11,942 results match your criteria Human Genetics [Journal]


The Four Horsemen of the 'Omicsalypse': ontology, replicability, probability and epistemology.

Authors:
Kenneth M Weiss

Hum Genet 2019 Apr 20. Epub 2019 Apr 20.

Penn State University, University park, PA, USA.

Much of modern genomics and the other 'omics' that tag along, assert that the causal bases of biomedical outcomes are genomically enumerable lists whose effects are predictable with 'precision', extensible from samples to all, and enabled by ever-greater hypothesis-free data accumulation. The assertion rests on fundamental, if often implicit assumptions, that (1) the phenomena are based on underlying law-like biological causation, and, therefore, are (2) replicable and (3) even if not deterministic, have specifiable, stable, essentially parametric, probabilities, all of which (4) essentially equates induction with deduction, enabling asymptotically accurate prediction based on past observation. These glowing promises are the four horsemen of a genocentric 'Omicsalypse'. Read More

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http://dx.doi.org/10.1007/s00439-019-02007-7DOI Listing

Quality assurance checklist and additional considerations for canine clinical genetic testing laboratories: a follow-up to the published standards and guidelines.

Hum Genet 2019 Apr 13. Epub 2019 Apr 13.

Paw Print Genetics, Genetic Veterinary Sciences, Inc., 220 E Rowan, Suite 220, Spokane, WA, 99207, USA.

There is currently no oversight for canine clinical genetic testing laboratories. We published an initial set of standards and guidelines with the goal of providing a basis for which canine testing laboratories could evaluate their quality assurance programs. To further those standards and guidelines, we have developed a checklist that can be used as a self-evaluation to identify gaps in their programs for continual quality improvement over time. Read More

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http://dx.doi.org/10.1007/s00439-019-02013-9DOI Listing

Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly.

Hum Genet 2019 Apr 13. Epub 2019 Apr 13.

Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, 1 Baylor Plaza 700D, Houston, TX, 77030, USA.

Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. Read More

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http://dx.doi.org/10.1007/s00439-019-02000-0DOI Listing

Prediction of skin color, tanning and freckling from DNA in Polish population: linear regression, random forest and neural network approaches.

Hum Genet 2019 Apr 12. Epub 2019 Apr 12.

Department of Histology and Embryology, University of Medical Sciences, 60-781, Poznan, Poland.

Predicting phenotypes from DNA has recently become extensively studied field in forensic research and is referred to as Forensic DNA Phenotyping. Systems based on single nucleotide polymorphisms for accurate prediction of iris, hair and skin color in global population, independent of bio-geographical ancestry, have recently been introduced. Here, we analyzed 14 SNPs for distinct skin pigmentation traits in a homogeneous cohort of 222 Polish subjects. Read More

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http://dx.doi.org/10.1007/s00439-019-02012-wDOI Listing

Mutation signatures in germline mitochondrial genome provide insights into human mitochondrial evolution and disease.

Hum Genet 2019 Apr 9. Epub 2019 Apr 9.

Center for Mitochondrial Biology and Medicine & Douglas C. Wallace Institute for Mitochondrial and Epigenetic Information Sciences, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.

Variations in mitochondrial DNA (mtDNA) have been fundamental for understanding human evolution and are causative for a plethora of inherited mitochondrial diseases, but the mutation signatures of germline mtDNA and their value in understanding mitochondrial pathogenicity remain unknown. Here, we carried out a systematic analysis of mutation patterns in germline mtDNA based on 97,566 mtDNA variants from 45,494 full-length sequences and revealed a highly non-stochastic and replication-coupled mutation signature characterized by nucleotide-specific mutation pressure (G > T>A > C) and position-specific selection pressure, suggesting the existence of an intensive mutation-selection interplay in germline mtDNA. We provide evidence that this mutation-selection interplay has strongly shaped the mtDNA sequence during evolution, which not only manifests as an oriented alteration of amino acid compositions of mitochondrial encoded proteins, but also explains the long-lasting mystery of CpG depletion in mitochondrial genome. Read More

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http://dx.doi.org/10.1007/s00439-019-02009-5DOI Listing
April 2019
1 Read

Whole-exome sequencing identified four loci influencing craniofacial morphology in northern Han Chinese.

