11,484 results match your criteria Am. J. Hum. Genet.[Journal]


A Transient Pulse of Genetic Admixture from the Crusaders in the Near East Identified from Ancient Genome Sequences.

Am J Hum Genet 2019 Apr 8. Epub 2019 Apr 8.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK. Electronic address:

During the medieval period, hundreds of thousands of Europeans migrated to the Near East to take part in the Crusades, and many of them settled in the newly established Christian states along the Eastern Mediterranean coast. Here, we present a genetic snapshot of these events and their aftermath by sequencing the whole genomes of 13 individuals who lived in what is today known as Lebanon between the 3 and 13 centuries CE. These include nine individuals from the "Crusaders' pit" in Sidon, a mass burial in South Lebanon identified from the archaeology as the grave of Crusaders killed during a battle in the 13 century CE. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.03.015DOI Listing

Conformational Dynamics and Allosteric Regulation Landscapes of Germline PTEN Mutations Associated with Autism Compared to Those Associated with Cancer.

Am J Hum Genet 2019 Apr 11. Epub 2019 Apr 11.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address:

Individuals with germline PTEN tumor-suppressor variants have PTEN hamartoma tumor syndrome (PHTS). Clinically, PHTS has variable presentations; there are distinct subsets of PHTS-affected individuals, such as those diagnosed with autism spectrum disorder (ASD) or cancer. It remains unclear why mutations in one gene can lead to such seemingly disparate phenotypes. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.03.009DOI Listing

Defective DNA Polymerase α-Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism.

Am J Hum Genet 2019 Apr 11. Epub 2019 Apr 11.

Genome Damage and Stability Centre, University of Sussex, BN1 9RQ Sussex, UK. Electronic address:

Replicating the human genome efficiently and accurately is a daunting challenge involving the duplication of upward of three billion base pairs. At the core of the complex machinery that achieves this task are three members of the B family of DNA polymerases: DNA polymerases α, δ, and ε. Collectively these multimeric polymerases ensure DNA replication proceeds at optimal rates approaching 2 × 10 nucleotides/min with an error rate of less than one per million nucleotides polymerized. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.03.006DOI Listing

IMPACT: Genomic Annotation of Cell-State-Specific Regulatory Elements Inferred from the Epigenome of Bound Transcription Factors.

Am J Hum Genet 2019 Apr 6. Epub 2019 Apr 6.

Center for Data Sciences, Harvard Medical School, Boston, MA 02115, USA; Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Graduate School of Arts and Sciences, Harvard University, Cambridge, MA 02138, USA; Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK. Electronic address:

Despite significant progress in annotating the genome with experimental methods, much of the regulatory noncoding genome remains poorly defined. Here we assert that regulatory elements may be characterized by leveraging local epigenomic signatures where specific transcription factors (TFs) are bound. To link these two features, we introduce IMPACT, a genome annotation strategy that identifies regulatory elements defined by cell-state-specific TF binding profiles, learned from 515 chromatin and sequence annotations. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.03.012DOI Listing

CCR4-NOT transcription complex, subunit 1 (CNOT1) Variant Associated with Holoprosencephaly.

Am J Hum Genet 2019 Apr 5. Epub 2019 Apr 5.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Holoprosencephaly is the incomplete separation of the forebrain during embryogenesis. Both genetic and environmental etiologies have been determined for holoprosencephaly; however, a genetic etiology is not found in most cases. In this report, we present two unrelated individuals with semilobar holoprosencephaly who have the identical de novo missense variant in the gene CCR4-NOT transcription complex, subunit 1 (CNOT1). Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.03.017DOI Listing

The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG.

Am J Hum Genet 2019 Apr 2. Epub 2019 Apr 2.

Metabolomics Expertise Center, Center for Cancer Biology, VIB Center for Cancer Biology, 3000 Leuven, Belgium; Metabolomics Expertise Center, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium. Electronic address:

Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297193009
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http://dx.doi.org/10.1016/j.ajhg.2019.03.003DOI Listing
April 2019
1 Read
10.931 Impact Factor

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

Am J Hum Genet 2019 Apr 10. Epub 2019 Apr 10.

Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK; Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK. Electronic address:

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297193010
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http://dx.doi.org/10.1016/j.ajhg.2019.03.005DOI Listing
April 2019
6 Reads

Pathogenic Variants in GPC4 Cause Keipert Syndrome.

Am J Hum Genet 2019 Apr 5. Epub 2019 Apr 5.

Murdoch Children's Research Institute, Flemington Road, Parkville, Victoria 3052, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia. Electronic address:

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297193007
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http://dx.doi.org/10.1016/j.ajhg.2019.02.026DOI Listing
April 2019
1 Read

Dynamic Scan Procedure for Detecting Rare-Variant Association Regions in Whole-Genome Sequencing Studies.

Am J Hum Genet 2019 Apr 11. Epub 2019 Apr 11.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Statistics, Harvard University, Cambridge, MA 02138, USA. Electronic address:

Whole-genome sequencing (WGS) studies are being widely conducted in order to identify rare variants associated with human diseases and disease-related traits. Classical single-marker association analyses for rare variants have limited power, and variant-set-based analyses are commonly used by researchers for analyzing rare variants. However, existing variant-set-based approaches need to pre-specify genetic regions for analysis; hence, they are not directly applicable to WGS data because of the large number of intergenic and intron regions that consist of a massive number of non-coding variants. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297193009
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http://dx.doi.org/10.1016/j.ajhg.2019.03.002DOI Listing
April 2019
2 Reads
10.931 Impact Factor

Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation.

Am J Hum Genet 2019 Mar 29. Epub 2019 Mar 29.

Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan. Electronic address:

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297193010
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http://dx.doi.org/10.1016/j.ajhg.2019.03.004DOI Listing
March 2019
3 Reads

Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia.

Am J Hum Genet 2019 Mar 29. Epub 2019 Mar 29.

Department of Pediatrics, Division of Genetic Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA. Electronic address:

Microglia are CNS-resident macrophages that scavenge debris and regulate immune responses. Proliferation and development of macrophages, including microglia, requires Colony Stimulating Factor 1 Receptor (CSF1R), a gene previously associated with a dominant adult-onset neurological condition (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia). Here, we report two unrelated individuals with homozygous CSF1R mutations whose presentation was distinct from ALSP. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.03.010DOI Listing
March 2019
10.931 Impact Factor

Response to ASHG: Science and Politics Should Be Mutually Sanctuarized.

Authors:
Michel Tibayrenc

Am J Hum Genet 2019 Apr;104(4):774-775

Maladies Infectieuses et Vecteurs Ecologie, Génétique, Evolution et Contrôle (Institut de Recherche pour le Développement 224-Centre National de la Recherche Scientifique 5290-UM1-UM2), Institut de Recherche Pour le Développement, BP 64501, 34394 Montpellier Cedex 5, France. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2019.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451691PMC

The Responsibility to Recontact Research Participants after Reinterpretation of Genetic and Genomic Research Results.

Am J Hum Genet 2019 Apr;104(4):578-595

Social Issues Committee, American Society of Human Genetics, Rockville, MD 20852, USA; Division of General Internal Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.

The evidence base supporting genetic and genomic sequence-variant interpretations is continuously evolving. An inherent consequence is that a variant's clinical significance might be reinterpreted over time as new evidence emerges regarding its pathogenicity or lack thereof. This raises ethical, legal, and financial issues as to whether there is a responsibility to recontact research participants to provide updates on reinterpretations of variants after the initial analysis. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451731PMC
April 2019
2 Reads

The Iceberg under Water: Unexplored Complexity of Chromoanagenesis in Congenital Disorders.

Am J Hum Genet 2019 Apr;104(4):565-577

Departments of Obstetrics and Gynecology and of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Manchester Center for Audiology and Deafness, School of Health Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9NT, UK. Electronic address:

Structural variation, composed of balanced and unbalanced genomic rearrangements, is an important contributor to human genetic diversity with prominent roles in somatic and congenital disease. At the nucleotide level, structural variants (SVs) have been shown to frequently harbor additional breakpoints and copy-number imbalances, a complexity predicted to emerge wholly as a single-cell division event. Chromothripsis, chromoplexy, and chromoanasynthesis, collectively referred to as chromoanagenesis, are three major mechanisms that explain the occurrence of complex germline and somatic SVs. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451730PMC

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment.

