5,557 results match your criteria Human mutation[Journal]


Heterozygosity mapping for human dominant trait variants.

Hum Mutat 2019 Apr 24. Epub 2019 Apr 24.

Laboratory of Statistical Genetics, Rockefeller University, New York, New York.

Homozygosity mapping is a well-known technique to identify runs of homozygous variants that are likely to harbor genes responsible for autosomal recessive disease, but a comparable method for autosomal dominant traits has been lacking. We developed an approach to map dominant disease genes based on heterozygosity frequencies of sequence variants in the immediate vicinity of a dominant trait. We demonstrate through theoretical analysis that DNA variants surrounding an inherited dominant disease variant tend to have increased heterozygosity compared with variants elsewhere in the genome. Read More

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http://dx.doi.org/10.1002/humu.23765DOI Listing

Concern regarding classification of germline TP53 variants as likely pathogenic.

Hum Mutat 2019 Apr 24. Epub 2019 Apr 24.

Manchester Centre for Genomic Medicine and NW Laboratory Genetics Hub, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.

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http://dx.doi.org/10.1002/humu.23750DOI Listing

A2ML1 and otitis media: novel variants, differential expression and relevant pathways.

Hum Mutat 2019 Apr 22. Epub 2019 Apr 22.

Department of Otolaryngology, University of Colorado School of Medicine (CUSOM), Aurora, Colorado, USA.

A genetic basis for otitis media is established, however the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, and Finnish and Pakistani families with otitis media. Read More

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https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23769
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http://dx.doi.org/10.1002/humu.23769DOI Listing
April 2019
1 Read

Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa.

Hum Mutat 2019 Apr 18. Epub 2019 Apr 18.

Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China.

Retinitis pigmentosa (RP) is the most common manifestation of inherited retinal diseases with high degree of genetic, allelic, and phenotypic heterogeneity. CEP250 encodes the C-Nap1 protein and has been associated with various retinal phenotypes. Here, we report the identification of a mutation (c. Read More

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http://dx.doi.org/10.1002/humu.23759DOI Listing

A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein-truncating variant.

Hum Mutat 2019 Apr 13. Epub 2019 Apr 13.

Brain and Mitochondrial Research, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.

Leigh syndrome is a mitochondrial disease caused by pathogenic variants in over 85 genes. Whole exome sequencing of a patient with Leigh-like syndrome identified homozygous protein-truncating variants in two genes associated with Leigh syndrome; a reported pathogenic variant in PDHX (NP_003468.2:p. Read More

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http://dx.doi.org/10.1002/humu.23753DOI Listing
April 2019
3 Reads

A snapshot of some pLI score pitfalls.

Hum Mutat 2019 Apr 12. Epub 2019 Apr 12.

Biochemistry and Genetics Department, University Hospital of Angers, Angers, France.

The pLI score reflects the tolerance of a given gene to the loss of function on the basis of the number of protein truncating variants, i.e. the frameshift, splice donor, splice acceptor, and stop-gained variants referenced for this gene in control databases weighted by the size of the gene and the sequencing coverage. Read More

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http://dx.doi.org/10.1002/humu.23763DOI Listing

Characterizing variants of unknown significance in rhodopsin: a functional genomics approach.

Hum Mutat 2019 Apr 12. Epub 2019 Apr 12.

Ocular Genomics Institute, Berman-Gund Laboratory for the Study of Retinal Degenerations, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

Characterizing the pathogenicity of DNA sequence variants of unknown significance (VUS) is a major bottleneck in human genetics, and is increasingly important in determining which patients with inherited retinal diseases could benefit from gene therapy. A library of 210 rhodopsin (RHO) variants from literature and in-house genetic diagnostic testing was created to efficiently detect pathogenic RHO variants that fail to express on the cell surface. This study, while focused on RHO, demonstrates a streamlined, generalizable method for detecting pathogenic VUS. Read More

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http://dx.doi.org/10.1002/humu.23762DOI Listing

Functional and Structural Analysis of Rare SLC2A2 Variants Associated with Fanconi-Bickel Syndrome and Metabolic Traits.