Hum Genet 2019 Apr 9. Epub 2019 Apr 9.

Biological Anthropology Institute, Jinzhou Medical University, No. 40, Section 3, Songpo Road, Linghe District, Jinzhou, 121001, Liaoning, People's Republic of China.

Facial shape differences are one of the most significant phenotypes in humans. It is affected largely by skull shape. However, research into the genetic basis of the craniofacial morphology has rarely been reported. Read More

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http://dx.doi.org/10.1007/s00439-019-02008-6DOI Listing
April 2019
1 Read

A review of gene-by-air pollution interactions for cardiovascular disease, risk factors, and biomarkers.

Hum Genet 2019 Apr 9. Epub 2019 Apr 9.

National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, NC, USA.

Air pollution is recognized as causal factor for cardiovascular disease (CVD) and is associated with multiple CVD risk factors. Substantial research effort has been invested in understanding the linkages between genetic variation and CVD risk, resulting in over 50 CVD-associated genetic loci. More recently, gene-air pollution interaction studies have quantified the contribution of genetic variation to inter-individual heterogeneity in air pollution health risks, and aided in elucidating mechanisms of air pollution exposure health risks. Read More

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http://link.springer.com/10.1007/s00439-019-02004-w
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http://dx.doi.org/10.1007/s00439-019-02004-wDOI Listing
April 2019
1 Read

Biallelic variants in SMAD6 are associated with a complex cardiovascular phenotype.

Hum Genet 2019 Apr 8. Epub 2019 Apr 8.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Rare heterozygous variants in SMAD6 have been identified as a significant genetic contributor to bicuspid aortic valve-associated thoracic aortic aneurysm on one hand and non-syndromic midline craniosynostosis on the other. In this study, we report two individuals with biallelic missense variants in SMAD6 and a complex cardiac phenotype. Trio exome sequencing in Proband 1, a male who had aortic isthmus stenosis, revealed the homozygous SMAD6 variant p. Read More

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http://dx.doi.org/10.1007/s00439-019-02011-xDOI Listing
April 2019
1 Read

Canine neuropathies: powerful spontaneous models for human hereditary sensory neuropathies.

Hum Genet 2019 Apr 6. Epub 2019 Apr 6.

Univ Rennes, CNRS, IGDR (Institut de Génétique et Développement de Rennes)-UMR6290, 35000, Rennes, France.

In humans, hereditary sensory neuropathies (HSN), also known as hereditary sensory and autonomic neuropathies (HSAN), constitute a clinically and genetically heterogeneous group of disorders characterized by progressive sensory loss, often accompanied by chronic skin ulcerations and nail dystrophic changes. To date, although around 20 genes have already been discovered, they do not explain the genetic causes of all patients. In dogs, similar neuropathies are also diagnosed, several breeds being predisposed to specific forms of the disease. Read More

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http://dx.doi.org/10.1007/s00439-019-02003-xDOI Listing
April 2019
2 Reads

On the relationship between the heritability and the attributable fraction.

Hum Genet 2019 Apr 2. Epub 2019 Apr 2.

Karolinska Institute, Nobels väg 12A, 171 77, Stockholm, Sweden.

Heritability is the most commonly used measure of genetic contribution to disease outcomes. Being the fraction of the variance of latent trait liability attributable to genetic factors, heritability of binary traits is a difficult technical concept that is sometimes misinterpreted as the more-easily understandable concept of attributable fraction. In this paper we use the liability threshold model to describe the analytical relationship between heritability and attributable fraction. Read More

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http://dx.doi.org/10.1007/s00439-019-02006-8DOI Listing

A frameshift insertion in SGK3 leads to recessive hairlessness in Scottish Deerhounds: a candidate gene for human alopecia conditions.

Hum Genet 2019 Mar 29. Epub 2019 Mar 29.

Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.

Hairlessness is a breed-specific feature selected for in some dog breeds but a rare abnormality in some others such as Scottish Deerhounds (SD). In SDs, the affected puppies are born with sparse hair but lose it within the first 2 months leaving the dogs completely hairless. The previous studies have implicated variants in FOXI3 and SGK3 in hairlessness; however, the known variants do not explain hairlessness in all breeds such as SDs. Read More

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http://dx.doi.org/10.1007/s00439-019-02005-9DOI Listing
March 2019
2 Reads

Genetic kinship and admixture in Iron Age Scytho-Siberians.

