5,521 results match your criteria Human mutation[Journal]


MT-ATP6 Mitochondrial Disease Variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases.

Hum Mutat 2019 Feb 14. Epub 2019 Feb 14.

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

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

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http://dx.doi.org/10.1002/humu.23723DOI Listing
February 2019

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

Kilquist Syndrome: A Novel Syndromic Hearing Loss Disorder Caused by Homozygous Deletion of SLC12A2.

Hum Mutat 2019 Feb 10. Epub 2019 Feb 10.

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

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 22kb homozygous deletion in SLC12A2, which encodes for a 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
February 2019
1 Read

Corrigendum.

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

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

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

Hum Mutat 2019 Feb 10. Epub 2019 Feb 10.

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

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

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http://dx.doi.org/10.1002/humu.23719DOI Listing
February 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 Feb 10. Epub 2019 Feb 10.

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 paediatric 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
February 2019

Cerebral hypomyelination associated with biallelic variants of FIG4.

Hum Mutat 2019 Feb 10. Epub 2019 Feb 10.

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

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 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
February 2019
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High prevalence of cancer-associated TP53 variants in the gnomAD database: a word of caution concerning the use of variant filtering.

Hum Mutat 2019 Feb 5. Epub 2019 Feb 5.

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

The 1000 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
February 2019

Genotypic and phenotypic characterization of Chinese patients with osteogenesis imperfecta.

Hum Mutat 2019 Feb 4. Epub 2019 Feb 4.

Department of Medical Genetics, 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 non-collagen 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
February 2019
2 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 Feb 2. Epub 2019 Feb 2.

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
February 2019
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 Jan 31. Epub 2019 Jan 31.

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
January 2019
1 Read
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 Jan 22. Epub 2019 Jan 22.

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
January 2019

Phenylalanine hydroxylase variants interact with the co-chaperone DNAJC12.

Hum Mutat 2019 Jan 22. Epub 2019 Jan 22.

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
January 2019

Analysis of MUTYH alternative transcript expression, promoter function, and the effect of human genetic variants.

Hum Mutat 2019 Jan 17. Epub 2019 Jan 17.

Biomedizinisches Forschungslabor, Medizinische Klinik 1, Universitätsklinikum, Frankfurt, Germany.

The human DNA repair gene MUTYH, whose mutational loss causes a colorectal polyposis and cancer predisposition, contains three alternative first exons. In order to analyze alternative transcription and the effect of genetic alterations found in humans, we established a cell-based minigene experimental model supporting transcription and splicing and thoroughly verified its functionality. We identified highly conserved promoter areas and inactivated them in the minigene, and also introduced six human variants. Read More

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http://dx.doi.org/10.1002/humu.23709DOI Listing
January 2019

Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene.

Hum Mutat 2019 Jan 17. Epub 2019 Jan 17.

Mitchell Cancer Institute, The University of South Alabama, Mobile, Alabama.

Lynch syndrome (LS) is an autosomal dominant inherited disorder that is associated with an increased predisposition to certain cancers caused by loss-of-function mutations in one of four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2). The diagnosis of LS is often challenged by the identification of missense mutations where the functional effects are not known. These are termed variants of uncertain significance (VUSs) and account for 20%-30% of noncoding and missense mutations. Read More

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http://dx.doi.org/10.1002/humu.23708DOI Listing
January 2019
2 Reads

Toward mechanistic models for genotype-phenotype correlations in phenylketonuria using protein stability calculations.

Hum Mutat 2019 Jan 16. Epub 2019 Jan 16.

The Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark.

Phenylketonuria (PKU) is a genetic disorder caused by variants in the gene encoding phenylalanine hydroxylase (PAH), resulting in accumulation of phenylalanine to neurotoxic levels. Here, we analyzed the cellular stability, localization, and interaction with wild-type PAH of 20 selected PKU-linked PAH protein missense variants. Several were present at reduced levels in human cells, and the levels increased in the presence of a proteasome inhibitor, indicating that proteins are proteasome targets. Read More

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http://dx.doi.org/10.1002/humu.23707DOI Listing
January 2019
2 Reads

Comutation and exclusion analysis in human tumors: A tool for cancer biology studies and for rational selection of multitargeted therapeutic approaches.

Hum Mutat 2019 Jan 10. Epub 2019 Jan 10.

Fundación Instituto Leloir, Avda. Patricias Argentinas 435, Buenos Aires, Argentina.