Hum Mutat 2019 Apr 5. Epub 2019 Apr 5.

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States.

Deleterious variants in SLC2A2 cause Fanconi-Bickel Syndrome (FBS), a glycogen storage disorder, whereas less common variants in SLC2A2 associate with numerous metabolic diseases. Phenotypic heterogeneity in FBS has been observed, but its causes remain unknown. Our goal was to functionally characterize rare SLC2A2 variants found in FBS and metabolic disease-associated variants to understand the impact of these variants on GLUT2 activity and expression, and establish genotype-phenotype correlations. Read More

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http://dx.doi.org/10.1002/humu.23758DOI Listing

PMS2 expression decrease causes severe problems in mismatch repair.

Hum Mutat 2019 Apr 4. Epub 2019 Apr 4.

Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.

PMS2 is one of the four susceptibility genes in Lynch syndrome (LS), the most common cancer syndrome in the world. Inherited mutations in DNA mismatch repair (MMR) genes, MLH1, MSH2, and MSH6, account for approximately 90% of LS, while a relatively small number of LS families segregate a PMS2 mutation. This and the low cancer penetrance in PMS2 families suggest that PMS2 is only a moderate or low-risk susceptibility gene. Read More

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http://dx.doi.org/10.1002/humu.23756DOI Listing
April 2019
1 Read

Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N-related myopathies.

Hum Mutat 2019 Apr 1. Epub 2019 Apr 1.

Department of Biomedicine, Basel University Hospital, Basel, Switzerland.

Congenital myopathies are early onset, slowly progressive neuromuscular disorders of variable severity. They are genetically and phenotypically heterogeneous and caused by pathogenic variants in several genes. Multi-minicore Disease, one of the more common congenital myopathies, is frequently caused by recessive variants in either SELENON, encoding the endoplasmic reticulum glycoprotein selenoprotein N or RYR1, encoding a protein involved in calcium homeostasis and excitation-contraction coupling. Read More

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https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23745
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http://dx.doi.org/10.1002/humu.23745DOI Listing
April 2019
5 Reads

p.Ser891Ala RET Gene Mutations in Medullary Thyroid Cancer: phenotypical and genealogical characterization of 28 apparently unrelated kindreds and founder effect uncovering in Northern Italy.

Hum Mutat 2019 Mar 30. Epub 2019 Mar 30.

Endocrine and Metabolic Disease Unit - Department of Medicine ASST Spedali Civili of Brescia, Molecular Medicine Laboratory - Department of Clinical and Experimental Sciences. University of Brescia.

Applying genetic screening in Medullary Thyroid Cancer (MTC) patients we identified an unexpected high frequency of c.2671T>G, p.Ser891Ala RET mutation carriers. Read More

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http://dx.doi.org/10.1002/humu.23754DOI Listing
March 2019
1 Read

Primary microcephaly, primordial dwarfism and brachydactyly in adult cases with bi-allelic skipping of RTTN exon 42.

Hum Mutat 2019 Mar 30. Epub 2019 Mar 30.

Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Biallelic and pathogenic variants in the RTTN gene, encoding the centrosomal protein Rotatin, are associated with variable degrees of neurodevelopmental abnormalities, microcephaly and extracranial malformations. To date, no reported case has reached their third decade. Herein, we report on a consanguineous family with three adult members, age 43, 57 and 60 years respectively, with primary microcephaly, developmental delay, primordial dwarfism and brachydactyly segregating a homozygous splice site variant NM_173630. Read More

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http://dx.doi.org/10.1002/humu.23755DOI Listing
March 2019
5.144 Impact Factor

Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype.

Hum Mutat 2019 Mar 29. Epub 2019 Mar 29.

Comprehensive Heart Failure Center (CHFC) and Department of Medicine I, University and University Hospital Würzburg, Würzburg, Germany.