Am J Hum Genet 2019 Apr 28;104(4):721-730. Epub 2019 Mar 28.

Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London WC1N 3BG, UK. Electronic address:

VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451933PMC
April 2019
9 Reads

Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia.

Am J Hum Genet 2019 Apr 28;104(4):767-773. Epub 2019 Mar 28.

Persian BayanGene Research and Training Center, Shiraz, Iran; Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136 USA. Electronic address:

The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide. Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1 (ubiquitin-associated protein 1). Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451742PMC
April 2019
2 Reads

De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism.

Am J Hum Genet 2019 Apr 28;104(4):758-766. Epub 2019 Mar 28.

Department of Human Genetics, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands; Princess Máxima Center for Pediatric Oncology, 3584CS Utrecht, the Netherlands; Department of Genetics, University Medical Center Utrecht, 3508AB Utrecht, the Netherlands. Electronic address:

By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451728PMC
April 2019
1 Read

Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.

Am J Hum Genet 2019 Apr 28;104(4):665-684. Epub 2019 Mar 28.

Department of Medical Epidemiology and Biostatistics and the Swedish Twin Registry, Karolinska Institutet, Stockholm 171 77, Sweden; Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm 171 76, Sweden.

The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h = 25.6%) than for AOA (onset at ages between 20 and 60 years; h = 10. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297193006
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http://dx.doi.org/10.1016/j.ajhg.2019.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451732PMC
April 2019
4 Reads

Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions.

Am J Hum Genet 2019 Apr 28;104(4):685-700. Epub 2019 Mar 28.

Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada; Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A 5W9, Canada. Electronic address:

Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial proportion of them unexplained. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297193010
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http://dx.doi.org/10.1016/j.ajhg.2019.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451739PMC
April 2019
3 Reads

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas.

Am J Hum Genet 2019 Apr 28;104(4):651-664. Epub 2019 Mar 28.

Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Madrid 28029, Spain. Electronic address:

Pheochromocytomas and paragangliomas (PPGLs) provide some of the clearest genetic evidence for the critical role of metabolism in the tumorigenesis process. Approximately 40% of PPGLs are caused by driver germline mutations in 16 known susceptibility genes, and approximately half of these genes encode members of the tricarboxylic acid (TCA) cycle. Taking as a starting point the involvement of the TCA cycle in PPGL development, we aimed to identify unreported mutations that occurred in genes involved in this key metabolic pathway and that could explain the phenotypes of additional individuals who lack mutations in known susceptibility genes. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451733PMC
April 2019
1 Read

Bi-allelic Mutations in TTC21A Induce Asthenoteratospermia in Humans and Mice.

Am J Hum Genet 2019 Apr 28;104(4):738-748. Epub 2019 Mar 28.

Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China; State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211116, China; Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China. Electronic address:

Male infertility is a major concern affecting human reproductive health. Asthenoteratospermia can cause male infertility through reduced motility and abnormal morphology of spermatozoa. Several genes, including DNAH1 and some CFAP family members, are involved in multiple morphological abnormalities of the sperm flagella (MMAF). Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451729PMC
April 2019
1 Read

Bi-allelic Mutations in FAM149B1 Cause Abnormal Primary Cilium and a Range of Ciliopathy Phenotypes in Humans.

Am J Hum Genet 2019 Apr 21;104(4):731-737. Epub 2019 Mar 21.

Department of Genetics, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12371, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address:

Ciliopathies are clinical disorders of the primary cilium with widely recognized phenotypic and genetic heterogeneity. In two Arab consanguineous families, we mapped a ciliopathy phenotype that most closely matches Joubert syndrome (hypotonia, developmental delay, typical facies, oculomotor apraxia, polydactyly, and subtle posterior fossa abnormalities) to a single locus in which a founder homozygous truncating variant in FAM149B1 was identified by exome sequencing. We subsequently identified a third Arab consanguineous multiplex family in which the phenotype of Joubert syndrome/oral-facial-digital syndrome (OFD VI) was found to co-segregate with the same founder variant in FAM149B1. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451727PMC
April 2019
11 Reads

De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.