Malignant tumors originate from somatic mutations and other genomic and epigenomic alterations, which lead to loss of control of the cellular circuitry. These alterations present patterns of co-occurrence and mutual exclusivity that can influence prognosis and modify response to drugs, highlighting the need for multitargeted therapies. Studies in this area have generally focused in particular malignancies and considered whole genes instead of specific mutations, ignoring the fact that different alterations in the same gene can have widely different effects. Read More

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http://dx.doi.org/10.1002/humu.23705DOI Listing
January 2019
7 Reads

Aberrant RNA splicing is the major pathogenic effect in a knock-in mouse model of the dominantly inherited c.1430A>G human RPE65 mutation.

Hum Mutat 2019 Jan 10. Epub 2019 Jan 10.

Laboratory of Retinal Cell & Molecular Biology, National Eye Institute, NIH, Bethesda, Maryland.

Human RPE65 mutations cause a spectrum of retinal dystrophies that result in blindness. While RPE65 mutations have been almost invariably recessively inherited, a c.1430A>G (p. Read More

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http://dx.doi.org/10.1002/humu.23706DOI Listing
January 2019
2 Reads
5.144 Impact Factor

UVEOGENE: An SNP database for investigations on genetic factors associated with uveitis and their relationship with other systemic autoimmune diseases.

Hum Mutat 2019 Mar 16;40(3):258-266. Epub 2019 Jan 16.

The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, and Chongqing Eye Institute, Chongqing, People's Republic of China.

Uveitis is an intraocular inflammatory disease which can lead to serious visual impairment. Genetic factors have been shown to be involved in its development. However, few databases have focused on the information of associations between single nucleotide polymorphisms (SNPs) and uveitis. Read More

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http://dx.doi.org/10.1002/humu.23702DOI Listing

Spectrum of SLC20A2, PDGFRB, PDGFB, and XPR1 mutations in a large cohort of patients with primary familial brain calcification.

Hum Mutat 2019 Jan 4. Epub 2019 Jan 4.

Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder with four causative genes (SLC20A2, PDGFRB, PDGFB, and XPR1) that have been identified. Here, we aim to describe the mutational spectrum of four causative genes in a series of 226 unrelated Chinese PFBC patients. Mutations in four causative genes were detected in 16. Read More

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http://dx.doi.org/10.1002/humu.23703DOI Listing
January 2019
1 Read

Mutational mechanism for DAB1 (ATTTC) insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution.

Hum Mutat 2018 Dec 26. Epub 2018 Dec 26.

Genetics of Cognitive Dysfunction Laboratory, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.

Dynamic mutations by microsatellite instability are the molecular basis of a growing number of neuromuscular and neurodegenerative diseases. Repetitive stretches in the human genome may drive pathogenicity, either by expansion above a given threshold, or by insertion of abnormal tracts in nonpathogenic polymorphic repetitive regions, as is the case in spinocerebellar ataxia type 37 (SCA37). We have recently established that this neurodegenerative disease is caused by an (ATTTC) insertion within an (ATTTT) in a noncoding region of DAB1. Read More

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http://doi.wiley.com/10.1002/humu.23704
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http://dx.doi.org/10.1002/humu.23704DOI Listing
December 2018
8 Reads

A novel mutation of PANK4 causes autosomal dominant congenital posterior cataract.

Hum Mutat 2018 Dec 25. Epub 2018 Dec 25.

Department of Ophthalmology, Research Institute of Surgery and Daping Hospital, Army Medical University, Chongqing, China.

Though many mutations have been identified to be associated with the occurrence of congenital cataract, pathogenic loci in some affected families are still unknown. Clinical data and genomic DNA were collected from a four-generation Chinese family. Candidate mutations were independently verified for cosegregation in the whole pedigree. Read More

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http://doi.wiley.com/10.1002/humu.23696
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http://dx.doi.org/10.1002/humu.23696DOI Listing
December 2018
8 Reads

A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern.

Hum Mutat 2019 Mar 10;40(3):243-257. Epub 2019 Jan 10.

Al Jalila Children's Specialty Hospital, Dubai, United Arab Emirates.