Dominant mutations in the MYH7 and MYBPC3 genes are common causes of inherited cardiomyopathies, which often demonstrate variable phenotypic expression and incomplete penetrance across family members. Biallelic inheritance is rare but allows gaining insights into the genetic mode of action of single variants. Here, we present three cases carrying a loss-of-function (LoF) variant in a compound heterozygous state with a missense variant in either MYH7 or MYBPC3 leading to severe cardiomyopathy with left ventricular noncompaction. Read More

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http://dx.doi.org/10.1002/humu.23757DOI Listing
March 2019
3 Reads

TP63-truncating variants cause isolated premature ovarian insufficiency.

Hum Mutat 2019 Mar 29. Epub 2019 Mar 29.

Reproductive Development, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Premature ovarian insufficiency involves amenorrhea and elevated follicle-stimulating hormone before age 40, and its genetic basis is poorly understood. Here, we study 13 premature ovarian insufficiency (POI) patients using whole-exome sequencing. We identify PREPL and TP63 causative variants, and variants in other potentially novel POI genes. Read More

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http://dx.doi.org/10.1002/humu.23744DOI Listing
March 2019
1 Read

Identification of a p.Trp403* nonsense variant in PHEX causing X-linked hypophosphatemia by inhibiting p38 MAPK signaling.

Hum Mutat 2019 Mar 28. Epub 2019 Mar 28.

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, China.

X-linked hypophosphatemia (XLH) is the most common hereditary rickets, caused by mutations in PHEX encoding the phosphate regulating endopeptidase homolog X-linked. Here, we report a nonsense variant in exon 11 of PHEX (c.1209G>A p. Read More

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http://dx.doi.org/10.1002/humu.23743DOI Listing
March 2019
1 Read
5.144 Impact Factor

Noncompaction cardiomyopathy is caused by a novel in-frame desmin (DES) deletion mutation within the 1A coiled-coil rod segment leading to a severe filament assembly defect.

Hum Mutat 2019 Mar 25. Epub 2019 Mar 25.

Laboratory of Functional Genomics, Research Centre for Medical Genetics (RCMG), Moscow, Russia, Russia.

Mutations in DES, encoding desmin protein, are associated with different kinds of skeletal and/or cardiac myopathies. However, it is unknown, whether DES mutations are associated with left ventricular hypertrabeculation (LVHT). Here, we performed a clinical examination and subsequent genetic analysis in a family, with two individuals presenting LVHT with conduction disease and skeletal myopathy. Read More

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http://dx.doi.org/10.1002/humu.23747DOI Listing
March 2019
2 Reads

D-2-hydroxyglutaric aciduria Type I: Functional analysis of D2HGDH missense variants.

Hum Mutat 2019 Mar 25. Epub 2019 Mar 25.

Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology & Metabolism, Amsterdam, The Netherlands.

D-2-hydroxyglutaric aciduria Type I (D-2-HGA Type I), a neurometabolic disorder with a broad clinical spectrum, is caused by recessive variants in the D2HGDH gene encoding D-2-hydroxyglutarate dehydrogenase (D-2-HGDH). We and others detected 42 potentially pathogenic variants in D2HGDH of which 31 were missense. We developed functional studies to investigate the effect of missense variants on D-2-HGDH catalytic activity. Read More

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http://dx.doi.org/10.1002/humu.23751DOI Listing
March 2019
2 Reads

Screening for rare epigenetic variations in autism and schizophrenia.

Hum Mutat 2019 Mar 21. Epub 2019 Mar 21.

Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, Hess Center for Science and Medicine, New York, New York.

While many studies have led to the identification of rare sequence variants linked with susceptibility to autism and schizophrenia, the contribution of rare epigenetic variations (epivariations) in these disorders remains largely unexplored. Previously we presented evidence that epivariations occur relatively frequently in the human genome, and likely contribute to a subset of congenital and neurodevelopmental disorders through the disruption of dosage-sensitive genes. Here we extend this approach, studying methylation profiles from 297 samples with autism and 767 cases with schizophrenia, identifying 84 and 268 rare epivariations in these two cohorts, respectively, that were absent from 4,860 population controls. Read More

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http://dx.doi.org/10.1002/humu.23740DOI Listing
March 2019
3 Reads

The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update on GNPTAB and GNPTG mutations.