Am J Hum Genet 2019 Apr 21;104(4):709-720. Epub 2019 Mar 21.

Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. Electronic address:

The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451695PMC
April 2019
1 Read

The Discovery of a LEMD2-Associated Nuclear Envelopathy with Early Progeroid Appearance Suggests Advanced Applications for AI-Driven Facial Phenotyping.

Am J Hum Genet 2019 Apr 21;104(4):749-757. Epub 2019 Mar 21.

Faculty of Medicine, University of Cologne, Cologne, 50931, Germany; Institute of Human Genetics, University Hospital Cologne, Cologne, 50931, Germany. Electronic address:

Over a relatively short period of time, the clinical geneticist's "toolbox" has been expanded by machine-learning algorithms for image analysis, which can be applied to the task of syndrome identification on the basis of facial photographs, but these technologies harbor potential beyond the recognition of established phenotypes. Here, we comprehensively characterized two individuals with a hitherto unknown genetic disorder caused by the same de novo mutation in LEMD2 (c.1436C>T;p. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451726PMC
April 2019
1 Read

ELP1 Splicing Correction Reverses Proprioceptive Sensory Loss in Familial Dysautonomia.

Am J Hum Genet 2019 Apr 21;104(4):638-650. Epub 2019 Mar 21.

Center for Genomic Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Familial dysautonomia (FD) is a recessive neurodegenerative disease caused by a splice mutation in Elongator complex protein 1 (ELP1, also known as IKBKAP); this mutation leads to variable skipping of exon 20 and to a drastic reduction of ELP1 in the nervous system. Clinically, many of the debilitating aspects of the disease are related to a progressive loss of proprioception; this loss leads to severe gait ataxia, spinal deformities, and respiratory insufficiency due to neuromuscular incoordination. There is currently no effective treatment for FD, and the disease is ultimately fatal. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451698PMC
April 2019
3 Reads

Disease Heritability Enrichment of Regulatory Elements Is Concentrated in Elements with Ancient Sequence Age and Conserved Function across Species.

Am J Hum Genet 2019 Apr 21;104(4):611-624. Epub 2019 Mar 21.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

Regulatory elements, e.g., enhancers and promoters, have been widely reported to be enriched for disease and complex trait heritability. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451699PMC
April 2019
10.931 Impact Factor

A Syndromic Neurodevelopmental Disorder Caused by Mutations in SMARCD1, a Core SWI/SNF Subunit Needed for Context-Dependent Neuronal Gene Regulation in Flies.

Am J Hum Genet 2019 Apr 14;104(4):596-610. Epub 2019 Mar 14.

Centre Hospitalier Universitaire Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H4A 3J1, Canada. Electronic address:

Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause neurodevelopmental disorders (NDDs). Here, we report on five individuals with mutations in SMARCD1; the individuals present with developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. Trio exome sequencing proved the mutations to be de novo in four of the five individuals. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451697PMC
April 2019
1 Read
10.931 Impact Factor

Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates.

Am J Hum Genet 2019 Apr 14;104(4):625-637. Epub 2019 Mar 14.

Moderna Inc, 200 Technology Square, Cambridge, MA 02139, USA. Electronic address:

Fabry disease is an X-linked lysosomal storage disease caused by loss of alpha galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of globotriaosylceramide and its analogs in all cells and tissues. Although enzyme replacement therapy (ERT) is considered standard of care, the long-term effects of ERT on renal and cardiac manifestations remain uncertain and thus novel therapies are desirable. We herein report preclinical studies evaluating systemic messenger RNA (mRNA) encoding human α-Gal A in wild-type (WT) mice, α-Gal A-deficient mice, and WT non-human primates (NHPs). Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451694PMC
April 2019
3 Reads

Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder.

Am J Hum Genet 2019 Apr 14;104(4):701-708. Epub 2019 Mar 14.

HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA. Electronic address:

Developmental delay and intellectual disability (DD and ID) are heterogeneous phenotypes that arise in many rare monogenic disorders. Because of this rarity, developing cohorts with enough individuals to robustly identify disease-associated genes is challenging. Social-media platforms that facilitate data sharing among sequencing labs can help to address this challenge. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451696PMC
April 2019
5 Reads
10.931 Impact Factor

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.