Hum Genet 2019 Mar 28. Epub 2019 Mar 28.

Institut de Médecine Légale, Université de Strasbourg, Strasbourg, France.

Scythians are known from written sources as horse-riding nomadic peoples who dominated the Eurasian steppe throughout the Iron Age. However, their origins and the exact nature of their social organization remain debated. Three hypotheses prevail regarding their origins that can be summarized as a "western origin", an "eastern origin" and a "multi-regional origin". Read More

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http://link.springer.com/10.1007/s00439-019-02002-y
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http://dx.doi.org/10.1007/s00439-019-02002-yDOI Listing
March 2019
3 Reads

Mouse models for microphthalmia, anophthalmia and cataracts.

Authors:
Jochen Graw

Hum Genet 2019 Mar 27. Epub 2019 Mar 27.

Institute of Developmental Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.

Mouse mutants are a long-lasting, valuable tool to identify genes underlying eye diseases, because the absence of eyes, very small eyes and severely affected, cataractous eyes are easily to detect without major technical equipment. In mice, actually 145 genes or loci are known for anophthalmia, 269 for microphthalmia, and 180 for cataracts. Approximately, 25% of the loci are not yet characterized; however, some of the ancient lines are extinct and not available for future research. Read More

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http://dx.doi.org/10.1007/s00439-019-01995-wDOI Listing

OPENMENDEL: a cooperative programming project for statistical genetics.

Hum Genet 2019 Mar 26. Epub 2019 Mar 26.

Department of Biomathematics, David Geffen School of Medicine at UCLA, Los Angeles, USA.

Statistical methods for genome-wide association studies (GWAS) continue to improve. However, the increasing volume and variety of genetic and genomic data make computational speed and ease of data manipulation mandatory in future software. In our view, a collaborative effort of statistical geneticists is required to develop open source software targeted to genetic epidemiology. Read More

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http://dx.doi.org/10.1007/s00439-019-02001-zDOI Listing

Natural models for retinitis pigmentosa: progressive retinal atrophy in dog breeds.

Hum Genet 2019 Mar 23. Epub 2019 Mar 23.

University of Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes)-UMR6290, 35000, Rennes, France.

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders eventually leading to blindness with different ages of onset, progression and severity. Human RP, first characterized by the progressive degeneration of rod photoreceptor cells, shows high genetic heterogeneity with more than 90 genes identified. However, about one-third of patients have no known genetic causes. Read More

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http://dx.doi.org/10.1007/s00439-019-01999-6DOI Listing

Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals.

Hum Genet 2019 Mar 18. Epub 2019 Mar 18.

Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan.

Incidence rates of Mendelian diseases vary among ethnic groups, and frequencies of variant types of causative genes also vary among human populations. In this study, we examined to what extent we can predict population frequencies of recessive disorders from genomic data, and explored better strategies for variant interpretation and classification. We used a whole-genome reference panel from 3552 general Japanese individuals constructed by the Tohoku Medical Megabank Organization (ToMMo). Read More

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http://dx.doi.org/10.1007/s00439-019-01998-7DOI Listing
March 2019
4 Reads

Canine models of human amelogenesis imperfecta: identification of novel recessive ENAM and ACP4 variants.

Hum Genet 2019 Mar 15. Epub 2019 Mar 15.

Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.

Amelogenesis imperfecta (AI) refers to a genetically and clinically heterogeneous group of inherited disorders affecting the structure, composition, and quantity of tooth enamel. Both non-syndromic and syndromic forms of AI have been described and several genes affecting various aspects of the enamel physiology have been reported. Genetically modified murine models of various genes have provided insights into the complex regulation of proper amelogenesis. Read More

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http://dx.doi.org/10.1007/s00439-019-01997-8DOI Listing

The metabolic network coherence of human transcriptomes is associated with genetic variation at the cadherin 18 locus.

Hum Genet 2019 Mar 9. Epub 2019 Mar 9.

Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany.