Hum Mutat 2019 Mar 18. Epub 2019 Mar 18.

Section Cell Biology of Rare Diseases, Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Mutations in the GNPTAB and GNPTG genes cause mucolipidosis (ML) type II, type III alpha/beta, and type III gamma, which are autosomal recessively inherited lysosomal storage disorders. GNPTAB and GNPTG encode the α/β-precursor and the γ-subunit of N-acetylglucosamine (GlcNAc)-1-phosphotransferase, respectively, the key enzyme for the generation of mannose 6-phosphate targeting signals on lysosomal enzymes. Defective GlcNAc-1-phosphotransferase results in missorting of lysosomal enzymes and accumulation of non-degradable macromolecules in lysosomes, strongly impairing cellular function. Read More

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http://dx.doi.org/10.1002/humu.23748DOI Listing
March 2019
5.144 Impact Factor

Pyruvate carboxylase deficiency type A and type C: Characterization of five novel pathogenic variants in PC and analysis of the genotype-phenotype correlation.

Hum Mutat 2019 Mar 14. Epub 2019 Mar 14.

Department of Pediatrics, Klinikum Reutlingen, Reutlingen, Germany.

Pyruvate carboxylase deficiency (PCD) is caused by biallelic mutations of the PC gene. The reported clinical spectrum includes a neonatal form with early death (type B), an infantile fatal form (type A), and a late-onset form with isolated mild intellectual delay (type C). Apart from homozygous stop-codon mutations leading to type B PCD, a genotype-phenotype correlation has not otherwise been discernible. Read More

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https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23742
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http://dx.doi.org/10.1002/humu.23742DOI Listing
March 2019
8 Reads

Proposition of adjustments to the ACMG-AMP framework for the interpretation of MEN1 missense variants.

Hum Mutat 2019 Mar 14. Epub 2019 Mar 14.

Aix Marseille Univ, APHM, INSERM, MMG, Laboratory of Molecular Biology Hospital La Conception, Marseille, France.

In 2015, the ACMG-AMP guidelines provided a general procedure for the objective and reproducible classification of genomic variants. While the benefits of this framework are of major importance, its adaptation for locus-specific use is needed. Multiple Endocrine Neoplasia type 1 (MEN1) occurs due to inactivating mutations in the tumour suppressor gene MEN1, including 20% of missense variants. Read More

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http://dx.doi.org/10.1002/humu.23746DOI Listing
March 2019
2 Reads

Two CFTR mutations within codon 970 differently impact on the chloride channel functionality.

Hum Mutat 2019 Mar 9. Epub 2019 Mar 9.

Cell Biology and Disease Mechanisms Program, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.

Pharmacological rescue of mutant cystic fibrosis transmembrane conductance regulator (CFTR) in cystic fibrosis (CF) depends on the specific defect caused by different mutation classes. We asked whether a patient with the rare p.Gly970Asp (c. Read More

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http://dx.doi.org/10.1002/humu.23741DOI Listing
March 2019
1 Read

Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system.

Hum Mutat 2019 May 9;40(5):631-648. Epub 2019 Mar 9.

Molecular Diagnostics Laboratory, INRaSTES, National Center for Scientific Research "Demokritos", Athens, Greece.

Genetic testing for cancer predisposition leads to the identification of a number of variants with uncertain significance. To some extent, variants of BRCA1/2 have been classified, in contrast to variants of other genes. CHEK2 is a typical example, in which a large number of variants of unknown clinical significance were identified and still remained unclassified. Read More

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http://dx.doi.org/10.1002/humu.23728DOI Listing
May 2019
1 Read

UniProt genomic mapping for deciphering functional effects of missense variants.

Hum Mutat 2019 Mar 6. Epub 2019 Mar 6.

European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, United Kingdom.