The PCDH19 gene consists of six exons encoding a 1,148 amino acid transmembrane protein, Protocadherin 19, which is involved in brain development. Heterozygous pathogenic variants in this gene are inherited in an unusual X-linked dominant pattern in which heterozygous females are affected, while hemizygous males are typically unaffected, although they pass on the pathogenic variant to each affected daughter. PCDH19-related disorder is known to cause early-onset epilepsy in females characterized by seizure clusters exacerbated by fever and in most cases, onset is within the first year of life. Read More

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http://doi.wiley.com/10.1002/humu.23701
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http://dx.doi.org/10.1002/humu.23701DOI Listing
March 2019
6 Reads
5.144 Impact Factor

Autosomal recessive congenital ichthyosis: Genomic landscape and phenotypic spectrum in a cohort of 125 consanguineous families.

Hum Mutat 2019 Mar 16;40(3):288-298. Epub 2019 Jan 16.

Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.

Autosomal recessive congenital ichthyosis (ARCI), a phenotypically heterogeneous group of non-syndromic Mendelian disorders of keratinization, is caused by mutations in as many as 13 distinct genes. We examined a cohort of 125 consanguineous families with ARCI for underlying genetic mutations. The patients' DNA was analyzed with a gene-targeted next generation sequencing panel comprising 38 ichthyosis associated genes. Read More

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http://dx.doi.org/10.1002/humu.23695DOI Listing
March 2019
2 Reads
5.144 Impact Factor

Molecular subtyping of gastric cancer combining genetic and epigenetic anomalies provides distinct clinicopathological features and prognostic impacts.

Hum Mutat 2019 Mar 15;40(3):347-354. Epub 2019 Jan 15.

Department of Gastroenterology, School of Medicine, Fujita Health University, Toyoake, Japan.

Both genetic and epigenetic abnormalities play important roles in gastric cancer (GC) development. We investigated whether the molecular subtypes of gastric cancer by combining genetic and epigenetic anomalies define its clinicopathological features and prognosis. The CpG island methylator phenotype (CIMP), MLH1 methylation, TP53, and KRAS mutation statuses were characterized in 214 GCs in relation to their clinicopathological features and prognosis. Read More

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http://doi.wiley.com/10.1002/humu.23700
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http://dx.doi.org/10.1002/humu.23700DOI Listing
March 2019
5 Reads

Autosomal recessive primary microcephaly due to ASPM mutations: An update.

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Hum Mutat 2019 Jan;40(1):127

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http://dx.doi.org/10.1002/humu.23617DOI Listing
January 2019

Reanalysis and optimisation of bioinformatic pipelines is critical for mutation detection.

Hum Mutat 2018 Dec 17. Epub 2018 Dec 17.

Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, Australia.

Rapid advances in genomic technologies have facilitated the identification pathogenic variants causing human disease. We report siblings with developmental and epileptic encephalopathy due to a novel, shared heterozygous pathogenic 13 bp duplication in SYNGAP1 (c.435_447dup, p. Read More

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http://doi.wiley.com/10.1002/humu.23699
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http://dx.doi.org/10.1002/humu.23699DOI Listing
December 2018
4 Reads

A recurrent mutation in KCNQ4 in Korean families with nonsyndromic hearing loss and rescue of the channel activity by KCNQ activators.

Hum Mutat 2019 Mar 25;40(3):335-346. Epub 2018 Dec 25.

Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, 03722, Korea.

Mutations in potassium voltage-gated channel subfamily Q member 4 (KCNQ4) are etiologically linked to nonsyndromic hearing loss (NSHL), deafness nonsyndromic autosomal dominant 2 (DFNA2). To identify causative mutations of hearing loss in 98 Korean families, we performed whole exome sequencing. In four independent families with NSHL, we identified a cosegregating heterozygous missense mutation, c. Read More

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http://dx.doi.org/10.1002/humu.23698DOI Listing
March 2019
3 Reads

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis.

Hum Mutat 2018 Dec 17. Epub 2018 Dec 17.

Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece.

Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disorder. Two forms are recognized, familial (FALS) that accounts for 5-10% of ALS cases, and sporadic (SALS) that accounts for the rest. Early diagnosis of ALS is important because it improves their therapeutic efficacy. Read More

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http://dx.doi.org/10.1002/humu.23697DOI Listing
December 2018

Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function.

Hum Mutat 2019 Mar 25;40(3):267-280. Epub 2018 Dec 25.

Genome Research Division, Human Genetics Department, Radboud University Medical Center Nijmegen and Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.

Next-generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c. Read More

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http://dx.doi.org/10.1002/humu.23694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370506PMC
March 2019
8 Reads

A de novo pathogenic CSNK1E mutation identified by exome sequencing in family trios with epileptic encephalopathy.