Metabolic coherence (MC) is a network-based approach to dimensionality reduction that can be used, for example, to interpret the joint expression of genes linked to human metabolism. Computationally, the derivation of 'transcriptomic' MC involves mapping of an individual gene expression profile onto a gene-centric network derived beforehand from a metabolic network (currently Recon2), followed by the determination of the connectivity of a particular, profile-specific subnetwork. The biological significance of MC has been exemplified previously in the context of human inflammatory bowel disease, among others, but the genetic architecture of this quantitative cellular trait is still unclear. Read More

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http://dx.doi.org/10.1007/s00439-019-01994-xDOI Listing
March 2019
1 Read

A glycine transporter SLC6A5 frameshift mutation causes startle disease in Spanish greyhounds.

Hum Genet 2019 Mar 7. Epub 2019 Mar 7.

Department of Genetics and Biochemistry, Clemson University, Clemson, SC, 29634, USA.

Startle disease, or hyperekplexia, is a glycinergic disorder characterized by hypertonia and apnea that is triggered by noise and/or touch. Mutations in five genes have been associated with startle disease in humans, dogs, cattle, and mice. We identified a novel recessive startle disease in a family of Spanish greyhounds. Read More

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http://link.springer.com/10.1007/s00439-019-01986-x
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http://dx.doi.org/10.1007/s00439-019-01986-xDOI Listing
March 2019
6 Reads

How to increase our belief in discovered statistical interactions via large-scale association studies?

Hum Genet 2019 Mar 6. Epub 2019 Mar 6.

Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, USA.

The understanding that differences in biological epistasis may impact disease risk, diagnosis, or disease management stands in wide contrast to the unavailability of widely accepted large-scale epistasis analysis protocols. Several choices in the analysis workflow will impact false-positive and false-negative rates. One of these choices relates to the exploitation of particular modelling or testing strategies. Read More

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http://dx.doi.org/10.1007/s00439-019-01987-wDOI Listing

Targeted panel sequencing establishes the implication of planar cell polarity pathway and involves new candidate genes in neural tube defect disorders.

Hum Genet 2019 Mar 5. Epub 2019 Mar 5.

Service de Génétique Moléculaire et Génomique, CHU Pontchaillou, 2 rue Henri le Guilloux, 35033, Rennes, France.

Neural tube defect disorders are developmental diseases that originate from an incomplete closure of the neural tube during embryogenesis. Despite high prevalence-1 out of 3000 live births-their etiology is not yet established and both environmental and genetic factors have been proposed, with a heritability rate of about 60%. Studies in mouse models as well as in human have further suggested a multifactorial pattern of inheritance for neural tube defect disorders. Read More

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http://dx.doi.org/10.1007/s00439-019-01993-yDOI Listing

Genome-wide scans of myopia in Pennsylvania Amish families reveal significant linkage to 12q15, 8q21.3 and 5p15.33.

Hum Genet 2019 Mar 2. Epub 2019 Mar 2.

Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, 333 Cassell Dr, Suite 1200, Baltimore, MD, 21224, USA.

Myopia is one of the most common ocular disorders in the world, yet the genetic etiology of the disease remains poorly understood. Specialized founder populations, such as the Pennsylvania Amish, provide the opportunity to utilize exclusive genomic architecture, like unique haplotypes, to better understand the genetic causes of myopia. We perform genetic linkage analysis on Pennsylvania Amish families that have a strong familial history of myopia to map any potential causal variants and genes for the disease. Read More

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http://dx.doi.org/10.1007/s00439-019-01991-0DOI Listing

Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer.

Hum Genet 2019 Feb 28. Epub 2019 Feb 28.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.

Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Read More

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http://dx.doi.org/10.1007/s00439-019-01989-8DOI Listing
February 2019
5 Reads
4.824 Impact Factor

Molybdenum cofactor deficiency type B knock-in mouse models carrying patient-identical mutations and their rescue by singular AAV injections.

Authors:
Jochen Reiss

Hum Genet 2019 Feb 27. Epub 2019 Feb 27.

Institut für Humangenetik der Universitätsmedizin Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany.