Authors:
Katherine L Helbig Robert J Lauerer Jacqueline C Bahr Ivana A Souza Candace T Myers Betül Uysal Niklas Schwarz Maria A Gandini Sun Huang Boris Keren Cyril Mignot Alexandra Afenjar Thierry Billette de Villemeur Delphine Héron Caroline Nava Stéphanie Valence Julien Buratti Christina R Fagerberg Kristina P Soerensen Maria Kibaek Erik-Jan Kamsteeg David A Koolen Boudewijn Gunning H Jurgen Schelhaas Michael C Kruer Jordana Fox Somayeh Bakhtiari Randa Jarrar Sergio Padilla-Lopez Kristin Lindstrom Sheng Chih Jin Xue Zeng Kaya Bilguvar Antigone Papavasileiou Qinghe Xing Changlian Zhu Katja Boysen Filippo Vairo Brendan C Lanpher Eric W Klee Jan-Mendelt Tillema Eric T Payne Margot A Cousin Teresa M Kruisselbrink Myra J Wick Joshua Baker Eric Haan Nicholas Smith Azita Sadeghpour Erica E Davis Nicholas Katsanis Mark A Corbett Alastair H MacLennan Jozef Gecz Saskia Biskup Eva Goldmann Lance H Rodan Elizabeth Kichula Eric Segal Kelly E Jackson Alexander Asamoah David Dimmock Julie McCarrier Lorenzo D Botto Francis Filloux Tatiana Tvrdik Gregory D Cascino Sherry Klingerman Catherine Neumann Raymond Wang Jessie C Jacobsen Melinda A Nolan Russell G Snell Klaus Lehnert Lynette G Sadleir Britt-Marie Anderlid Malin Kvarnung Renzo Guerrini Michael J Friez Michael J Lyons Jennifer Leonhard Gabriel Kringlen Kari Casas Christelle M El Achkar Lacey A Smith Alexander Rotenberg Annapurna Poduri Alba Sanchis-Juan Keren J Carss Julia Rankin Adam Zeman F Lucy Raymond Moira Blyth Bronwyn Kerr Karla Ruiz Jill Urquhart Imelda Hughes Siddharth Banka Ulrike B S Hedrich Ingrid E Scheffer Ingo Helbig Gerald W Zamponi Holger Lerche Heather C Mefford

Am J Hum Genet 2019 Mar;104(3):562

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http://dx.doi.org/10.1016/j.ajhg.2019.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407522PMC
March 2019
2 Reads

ACAT: A Fast and Powerful p Value Combination Method for Rare-Variant Analysis in Sequencing Studies.

Am J Hum Genet 2019 Mar;104(3):410-421

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address:

Set-based analysis that jointly tests the association of variants in a group has emerged as a popular tool for analyzing rare and low-frequency variants in sequencing studies. The existing set-based tests can suffer significant power loss when only a small proportion of variants are causal, and their powers can be sensitive to the number, effect sizes, and effect directions of the causal variants and the choices of weights. Here we propose an aggregated Cauchy association test (ACAT), a general, powerful, and computationally efficient p value combination method for boosting power in sequencing studies. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407498PMC
March 2019
8 Reads

A Global Collaborative to Advance Genomic Medicine.

Am J Hum Genet 2019 Mar;104(3):407-409

The Global Genomic Medicine Collaborative, The Duke Center for Applied Genomics & Precision Medicine, Durham, NC 27708, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2019.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407494PMC

2018 Victor A. McKusick Leadership Award: Molecular Mechanisms for Genomic and Chromosomal Rearrangements.

Authors:
James R Lupski

Am J Hum Genet 2019 Mar;104(3):391-406

Department of Molecular and Human Genetics, Baylor College of Medicine, and Texas Children's Hospital, Houston, TX 77030, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2018.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407437PMC

2018 Victor A. McKusick Leadership Award Introduction: James R. Lupski.

Authors:
David Valle

Am J Hum Genet 2019 Mar;104(3):389-390

McKusick-Nathans Institute of Genetic Medicine, the Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2019.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407521PMC

