOPS component GON7 in Galloway-Mowat syndrome and determine the crystal structure of a GON7-containg subcomplex that suggests a role in KEOPS complex stability.

  • Christelle Arrondel
  • , Sophia Missoury
  •  & Géraldine Mollet

• Article
  13 August 2019 | Open Access

  Mutations in topoisomerase IIβ result in a B cell immunodeficiency

  Topoisomerases are required to release topological stress on DNA during replication and transcription. Here, Broderick et al. report genetic variants in TOP2B that cause a syndromic B cell immunodeficiency associated with reduced TOP2B function, defects in B cell development and B cell activation.

  • Lori Broderick
  • , Shawn Yost
  •  & Hal M. Hoffman

• Article
  10 July 2019 | Open Access

  Paternal-age-related de novo mutations and risk for five disorders

  Advanced paternal age associates with increased risk for psychiatric and developmental disorders in offspring. Here, Taylor et al. utilize parent-child trio exome sequencing data sets to estimate the contribution of paternal age-related de novo mutations to multiple disorders, including heart disease and schizophrenia.

  • Jacob L. Taylor
  • , Jean-Christophe P. G. Debost
  •  & Elise B. Robinson

• Article
  28 June 2019 | Open Access

  Improving the diagnostic yield of exome- sequencing by predicting gene–phenotype associations using large-scale gene expression analysis

  A genetic diagnosis remains unattainable for many individuals with a rare disease because of incomplete knowledge about the genetic basis of many diseases. Here, the authors present the web-based tool GADO (GeneNetwork Assisted Diagnostic Optimization) that uses public RNA-seq data for prioritization of candidate genes.

  • Patrick Deelen
  • , Sipko van Dam
  •  & Lude Franke

• Article
  24 June 2019 | Open Access

  Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data

  Dental caries and periodontitis are among the most common medical conditions. Here, the authors report a GWAS for measures of oral health that reveals 47 risk loci for caries, find genetic correlation with 31 other complex traits and use Mendelian randomization analyses to explore potential causal relationships.

  • Dmitry Shungin
  • , Simon Haworth
  •  & Ingegerd Johansson

• Article
  27 March 2019 | Open Access

  Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions

  Myoglobin is a hemeprotein that reversibly binds oxygen and gives muscle its red color. Here, the authors report a genetic variant in the MB gene that associates with myoglobinopathy, an autosomal dominant progressive myopathy, and altered oxygen binding properties of the mutant protein.

  • Montse Olivé
  • , Martin Engvall
  •  & Nigel G. Laing

• Article
  12 March 2019 | Open Access

  Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly

  Loss of the cadherin FAT1 has been associated with nephropathy and epithelial cell adhesion defects. Here, the authors report five families with a syndromic form of coloboma associated with homozygous frameshift variants in FAT1 and recapitulate the phenotype in mutant mice and zebrafish.

  • Najim Lahrouchi
  • , Aman George
  •  & Abdelaziz Sefiani

• Article
  05 February 2019 | Open Access

  Combined loss of LAP1B and LAP1C results in an early onset multisystemic nuclear envelopathy

  Nuclear envelopathies are a group of diseases caused by genetic mutations in essential nuclear envelope genes. Here, the authors report a nuclear envelopathy with a homozygous nonsense variant in TOR1AIP1 which leads to changes in the nuclear morphology including large nuclear-spanning channels in patients’ fibroblasts.

  • Boris Fichtman
  • , Fadia Zagairy
  •  & Ronen Spiegel

• Article
  25 January 2019 | Open Access

  Loss-of-function mutations in QRICH2 cause male infertility with multiple morphological abnormalities of the sperm flagella

  Multiple morphological abnormalities of the sperm flagella (MMAF) is a cause of male infertility. Here the authors identify homozygous nonsense mutations of the glutamine rich 2 (QRICH2) gene in two MMAF patients from 2 consanguineous families and show using QRICH2 knockout mice that the protein is required for sperm flagellar formation and motility.

  • Ying Shen
  • , Feng Zhang
  •  & Wenming Xu

• Article
  12 December 2018 | Open Access

  Genome-wide meta-analysis implicates mediators of hair follicle development and morphogenesis in risk for severe acne

  Acne vulgaris is a chronic inflammation of the skin, the genetic basis of which is incompletely understood. Here, Petridis et al. perform GWAS and meta-analysis for acne in 26,722 individuals and identify 12 novel risk loci that implicate structure and maintenance of the skin in severe acne risk.