Molybdenum cofactor deficiency is an autosomal, recessively inherited metabolic disorder, which, in the absence of an effective therapy, leads to early childhood death due to neurological deterioration. In type A of the disease, cyclic pyranopterin monophosphate (cPMP) is missing, the first intermediate in the biosynthesis of the cofactor, and a biochemical substitution therapy using cPMP has been developed. A comparable approach for type B of the disease with a defect in the second step of the synthesis, formation of molybdopterin, so far has been hampered by the extreme instability of the corresponding metabolites. Read More

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http://dx.doi.org/10.1007/s00439-019-01992-zDOI Listing
February 2019

Novel mutations in ZP1, ZP2, and ZP3 cause female infertility due to abnormal zona pellucida formation.

Hum Genet 2019 Feb 27. Epub 2019 Feb 27.

State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.

The human zona pellucida (ZP) is an extracellular glycoprotein matrix composed of ZP1, ZP2, ZP3, and ZP4 surrounding the oocyte, and it plays an important role in sperm-egg interactions during fertilization. Structural and functional changes in the ZP can influence the process of fertilization and lead to female infertility. Previous studies have identified mutations in ZP1, ZP2, and ZP3 that lead to female infertility caused by oocyte degeneration, empty follicle syndrome, or in vitro fertilization failure. Read More

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http://link.springer.com/10.1007/s00439-019-01990-1
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http://dx.doi.org/10.1007/s00439-019-01990-1DOI Listing
February 2019
5 Reads

Exploring by whole exome sequencing patients with initial diagnosis of Rubinstein-Taybi syndrome: the interconnections of epigenetic machinery disorders.

Hum Genet 2019 Mar 26;138(3):257-269. Epub 2019 Feb 26.

Genetica Medica, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.

Rubinstein-Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disease affecting 1:125,000 newborns characterized by intellectual disability, growth retardation, facial dysmorphisms and skeletal abnormalities. RSTS is caused by mutations in genes encoding for writers of the epigenetic machinery: CREBBP (~ 60%) or its homologous EP300 (~ 10%). No causative mutation is identified in up to 30% of patients. Read More

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http://dx.doi.org/10.1007/s00439-019-01985-yDOI Listing
March 2019
2 Reads

Shared genetic architecture between metabolic traits and Alzheimer's disease: a large-scale genome-wide cross-trait analysis.

Hum Genet 2019 Mar 25;138(3):271-285. Epub 2019 Feb 25.

Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

A growing number of studies clearly demonstrate a substantial link between metabolic dysfunction and the risk of Alzheimer's disease (AD), especially glucose-related dysfunction; one hypothesis for this comorbidity is the presence of a common genetic etiology. We conducted a large-scale cross-trait GWAS to investigate the genetic overlap between AD and ten metabolic traits. Among all the metabolic traits, fasting glucose, fasting insulin and HDL were found to be genetically associated with AD. Read More

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http://dx.doi.org/10.1007/s00439-019-01988-9DOI Listing
March 2019
1 Read

Author response to "a response to 'personalised medicine and population health: breast and ovarian cancer'".

Authors:
Steven A Narod

Hum Genet 2019 Mar 21;138(3):291-292. Epub 2019 Feb 21.

Women's College Research Institute, Women's College Hospital, 76 Grenville Street, M5S 1B2, Toronto, Ontario, Canada.

The author engages in further debate between numerous signatories of a letter who disputes that the author has put forward that the anticipated benefits of a personalised program for cancer prevention and screening are unwarranted. In the event that a cancer screening program is an effective means of mortality reduction, then the best strategy is universality. The benefit of a novel intervention should be evaluated prior to its introduction. Read More

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http://dx.doi.org/10.1007/s00439-019-01981-2DOI Listing
March 2019
2 Reads

Complete sequencing of the SMN2 gene in SMA patients detects SMN gene deletion junctions and variants in SMN2 that modify the SMA phenotype.

Hum Genet 2019 Mar 20;138(3):241-256. Epub 2019 Feb 20.

Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, USA.

Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by loss or mutation of the survival motor neuron 1 (SMN1) gene and retention of SMN2. We performed targeted capture and sequencing of the SMN2, CFTR, and PLS3 genes in 217 SMA patients. We identified a 6. Read More

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http://dx.doi.org/10.1007/s00439-019-01983-0DOI Listing
March 2019
1 Read

Correction to: Gene therapies in canine models for Duchenne muscular dystrophy.

Hum Genet 2019 Feb 19. Epub 2019 Feb 19.

Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, 4458 TAMU, College Station, TX, 77843-4458, USA.