Understanding the association of genetic variation with its functional consequences in proteins is essential for the interpretation of genomic data and identifying causal variants in diseases. Integration of protein function knowledge with genome annotation can assist in rapidly comprehending genetic variation within complex biological processes. Here, we describe mapping UniProtKB human sequences and positional annotations, such as active sites, binding sites, and variants to the human genome (GRCh38) and the release of a public genome track hub for genome browsers. Read More

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http://doi.wiley.com/10.1002/humu.23738
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http://dx.doi.org/10.1002/humu.23738DOI Listing
March 2019
8 Reads

A quantitative model to predict pathogenicity of missense variants in the TP53 gene.

Hum Mutat 2019 Mar 6. Epub 2019 Mar 6.

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.

Germline pathogenic variants in the TP53 gene cause Li-Fraumeni syndrome, a condition that predisposes individuals to a wide range of cancer types. Identification of individuals carrying a TP53 pathogenic variant is linked to clinical management decisions, such as the avoidance of radiotherapy and use of high-intensity screening programs. The aim of this study was to develop an evidence-based quantitative model that integrates independent in silico data (Align-GVGD and BayesDel) and somatic to germline ratio (SGR), to assign pathogenicity to every possible missense variant in the TP53 gene. Read More

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http://dx.doi.org/10.1002/humu.23739DOI Listing
March 2019
1 Read

Mutation update: TGFBI pathogenic and likely pathogenic variants in corneal dystrophies.

Hum Mutat 2019 Mar 4. Epub 2019 Mar 4.

Institute for Research in Ophthalmology, Sion, Switzerland.

Human transforming growth factor β-induced (TGFBI), is a gene responsible for various corneal dystrophies. TGFBI produces a protein called TGFBI, which is involved in cell adhesion and serves as a recognition sequence for integrins. An alteration in cell surface interactions could be the underlying cause for the progressive accumulation of extracellular deposits in different layers of the cornea with the resulting changes of refractive index and transparency. Read More

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http://dx.doi.org/10.1002/humu.23737DOI Listing

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders.

Hum Mutat 2019 Mar 2. Epub 2019 Mar 2.

INSERM, CNRS, Institut de la Vision, Sorbonne Université, Paris, France.

Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. Read More

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http://dx.doi.org/10.1002/humu.23735DOI Listing
March 2019
4 Reads

Prevalence, spectrum, and founder effect of BRCA1 and BRCA2 mutations in epithelial ovarian cancer from the Middle East.

Hum Mutat 2019 Mar 2. Epub 2019 Mar 2.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Germline mutations in breast cancer susceptibility gene 1 and 2 have previously been estimated to contribute to 13-18% of all epithelial ovarian cancer (EOC). To characterize the prevalence and effect of BRCA1 and BRCA2 mutations in Middle Eastern EOC patients, BRCA mutation screening was performed in 407 unselected ovarian cancer patients using targeted capture and/or Sanger sequencing. A total of 19 different pathogenic variants (PVs) were identified in 50 (12. Read More

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http://dx.doi.org/10.1002/humu.23736DOI Listing
March 2019
5.144 Impact Factor

NBAS pathogenic variants: Defining the associated clinical and facial phenotype and genotype-phenotype correlations.

Hum Mutat 2019 Mar 2. Epub 2019 Mar 2.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCSS, Rome, Italy.

The pathogenic variants in the neuroblastoma-amplified sequence (NBAS) are associated with a clinical spectrum involving the hepatic, skeletal, ocular, and immune systems. Here, we report on two unrelated subjects with a complex phenotype solved by whole-exome sequencing, who shared a synonymous change in NBAS that was documented to affect the transcript processing and co-occurring with a truncating change. Starting from these two cases, we systematically assessed the clinical information available for all subjects with biallelic NBAS pathogenic variants (73 cases in total). Read More

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http://dx.doi.org/10.1002/humu.23734DOI Listing
March 2019
1 Read

Genetic interpretation and clinical translation of minor genes related to Brugada syndrome.

Hum Mutat 2019 Feb 28. Epub 2019 Feb 28.

Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona, University of Girona, Girona, Spain.