  • Christos Petridis
  • , Alexander A. Navarini
  •  & Michael A. Simpson

• Article
  30 November 2018 | Open Access

  Genome-wide association meta-analysis yields 20 loci associated with gallstone disease

  Genome-wide association studies have so far identified eight risk loci for gallstone disease. Here, the authors perform meta-analysis in cohorts from Iceland and the UK which reveals further 21 common and low-frequency risk variants that highlight the role of bile acid homeostasis in gallstone disease.

  • Egil Ferkingstad
  • , Asmundur Oddsson
  •  & Kari Stefansson

• Article
  20 November 2018 | Open Access

  BAFopathies’ DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin–Siris and Nicolaides–Baraitser syndromes

  Mutations in genes encoding subunits of the BAF complex can cause Coffin–Siris and Nicolaides–Baraitser syndromes. Here the authors identify overlapping DNA methylation signatures in individuals with subtypes of these two syndromes that suggest a functional link and can be used to diagnose subjects with unclear clinical presentations.

  • Erfan Aref-Eshghi
  • , Eric G. Bend
  •  & Bekim Sadikovic

• Article
  17 October 2018 | Open Access

  Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation

  Common genetic variants in structural proteins contribute to risk of atrial fibrillation (AF). Here, using whole-exome sequencing, the authors identify rare truncating variants in TTN that associate with familial and early-onset AF and show defects in cardiac sarcomere assembly in ttn.2-mutant zebrafish.

  • Gustav Ahlberg
  • , Lena Refsgaard
  •  & Morten S. Olesen

• Article
  03 October 2018 | Open Access

  Pathogenic variants in glutamyl-tRNA^Gln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder

  Mitochondrial protein synthesis requires charging a mitochondrial tRNA with its amino acid. Here, the authors describe pathogenic variants in the GatCAB protein complex genes required for the generation of glutaminyl-mt-tRNA^Gln, that impairs mitochondrial translation and presents with cardiomyopathy.

  • Marisa W. Friederich
  • , Sharita Timal
  •  & Johan L. K. Van Hove

• Article
  27 August 2018 | Open Access

  MAP1B mutations cause intellectual disability and extensive white matter deficit

  Intellectual disability (ID) is characterized by an intelligence quotient of below 70 and impaired adaptive skills. Here, analyzing whole genome sequences from 31,463 Icelanders, Walters et al. identify variants in MAP1B associated with ID and extensive brain-wide white matter deficits.

  • G. Bragi Walters
  • , Omar Gustafsson
  •  & Kari Stefansson

• Article
  06 August 2018 | Open Access

  SLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects

  The majority of skeletal dysplasia are caused by pathogenic variants in genes required for glycosaminoglycan (GAG) metabolism. Here, Dubail et al. identify genetic variants in the solute carrier family protein SLC10A7 in families with skeletal dysplasia and amelogenesis imperfecta that disrupt GAG synthesis.

  • Johanne Dubail
  • , Céline Huber
  •  & Valérie Cormier-Daire

• Comment
  30 July 2018 | Open Access

  A critical view on transgenerational epigenetic inheritance in humans

  • Bernhard Horsthemke

• Article
  04 July 2018 | Open Access

  Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits

  Inherited germline variants and somatic mutations contribute to cancer. Here, the authors present the statistical method ALFRED that tests the two-hit hypothesis of tumorigenesis and apply it to ~10,000 tumor exomes to identify rare germline variants that affect putative cancer predisposition genes, contributing substantially to cancer risk.

  • Solip Park
  • , Fran Supek
  •  & Ben Lehner

• Article
  17 May 2018 | Open Access

  Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment

  Nephrotic syndrome is the second most common chronic kidney disease but there are no targeted treatment strategies available. Here the authors identify mutations of six genes codifying for proteins involved in cytoskeleton remodelling and modulation of small GTPases in 17 families with nephrotic syndrome.

  • Shazia Ashraf
  • , Hiroki Kudo
  •  & Friedhelm Hildebrandt

• Review Article
  19 February 2018 | Open Access

  Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference

  Recall-by-Genotype (RbG) is an approach to recall participants from genetic studies based on their specific genotype for further, more extensive phenotyping. Here, the authors discuss examples of RbG as well as practical and ethical considerations and provide an online tool to aid in designing RbG studies.

  • Laura J. Corbin
  • , Vanessa Y. Tan
  •  & Nicholas J. Timpson