The authors would like to correct the following information concerning Conflict of Interest. Read More

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http://dx.doi.org/10.1007/s00439-019-01982-1DOI Listing
February 2019

PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly.

Hum Genet 2019 Mar 18;138(3):231-239. Epub 2019 Feb 18.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Pseudouridylation is the most common post-transcriptional modification, wherein uridine is isomerized into 5-ribosyluracil (pseudouridine, Ψ). The resulting increase in base stacking and creation of additional hydrogen bonds are thought to enhance RNA stability. Pseudouridine synthases are encoded in humans by 13 genes, two of which are linked to Mendelian diseases: PUS1 and PUS3. Read More

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http://dx.doi.org/10.1007/s00439-019-01980-3DOI Listing
March 2019
1 Read

Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis.

Hum Genet 2019 Mar 18;138(3):211-219. Epub 2019 Feb 18.

Division of Nephrology, Department of Medicine, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA.

Nephrolithiasis (NL) affects 1 in 11 individuals worldwide and causes significant patient morbidity. We previously demonstrated a genetic cause of NL can be identified in 11-29% of pre-dominantly American and European stone formers. Pakistan, which resides within the Afro-Asian stone belt, has a high prevalence of nephrolithiasis (12%) as well as high rate of consanguinity (> 50%). Read More

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http://dx.doi.org/10.1007/s00439-019-01978-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426152PMC
March 2019
2 Reads
4.824 Impact Factor

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia.

Hum Genet 2019 Feb 14. Epub 2019 Feb 14.

Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK.

Eye formation is the result of coordinated induction and differentiation processes during embryogenesis. Disruption of any one of these events has the potential to cause ocular growth and structural defects, such as anophthalmia and microphthalmia (A/M). A/M can be isolated or occur with systemic anomalies, when they may form part of a recognizable syndrome. Read More

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http://dx.doi.org/10.1007/s00439-019-01977-yDOI Listing
February 2019

NUP214 deficiency causes severe encephalopathy and microcephaly in humans.

Hum Genet 2019 Mar 13;138(3):221-229. Epub 2019 Feb 13.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Nuclear pore complex (NPC) is a fundamental component of the nuclear envelope and is key to the nucleocytoplasmic transport. Mutations in several NUP genes that encode individual components of NPC known as nucleoporins have been identified in recent years among patients with static encephalopathies characterized by developmental delay and microcephaly. We describe a multiplex consanguineous family in which four affected members presented with severe neonatal hypotonia, profound global developmental delay, progressive microcephaly and early death. Read More

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http://dx.doi.org/10.1007/s00439-019-01979-wDOI Listing

Gene therapies in canine models for Duchenne muscular dystrophy.

Hum Genet 2019 Feb 7. Epub 2019 Feb 7.

Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, 4458 TAMU, College Station, TX, 77843-4458, USA.

Therapies for Duchenne muscular dystrophy (DMD) must first be tested in animal models to determine proof-of-concept, efficacy, and importantly, safety. The murine and canine models for DMD are genetically homologous and most commonly used in pre-clinical testing. Although the mouse is a strong, proof-of-concept model, affected dogs show more analogous clinical and immunological disease progression compared to boys with DMD. Read More

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http://dx.doi.org/10.1007/s00439-019-01976-zDOI Listing
February 2019

A missense variant in the titin gene in Doberman pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death.

Hum Genet 2019 Feb 4. Epub 2019 Feb 4.

Department of Physiology, University of Arizona, Tucson, AZ, 85724, USA.

The dog provides a large animal model of familial dilated cardiomyopathy for the study of important aspects of this common familial cardiovascular disease. We have previously demonstrated a form of canine dilated cardiomyopathy in the Doberman pinscher breed that is inherited as an autosomal dominant trait and is associated with a splice site variant in the pyruvate dehydrogenase kinase 4 (PDK4) gene, however, genetic heterogeneity exists in this species as well and not all affected dogs have the PDK4 variant. Whole genome sequencing of a family of Doberman pinchers with dilated cardiomyopathy and sudden cardiac death without the PDK4 variant was performed. Read More

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http://dx.doi.org/10.1007/s00439-019-01973-2DOI Listing
February 2019
5 Reads

Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus.