Brugada syndrome (BrS) is an inherited arrhythmogenic disease associated with sudden cardiac death. The main gene is SCN5A. Additional variants in 42 other genes have been reported as deleterious, although these variants have not yet received comprehensive pathogenic analysis. Read More

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http://dx.doi.org/10.1002/humu.23730DOI Listing
February 2019
1 Read

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.

Hum Mutat 2019 Feb 28. Epub 2019 Feb 28.

Metabolic Unit, Great Ormond Street Hospital NHS Trust, Institute for Child Health UCL, London, UK.

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Read More

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http://dx.doi.org/10.1002/humu.23731DOI Listing
February 2019
1 Read
5.144 Impact Factor

A new in silico approach to investigate molecular aspects of factor IX missense causative mutations and their impact on the hemophilia B severity.

Hum Mutat 2019 Feb 28. Epub 2019 Feb 28.

Programa de Pós-Graduação em Genética e Biologia Molecular, Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.

Factor IX (encoded by F9) is a protein in the coagulation process, where its lack or deficiency leads to hemophilia B. This condition has been much less studied than hemophilia A, especially in Latin America. We analyzed the structural and functional impact of 54 missense mutations (18 reported by us previously, and 36 other mutations from the Factor IX database) through molecular modeling approaches. Read More

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http://dx.doi.org/10.1002/humu.23733DOI Listing
February 2019
2 Reads

RECQL5: Another DNA helicase potentially involved in hereditary breast cancer susceptibility.

Hum Mutat 2019 May 13;40(5):566-577. Epub 2019 Mar 13.

Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain.

There is still around 50% of the familial breast cancer (BC) cases with an undefined genetic cause, here we have used next-generation sequencing (NGS) technology to identify new BC susceptibility genes. This approach has led to the identification of RECQL5, a member of RECQL-helicases family, as a new BC susceptibility candidate, which deserves further study. We have used a combination of whole exome sequencing in a family negative for mutations in BRCA1/2 throughout (BRCAX), in which we found a probably deleterious variant in RECQL5, and targeted NGS of the complete coding regions and exon-intron boundaries of the candidate gene in 699 BC Spanish BRCAX families and 665 controls. Read More

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http://dx.doi.org/10.1002/humu.23732DOI Listing
May 2019
3 Reads
5.144 Impact Factor

Alu element insertion in the MLH1 exon 6 coding sequence as a mutation predisposing to Lynch syndrome.

Hum Mutat 2019 Feb 28. Epub 2019 Feb 28.

Montpellier University Hospital, Department of Pathology and Oncobiology, Montpellier, France.

Lynch syndrome (LS) is the most frequent cause of hereditary colorectal cancer. A subset of patients with a history of LS shows no causal germline pathogenic alteration and are identified as having Lynch-like syndrome (LLS). Alu retrotransposons are the most abundant mobile DNA sequences in the human genome and have been associated with numerous human cancers by either disrupting coding regions or altering epigenetic modifications or splicing signals. Read More

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http://dx.doi.org/10.1002/humu.23725DOI Listing
February 2019
2 Reads

Clinical-genetic features and peculiar muscle histopathology in infantile DNM1L-related mitochondrial epileptic encephalopathy.

Hum Mutat 2019 May 9;40(5):601-618. Epub 2019 Mar 9.

Department of Neurosciences, Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family, responsible for fission of mitochondria, and having a role in the division of peroxisomes, as well. DRP1 impairment is implicated in several neurological disorders and associated with either de novo dominant or compound heterozygous mutations. Read More

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http://dx.doi.org/10.1002/humu.23729DOI Listing
May 2019
2 Reads

MT-ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases.

Hum Mutat 2019 May 4;40(5):499-515. Epub 2019 Mar 4.

Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Mitochondrial complex V (CV) generates cellular energy as adenosine triphosphate (ATP). Mitochondrial disease caused by the m.8993T>G pathogenic variant in the CV subunit gene MT-ATP6 was among the first described human mitochondrial DNA diseases. Read More

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http://dx.doi.org/10.1002/humu.23723DOI Listing
May 2019
1 Read

Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations.