2018 Curt Stern Award Address.

Authors:
Sekar Kathiresan

Am J Hum Genet 2019 Mar;104(3):384-388

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114 USA; Cardiovascular Disease Initiative, Broad Institute, Cambridge, MA, 02142 USA; Department of Medicine, Harvard Medical School, Boston, MA, 02115 USA. Electronic address:

This article is based on the address given by the author at the meeting of the American Society of Human Genetics (ASHG) on October 18, 2018, in San Diego, California. The audio of the original address can be found at the ASHG website. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407492PMC

2018 William Allan Award: Discovering the Genes for Common Disease: From Families to Populations.

Authors:
Eric S Lander

Am J Hum Genet 2019 Mar;104(3):375-383

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2019.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407606PMC

2018 William Allan Award Introduction: Eric S. Lander.

Authors:
Mark J Daly

Am J Hum Genet 2019 Mar;104(3):373-374

Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Institute for Molecular Medicine Finland, Helsinki 00290, Finland. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407490PMC

2018 Presidential Address: Who Are We?

Authors:
David L Nelson

Am J Hum Genet 2019 Mar;104(3):363-372

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2019.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407491PMC

2018 ASHG Awards and Addresses.

Authors:

Am J Hum Genet 2019 Mar;104(3):361-362

Each year at the annual meeting of The American Society of Human Genetics (ASHG), addresses are given in honor of the Society and a number of award winners. A summary of each of these is provided below. On the following pages, we have printed the Presidential Address as well as the addresses for the William Allan Award, the Curt Stern Award, and the McKusick Leadership Award. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.02.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407489PMC

Discovery of Allele-Specific Protein-RNA Interactions in Human Transcriptomes.

Am J Hum Genet 2019 Mar 28;104(3):492-502. Epub 2019 Feb 28.

Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Gene expression is tightly regulated at the post-transcriptional level through splicing, transport, translation, and decay. RNA-binding proteins (RBPs) play key roles in post-transcriptional gene regulation, and genetic variants that alter RBP-RNA interactions can affect gene products and functions. We developed a computational method ASPRIN (Allele-Specific Protein-RNA Interaction) that uses a joint analysis of CLIP-seq (cross-linking and immunoprecipitation followed by high-throughput sequencing) and RNA-seq data to identify genetic variants that alter RBP-RNA interactions by directly observing the allelic preference of RBP from CLIP-seq experiments as compared to RNA-seq. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407496PMC
March 2019
4 Reads

GRIK5 Genetically Regulated Expression Associated with Eye and Vascular Phenomes: Discovery through Iteration among Biobanks, Electronic Health Records, and Zebrafish.

Am J Hum Genet 2019 Mar 28;104(3):503-519. Epub 2019 Feb 28.

Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Data Science Institute, Vanderbilt University, Nashville, TN 37232, USA. Electronic address:

Although the use of model systems for studying the mechanism of mutations that have a large effect is common, we highlight here the ways that zebrafish-model-system studies of a gene, GRIK5, that contributes to the polygenic liability to develop eye diseases have helped to illuminate a mechanism that implicates vascular biology in eye disease. A gene-expression prediction derived from a reference transcriptome panel applied to BioVU, a large electronic health record (EHR)-linked biobank at Vanderbilt University Medical Center, implicated reduced GRIK5 expression in diverse eye diseases. We tested the function of GRIK5 by depletion of its ortholog in zebrafish, and we observed reduced blood vessel numbers and integrity in the eye and increased vascular permeability. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407495PMC
March 2019
2 Reads

Recent Adaptive Acquisition by African Rainforest Hunter-Gatherers of the Late Pleistocene Sickle-Cell Mutation Suggests Past Differences in Malaria Exposure.

Am J Hum Genet 2019 Mar 28;104(3):553-561. Epub 2019 Feb 28.