Hum Genet 2019 Feb 1;138(2):141-150. Epub 2019 Feb 1.

Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, 751 23, Uppsala, Sweden.

Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Read More

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http://link.springer.com/10.1007/s00439-018-01966-7
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http://dx.doi.org/10.1007/s00439-018-01966-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373277PMC
February 2019
5 Reads

Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data.

Hum Genet 2019 Feb 22;138(2):199-210. Epub 2019 Jan 22.

Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0. Read More

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http://dx.doi.org/10.1007/s00439-019-01975-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404531PMC
February 2019
6 Reads

Translating cancer genomics into precision medicine with artificial intelligence: applications, challenges and future perspectives.

Hum Genet 2019 Feb 22;138(2):109-124. Epub 2019 Jan 22.

IBM Watson Health, Cambridge, MA, USA.

In the field of cancer genomics, the broad availability of genetic information offered by next-generation sequencing technologies and rapid growth in biomedical publication has led to the advent of the big-data era. Integration of artificial intelligence (AI) approaches such as machine learning, deep learning, and natural language processing (NLP) to tackle the challenges of scalability and high dimensionality of data and to transform big data into clinically actionable knowledge is expanding and becoming the foundation of precision medicine. In this paper, we review the current status and future directions of AI application in cancer genomics within the context of workflows to integrate genomic analysis for precision cancer care. Read More

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http://dx.doi.org/10.1007/s00439-019-01970-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373233PMC
February 2019
1 Read

LncRNA ZBTB40-IT1 modulated by osteoporosis GWAS risk SNPs suppresses osteogenesis.

Hum Genet 2019 Feb 19;138(2):151-166. Epub 2019 Jan 19.

Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, 430079, China.

Previous genome-wide linkage and association studies have identified an osteoporosis-associated locus at 1p36 that harbors SNPs rs34920465 and rs6426749. The 1p36 locus also comprises the WNT4 gene with known role in bone metabolism and functionally unknown ZBTB40/lncRNA ZBTB40-IT1 genes. How these might interact to contribute to osteoporosis susceptibility is not known. Read More

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http://dx.doi.org/10.1007/s00439-019-01969-yDOI Listing
February 2019
12 Reads

Integrative genomic analysis predicts novel functional enhancer-SNPs for bone mineral density.

Hum Genet 2019 Feb 17;138(2):167-185. Epub 2019 Jan 17.

Department of Global Biostatistics and Data Science, Center for Bioinformatics and Genomics, School of Public Health and Tropical Medicine, Tulane University, 1440 Canal Street, Suite 1601, New Orleans, LA, 70112, USA.

Osteoporosis is a skeletal disorder characterized by low bone mineral density (BMD) and deterioration of bone microarchitecture. To identify novel genetic loci underlying osteoporosis, an effective strategy is to focus on scanning of variants with high potential functional impacts. Enhancers play a crucial role in regulating cell-type-specific transcription. Read More

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http://dx.doi.org/10.1007/s00439-019-01971-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425760PMC
February 2019
3 Reads

Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy.

Hum Genet 2019 Feb 17;138(2):187-198. Epub 2019 Jan 17.

Oasi Research Institute-IRCCS, Troina, Italy.

Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene (NM_016188:c. Read More

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http://dx.doi.org/10.1007/s00439-019-01972-3DOI Listing
February 2019
2 Reads

New insights into the genetics of spermatogenic failure: a review of the literature.

Hum Genet 2019 Feb 17;138(2):125-140. Epub 2019 Jan 17.

Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", via S. Sofia 78, 95123, Catania, Italy.

Genetic anomalies are known to affect about 15% of infertile patients with azoospermia or severe oligozoospermia. Despite a throughout diagnostic work-up, in up to the 72% of the male partners of infertile couples, no etiological factor can be found; hence, the cause of infertility remains unclear. Recently, several novel genetic causes of spermatogenic failure (SPGF) have been described. Read More

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http://dx.doi.org/10.1007/s00439-019-01974-1DOI Listing
February 2019
1 Read
4.824 Impact Factor

Downregulation of genes outside the deleted region in individuals with 22q11.2 deletion syndrome.

Hum Genet 2019 Jan 9;138(1):93-103. Epub 2019 Jan 9.