Hum Mutat 2019 Feb 14. Epub 2019 Feb 14.

Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.

Autism spectrum disorder (ASD) is a childhood neuropsychiatric disorder with a complex genetic architecture. The diagnostic potential of a targeted panel of ASD genes has only been evaluated in small cohorts to date and is especially understudied in the Chinese population. Here, we designed a capture panel with 358 genes (111 syndromic and 247 non-syndromic) for ASD and sequenced a Chinese cohort of 539 cases evaluated with the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) as well as 512 controls. Read More

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http://dx.doi.org/10.1002/humu.23724DOI Listing
February 2019
2 Reads

Kilquist syndrome: A novel syndromic hearing loss disorder caused by homozygous deletion of SLC12A2.

Hum Mutat 2019 May 12;40(5):532-538. Epub 2019 Mar 12.

National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, Bethesda, Maryland.

Syndromic sensorineural hearing loss is multigenic and associated with malformations of the ear and other organ systems. Herein we describe a child admitted to the NIH Undiagnosed Diseases Program with global developmental delay, sensorineural hearing loss, gastrointestinal abnormalities, and absent salivation. Next-generation sequencing revealed a uniparental isodisomy in chromosome 5, and a 22 kb homozygous deletion in SLC12A2, which encodes for sodium, potassium, and chloride transporter in the basolateral membrane of secretory epithelia. Read More

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http://dx.doi.org/10.1002/humu.23722DOI Listing
May 2019
9 Reads
5.144 Impact Factor

Corrigendum.

Authors:

Hum Mutat 2019 Mar;40(3):355-356

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http://dx.doi.org/10.1002/humu.23710DOI Listing

Corrigendum.

Hum Mutat 2019 Mar;40(3):357

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http://dx.doi.org/10.1002/humu.23711DOI Listing
March 2019
2 Reads

Clarification of glycosylphosphatidylinositol anchorage of OTOANCORIN and human OTOA variants associated with deafness.

Hum Mutat 2019 May 28;40(5):525-531. Epub 2019 Feb 28.

Department of Otorhinolaryngology - Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.

Otoancorin (OTOA), encoded by OTOA, is required for the development of the tectorial membrane in the inner ear. Mutations in this gene cause nonsyndromic hearing loss (DFNB22). The molecular mechanisms underlying most DFNB22 remain poorly understood. Read More

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http://dx.doi.org/10.1002/humu.23719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467692PMC
May 2019
5.144 Impact Factor

A sensitive and scalable microsatellite instability assay to diagnose constitutional mismatch repair deficiency by sequencing of peripheral blood leukocytes.

Hum Mutat 2019 May 6;40(5):649-655. Epub 2019 Mar 6.

Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.

Constitutional mismatch repair deficiency (CMMRD) is caused by germline pathogenic variants in both alleles of a mismatch repair gene. Patients have an exceptionally high risk of numerous pediatric malignancies and benefit from surveillance and adjusted treatment. The diversity of its manifestation, and ambiguous genotyping results, particularly from PMS2, can complicate diagnosis and preclude timely patient management. Read More

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http://dx.doi.org/10.1002/humu.23721DOI Listing
May 2019
2 Reads

Cerebral hypomyelination associated with biallelic variants of FIG4.

Hum Mutat 2019 May 28;40(5):619-630. Epub 2019 Feb 28.

Department of Human Genetics, University of Michigan, Ann Arbor, Michigan.

The lipid phosphatase gene FIG4 is responsible for Yunis-Varón syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Read More

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http://doi.wiley.com/10.1002/humu.23720
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http://dx.doi.org/10.1002/humu.23720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467804PMC
May 2019
6 Reads

High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering.

Hum Mutat 2019 May 28;40(5):516-524. Epub 2019 Mar 28.

Laboratory for Cancer Computational Biology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel.