Hum Mutat 2019 Mar 8;40(3):281-287. Epub 2018 Dec 8.

Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.

Recent whole-exome sequencing (WES) studies have demonstrated the contribution of de novo mutations (DNMs) to epileptic encephalopathies (EEs). Here, we performed WES on four trios with West syndrome and identified three loss-of-function DNMs in both CSNK1E (c.885+1G>A) and STXBP1 (splicing, c. Read More

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http://dx.doi.org/10.1002/humu.23690DOI Listing
March 2019
3 Reads

The homozygous variant c.797G>A/p.(Cys266Tyr) in PISD is associated with a Spondyloepimetaphyseal dysplasia with large epiphyses and disturbed mitochondrial function.

Hum Mutat 2019 Mar 21;40(3):299-309. Epub 2018 Dec 21.

Centre of Medical Genetics, University of Antwerp & University Hospital Antwerp, Antwerp, Belgium.

Spondyloepimetaphyseal dysplasias (SEMD) are a group of genetically heterogeneous skeletal disorders characterized by abnormal vertebral bodies and epimetaphyseal abnormalities. We investigated two families with a new SEMD type with one proband each. They showed mild facial dysmorphism, flat vertebral bodies (platyspondyly), large epiphyses, metaphyseal dysplasia, and hallux valgus as common clinical features. Read More

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http://doi.wiley.com/10.1002/humu.23693
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http://dx.doi.org/10.1002/humu.23693DOI Listing
March 2019
2 Reads

Lamin A mutation impairs interaction with nucleoporin NUP155 and disrupts nucleocytoplasmic transport in atrial fibrillation.

Hum Mutat 2019 Mar 8;40(3):310-325. Epub 2018 Dec 8.

The Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, P. R. China.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Here, we show the identification and functional characterization of one AF-associated mutation p.Arg399Cys in lamin A/C. Read More

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http://dx.doi.org/10.1002/humu.23691DOI Listing
March 2019
1 Read

The effect of premature termination codon mutations on CFTR mRNA abundance in human nasal epithelium and intestinal organoids: a basis for read-through therapies in cystic fibrosis.

Hum Mutat 2019 Mar 10;40(3):326-334. Epub 2018 Dec 10.

Faculty of Sciences, BioISI - Biosystems & Integrative Sciences Institute, University of Lisboa, Campo Grande, Portugal.

A major challenge in cystic fibrosis (CF) research is applying mutation-specific therapy to individual patients with diverse and rare CF transmembrane conductance regulator (CFTR) genotypes. Read-through agents are currently the most promising approach for Class I mutations that introduce premature termination codons (PTCs) into CFTR mRNA. However, variations in degradation of PTC containing transcripts by nonsense mediated decay (NMD) might lower read-through efficacy. Read More

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http://dx.doi.org/10.1002/humu.23692DOI Listing
March 2019
1 Read
5.144 Impact Factor

EPCAM mutation update: Variants associated with congenital tufting enteropathy and Lynch syndrome.

Hum Mutat 2019 Feb 29;40(2):142-161. Epub 2018 Nov 29.

Department of Pediatrics, University of California, San Diego, La Jolla, California.

The epithelial cell adhesion molecule gene (EPCAM, previously known as TACSTD1 or TROP1) encodes a membrane-bound protein that is localized to the basolateral membrane of epithelial cells and is overexpressed in some tumors. Biallelic mutations in EPCAM cause congenital tufting enteropathy (CTE), which is a rare chronic diarrheal disorder presenting in infancy. Monoallelic deletions of the 3' end of EPCAM that silence the downstream gene, MSH2, cause a form of Lynch syndrome, which is a cancer predisposition syndrome associated with loss of DNA mismatch repair. Read More

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http://dx.doi.org/10.1002/humu.23688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328345PMC
February 2019
11 Reads

Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome.

Hum Mutat 2019 Feb 12;40(2):162-176. Epub 2018 Dec 12.

Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA.

KCNE1 encodes a regulatory subunit of the KCNQ1 potassium channel-complex. Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization. Recessive variants in these genes are associated with Jervell and Lange-Nielson syndrome (JLNS1 and JLNS2), a cardio-auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death. Read More

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http://dx.doi.org/10.1002/humu.23689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328321PMC
February 2019
7 Reads

A novel autosomal recessive GJB2-associated disorder: Ichthyosis follicularis, bilateral severe sensorineural hearing loss, and punctate palmoplantar keratoderma.