Genetics Division, Universidade Federal de São Paulo, São Paulo, Brazil.

The 22q11.2 deletion syndrome (22q11.2DS) is caused by recurrent hemizygous deletions of chromosome 22q11. Read More

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http://link.springer.com/10.1007/s00439-018-01967-6
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http://dx.doi.org/10.1007/s00439-018-01967-6DOI Listing
January 2019
13 Reads

Prospects and modalities for the treatment of genetic ocular anomalies.

Hum Genet 2019 Jan 2. Epub 2019 Jan 2.

Department of Ophthalmology and Visual Sciences, University of British Columbia, 2550 Willow Street, Vancouver, BC, V5Z 3N9, Canada.

Over the last three decades, genetic studies have made great strides toward the identification of genes and genetic mechanisms underlying congenital disorders of the eye. However, despite the vast knowledge available this has not translated into treatments to prevent or repair the damage in the clinical setting. Recently, new research in technologies, such as tissue regeneration, next generation designer drugs, and genome editing, have become available for some genetic disorders that might be applicable to congenital ocular diseases in the near future. Read More

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http://link.springer.com/10.1007/s00439-018-01968-5
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http://dx.doi.org/10.1007/s00439-018-01968-5DOI Listing
January 2019
5 Reads

Whole-exome sequencing reveals SALL4 variants in premature ovarian insufficiency: an update on genotype-phenotype correlations.

Hum Genet 2019 Jan 2;138(1):83-92. Epub 2019 Jan 2.

Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai, 200011, China.

Premature ovarian insufficiency (POI) is a severe female disorder characterized by primary or secondary amenorrhea before 40 years of age. Genetic factors have been implicated in the pathogenesis of POI, but known POI-associated genes account for only a small fraction of heritability. Here, we performed whole-exome sequencing (WES) to explore pathogenic genes in Han Chinese subjects with POI. Read More

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http://dx.doi.org/10.1007/s00439-018-1962-4DOI Listing
January 2019
5 Reads

The contribution of parent-to-offspring transmission of telomeres to the heritability of telomere length in humans.

Hum Genet 2019 Jan 10;138(1):49-60. Epub 2018 Dec 10.

Department of Public Health Sciences, University of Chicago, Chicago, IL, 60615, USA.

Leukocyte telomere length (LTL) is a heritable trait with two potential sources of heritability (h): inherited variation in non-telomeric regions (e.g., SNPs that influence telomere maintenance) and variability in the lengths of telomeres in gametes that produce offspring zygotes (i. Read More

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http://link.springer.com/10.1007/s00439-018-1964-2
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http://dx.doi.org/10.1007/s00439-018-1964-2DOI Listing
January 2019
14 Reads
4.824 Impact Factor

De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment.

Hum Genet 2019 Jan 8;138(1):61-72. Epub 2018 Dec 8.

Hearing and Genes, Department of Otorhinolaryngology, Head and Neck Surgery, Radboud University Medical Center, Nijmegen, The Netherlands.

ATP2B2 encodes the PMCA2 Ca pump that plays an important role in maintaining ion homeostasis in hair cells among others by extrusion of Ca from the stereocilia to the endolymph. Several mouse models have been described for this gene; mice heterozygous for loss-of-function defects display a rapidly progressive high-frequency hearing impairment. Up to now ATP2B2 has only been reported as a modifier, or in a digenic mechanism with CDH23 for hearing impairment in humans. Read More

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http://link.springer.com/10.1007/s00439-018-1965-1
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http://dx.doi.org/10.1007/s00439-018-1965-1DOI Listing
January 2019
15 Reads

A novel ISLR2-linked autosomal recessive syndrome of congenital hydrocephalus, arthrogryposis and abdominal distension.

Hum Genet 2019 Jan 27;138(1):105-107. Epub 2018 Nov 27.

Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

ISLR2 (immunoglobulin superfamily containing leucine-rich repeat 2), encodes a protein involved in axon guidance in brain development (hence the other name leucine-rich repeat domain- and immunoglobulin domain-containing axon extension proteins; LINX). A recently described mouse knockout displays hydrocephalus. However, the corresponding phenotype in humans is unknown. Read More

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http://dx.doi.org/10.1007/s00439-018-1963-3DOI Listing
January 2019
4 Reads