The 1,000 genome project, the Exome Aggregation Consortium (ExAC) or the Genome Aggregation database (gnomAD) datasets, were developed to provide large-scale reference data of genetic variations for various populations to filter out common benign variants and identify rare variants of clinical importance based on their frequency in the human population. Using a TP53 repository of 80,000 cancer variants, as well as TP53 variants from multiple cancer genome projects, we have defined a set of certified oncogenic TP53 variants. This specific set has been independently validated by functional and in silico predictive analysis. Read More

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http://dx.doi.org/10.1002/humu.23717DOI Listing

Genotypic and phenotypic characterization of Chinese patients with osteogenesis imperfecta.

Hum Mutat 2019 May 25;40(5):588-600. Epub 2019 Feb 25.

Department of Medical Genetics & McKusick-Zhang Center for Genetic Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China.

Osteogenesis imperfecta (OI) is a rare hereditary skeletal dysplasia, characterized by recurrent fractures and bone deformity. This study presents a clinical characterization and mutation analysis of 668 patients, aiming to establish the mutation spectrum and to elucidate genotype-phenotype correlations in Chinese OI patients. We identified 274 sequence variants (230 in type I collagen encoding genes and 44 in noncollagen genes), including 102 novel variants, in 340 probands with a detection rate of 90%. Read More

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http://dx.doi.org/10.1002/humu.23718DOI Listing
May 2019
7 Reads
5.144 Impact Factor

Unique noncoding variants upstream of PRDM13 are associated with a spectrum of developmental retinal dystrophies including progressive bifocal chorioretinal atrophy.

Hum Mutat 2019 May 14;40(5):578-587. Epub 2019 Feb 14.

UCL Institute of Ophthalmology, University College London, London, United Kingdom.

The autosomal dominant progressive bifocal chorioretinal atrophy (PBCRA) disease locus has been mapped to chromosome 6q14-16.2 that overlaps the North Carolina macular dystrophy (NCMD) locus MCDR1. NCMD is a nonprogressive developmental macular dystrophy, in which variants upstream of PRDM13 have been implicated. Read More

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http://dx.doi.org/10.1002/humu.23715DOI Listing
May 2019
2 Reads
5.144 Impact Factor

Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants.

Hum Mutat 2019 May 14;40(5):552-565. Epub 2019 Feb 14.

Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

Wilson disease (WD) is a rare autosomal recessive genetic disorder that is associated with various mutations in the ATP7B gene. Although ATP7B variants are frequently identified, the exact mutation patterns remain unknown because of the absence of pedigree studies, and the functional consequences of individual ATP7B variants remain to be clarified. In this study, we recruited 65 clinically diagnosed WD patients from 60 unrelated families. Read More

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http://dx.doi.org/10.1002/humu.23714DOI Listing
May 2019
4 Reads
5.144 Impact Factor

The N-terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond.

Hum Mutat 2019 May 6;40(5):539-551. Epub 2019 Feb 6.

Center for Medical Genetics Ghent, Ghent University and Ghent University Hospital, Ghent, Belgium.

Sorsby fundus dystrophy (SFD) is a macular degeneration caused by mutations in TIMP3, the majority of which introduce a novel cysteine. However, the exact molecular mechanisms underlying SFD remain unknown. We aimed to provide novel insights into the functional consequences of a distinct N-terminal mutation. Read More

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http://dx.doi.org/10.1002/humu.23713DOI Listing

Phenylalanine hydroxylase variants interact with the co-chaperone DNAJC12.

Hum Mutat 2019 Apr 6;40(4):483-494. Epub 2019 Feb 6.

Department of Biomedicine, University of Bergen, Bergen, Norway.

DNAJC12, a type III member of the HSP40/DNAJ family, has been identified as the specific co-chaperone of phenylalanine hydroxylase (PAH) and the other aromatic amino acid hydroxylases. DNAJ proteins work together with molecular chaperones of the HSP70 family to assist in proper folding and maintenance of intracellular stability of their clients. Autosomal recessive mutations in DNAJC12 were found to reduce PAH levels, leading to hyperphenylalaninemia (HPA) in patients without mutations in PAH. Read More

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http://dx.doi.org/10.1002/humu.23712DOI Listing