Hum Mutat 2019 Feb 1;40(2):217-229. Epub 2018 Dec 1.

Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA.

Ichthyosis follicularis, a distinct cutaneous entity reported in combination with atrichia, and photophobia has been associated with mutations in MBTPS2. We sought the genetic cause of a novel syndrome of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma in two families. We performed whole exome sequencing on three patients from two families. Read More

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http://doi.wiley.com/10.1002/humu.23686
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http://dx.doi.org/10.1002/humu.23686DOI Listing
February 2019
16 Reads
5.144 Impact Factor

Evidence of predisposing epimutation in retinoblastoma.

Hum Mutat 2019 Feb 26;40(2):201-206. Epub 2018 Nov 26.

Medical Genetics, University of Siena, Siena, Italy.

Retinoblastoma (RB), which represents the most common childhood eye cancer, is caused by biallelic inactivation of RB1 gene. Promoter hypermethylation is quite frequent in RB tissues but conclusive evidence of soma-wide predisposing epimutations is currently scant. Here, 50 patients who tested negative for RB1 germline sequence alterations were screened for aberrant promoter methylation using methylation-specific MLPA. Read More

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http://doi.wiley.com/10.1002/humu.23684
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http://dx.doi.org/10.1002/humu.23684DOI Listing
February 2019
10 Reads

Small supernumerary marker chromosomes: A legacy of trisomy rescue?

Hum Mutat 2019 Feb 22;40(2):193-200. Epub 2018 Nov 22.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

We studied by a whole genomic approach and trios genotyping, 12 de novo, nonrecurrent small supernumerary marker chromosomes (sSMC), detected as mosaics during pre- or postnatal diagnosis and associated with increased maternal age. Four sSMCs contained pericentromeric portions only, whereas eight had additional non-contiguous portions of the same chromosome, assembled together in a disordered fashion by repair-based mechanisms in a chromothriptic event. Maternal hetero/isodisomy was detected with a paternal origin of the sSMC in some cases, whereas in others two maternal alleles in the sSMC region and biparental haplotypes of the homologs were detected. Read More

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http://dx.doi.org/10.1002/humu.23683DOI Listing
February 2019
4 Reads

Construction of cloning-friendly minigenes for mammalian expression of full-length human NF1 isoforms.

Hum Mutat 2019 Feb 24;40(2):187-192. Epub 2018 Nov 24.

Leibniz Institute on Aging, Fritz Lipmann Institute (FLI), Jena, Germany.

The neurofibromatosis type 1 (NF1) tumor suppressor gene is one of the most frequently mutated genes in human tumors. Research on the NF1 proteins has been partially hindered by the difficulties in cloning and propagating the full-length coding cDNAs. We have now established a condition for propagating the natural open reading frames (ORFs) and have assembled the ORFs for human NF1 type 1 and 2 isoforms. Read More

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http://doi.wiley.com/10.1002/humu.23681
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http://dx.doi.org/10.1002/humu.23681DOI Listing
February 2019
6 Reads

Disease-causing variants of the conserved +2T of 5' splice sites can be rescued by engineered U1snRNAs.

Hum Mutat 2019 Jan 19;40(1):48-52. Epub 2018 Nov 19.

Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.

The ability of variants of the spliceosomal U1snRNA to rescue splicing has been proven in several human disease models, but not for nucleotide changes at the conserved GT nucleotide of 5' splice sites (5'ss), frequent and associated with severe phenotypes. Here, we focused on variants at the 5'ss of F9 intron 3, leading to factor IX (FIX) deficiency (hemophilia B). Through minigene expression, we demonstrated that all changes induce complete exon 3 skipping, which explains the associated hemophilia B phenotype. Read More

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http://dx.doi.org/10.1002/humu.23680DOI Listing
January 2019
8 Reads

In silico and in vivo models for Qatari-specific classical homocystinuria as basis for development of novel therapies.

Hum Mutat 2019 Feb 23;40(2):230-240. Epub 2018 Nov 23.

Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar.

Homocystinuria is a rare inborn error of methionine metabolism caused by cystathionine β-synthase (CBS) deficiency. The prevalence of homocystinuria in Qatar is 1:1,800 births, mainly due to a founder Qatari missense mutation, c.1006C>T; p. Read More

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http://doi.wiley.com/10.1002/humu.23682
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http://dx.doi.org/10.1002/humu.23682DOI Listing
February 2019
11 Reads
5.144 Impact Factor

Genotype and phenotype variability in Sjögren-Larsson syndrome.

Hum Mutat 2019 Feb 26;40(2):177-186. Epub 2018 Nov 26.

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

The Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder caused by pathogenic variants in the ALDH3A2 gene, which codes for fatty aldehyde dehydrogenase (FALDH). FALDH prevents the accumulation of toxic fatty aldehydes by converting them into fatty acids. Pathogenic ALDH3A2 variants cause symptoms such as ichthyosis, spasticity, intellectual disability, and a wide range of less common clinical features. Read More

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http://doi.wiley.com/10.1002/humu.23679
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http://dx.doi.org/10.1002/humu.23679DOI Listing
February 2019
8 Reads

Recessive mutations in the neuronal isoforms of DST, encoding dystonin, lead to abnormal actin cytoskeleton organization and HSAN type VI.

Hum Mutat 2019 Jan 18;40(1):106-114. Epub 2018 Nov 18.

Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Rome, Italy.

Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders, characterized by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. Several pathways have been implicated in the pathogenesis of neuronal degeneration in HSAN, while recent observations point to an emerging role of cytoskeleton organization and function. Here, we report novel biallelic mutations in the DST gene encoding dystonin, a large cytolinker protein of the plakin family, in an adult form of HSAN type VI. Read More

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http://doi.wiley.com/10.1002/humu.23678
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http://dx.doi.org/10.1002/humu.23678DOI Listing
January 2019
8 Reads
5.144 Impact Factor

The role of translation elongation factor eEF1 subunits in neurodevelopmental disorders.

Hum Mutat 2019 Feb 23;40(2):131-141. Epub 2018 Nov 23.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UK.

The multi-subunit eEF1 complex plays a crucial role in de novo protein synthesis. The central functional component of the complex is eEF1A, which occurs as two independently encoded variants with reciprocal expression patterns: whilst eEF1A1 is widely expressed, eEF1A2 is found only in neurons and muscle. Heterozygous mutations in the gene encoding eEF1A2, EEF1A2, have recently been shown to cause epilepsy, autism, and intellectual disability. Read More

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http://dx.doi.org/10.1002/humu.23677DOI Listing
February 2019
1 Read

Novel POLE pathogenic germline variant in a family with multiple primary tumors results in distinct mutational signatures.

Hum Mutat 2019 Jan 20;40(1):36-41. Epub 2018 Nov 20.

Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

We describe a family in which four siblings exhibited multiple or classic colonic polyposis with or without colorectal carcinoma (CRC). One female developed three primary tumors, including CRC and carcinomas of the ovary and breast. Whole-exome sequencing of germline DNA from affected and unaffected individuals revealed a novel missense mutation in the exonuclease domain of POLE (c. Read More

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http://doi.wiley.com/10.1002/humu.23676
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http://dx.doi.org/10.1002/humu.23676DOI Listing
January 2019
9 Reads

Early infantile-onset epileptic encephalopathy 28 due to a homozygous microdeletion involving the WWOX gene in a region of uniparental disomy.

Hum Mutat 2019 Jan 18;40(1):42-47. Epub 2018 Nov 18.

NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, Maryland.

The genetic etiologies of many rare disorders, including early infantile epileptic encephalopathies, are largely undiagnosed. A 6-year-old girl was admitted to the National Institutes of Health Undiagnosed Diseases Program with profound intellectual disability, infantile-onset seizures, chronic respiratory failure, facial dysmorphisms, skeletal abnormalities, and atrial septum defect. A large region of homozygosity was discovered on chromosome 16, spanning 16q22. Read More

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http://doi.wiley.com/10.1002/humu.23675
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http://dx.doi.org/10.1002/humu.23675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296882PMC
January 2019
12 Reads

Allele balance bias identifies systematic genotyping errors and false disease associations.

Hum Mutat 2019 Jan 23;40(1):115-126. Epub 2018 Nov 23.

Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.

In recent years, next-generation sequencing (NGS) has become a cornerstone of clinical genetics and diagnostics. Many clinical applications require high precision, especially if rare events such as somatic mutations in cancer or genetic variants causing rare diseases need to be identified. Although random sequencing errors can be modeled statistically and deep sequencing minimizes their impact, systematic errors remain a problem even at high depth of coverage. Read More

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http://doi.wiley.com/10.1002/humu.23674
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http://dx.doi.org/10.1002/humu.23674DOI Listing
January 2019
8 Reads