Human Evolutionary Genetics Unit, Institut Pasteur, UMR 2000 Centre National de la Recherche Scientifique, Paris 75015, France; Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, Paris 75015, France. Electronic address:

The hemoglobin β sickle mutation is a textbook case in which natural selection maintains a deleterious mutation at high frequency in the human population. Homozygous individuals for this mutation develop sickle-cell disease, whereas heterozygotes benefit from higher protection against severe malaria. Because the overdominant β allele should be purged almost immediately from the population in the absence of malaria, the study of the evolutionary history of this iconic mutation can provide important information about the history of human exposure to malaria. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297193005
Publisher Site
http://dx.doi.org/10.1016/j.ajhg.2019.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407493PMC
March 2019
2 Reads

De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome.

Am J Hum Genet 2019 Mar 28;104(3):542-552. Epub 2019 Feb 28.

King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal 23955-6900, Saudi Arabia. Electronic address:

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407605PMC
March 2019
6 Reads
10.931 Impact Factor

Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease.

Am J Hum Genet 2019 Mar 28;104(3):466-483. Epub 2019 Feb 28.

Division of Neurology, the Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X8, Canada; Program in Genetics and Genome Biology, Research Institute, the Hospital for Sick Children, Toronto, ON M5G 0A4, Canada. Electronic address:

Gene-panel and whole-exome analyses are now standard methodologies for mutation detection in Mendelian disease. However, the diagnostic yield achieved is at best 50%, leaving the genetic basis for disease unsolved in many individuals. New approaches are thus needed to narrow the diagnostic gap. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00029297193001
Publisher Site
http://dx.doi.org/10.1016/j.ajhg.2019.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407525PMC
March 2019
3 Reads

Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Authors:
Benjamin Cogné Sophie Ehresmann Eliane Beauregard-Lacroix Justine Rousseau Thomas Besnard Thomas Garcia Slavé Petrovski Shiri Avni Kirsty McWalter Patrick R Blackburn Stephan J Sanders Kévin Uguen Jacqueline Harris Julie S Cohen Moira Blyth Anna Lehman Jonathan Berg Mindy H Li Usha Kini Shelagh Joss Charlotte von der Lippe Christopher T Gordon Jennifer B Humberson Laurie Robak Daryl A Scott Vernon R Sutton Cara M Skraban Jennifer J Johnston Annapurna Poduri Magnus Nordenskjöld Vandana Shashi Erica H Gerkes Ernie M H F Bongers Christian Gilissen Yuri A Zarate Malin Kvarnung Kevin P Lally Peggy A Kulch Brina Daniels Andres Hernandez-Garcia Nicholas Stong Julie McGaughran Kyle Retterer Kristian Tveten Jennifer Sullivan Madeleine R Geisheker Asbjorg Stray-Pedersen Jennifer M Tarpinian Eric W Klee Julie C Sapp Jacob Zyskind Øystein L Holla Emma Bedoukian Francesca Filippini Anne Guimier Arnaud Picard Øyvind L Busk Jaya Punetha Rolph Pfundt Anna Lindstrand Ann Nordgren Fayth Kalb Megha Desai Ashley Harmon Ebanks Shalini N Jhangiani Tammie Dewan Zeynep H Coban Akdemir Aida Telegrafi Elaine H Zackai Amber Begtrup Xiaofei Song Annick Toutain Ingrid M Wentzensen Sylvie Odent Dominique Bonneau Xénia Latypova Wallid Deb Sylvia Redon Frédéric Bilan Marine Legendre Caitlin Troyer Kerri Whitlock Oana Caluseriu Marine I Murphree Pavel N Pichurin Katherine Agre Ralitza Gavrilova Tuula Rinne Meredith Park Catherine Shain Erin L Heinzen Rui Xiao Jeanne Amiel Stanislas Lyonnet Bertrand Isidor Leslie G Biesecker Dan Lowenstein Jennifer E Posey Anne-Sophie Denommé-Pichon Claude Férec Xiang-Jiao Yang Jill A Rosenfeld Brigitte Gilbert-Dussardier Séverine Audebert-Bellanger Richard Redon Holly A F Stessman Christoffer Nellaker Yaping Yang James R Lupski David B Goldstein Evan E Eichler Francois Bolduc Stéphane Bézieau Sébastien Küry Philippe M Campeau

Am J Hum Genet 2019 Mar 28;104(3):530-541. Epub 2019 Feb 28.

Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada. Electronic address:

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407527PMC
March 2019
8 Reads
10.931 Impact Factor

Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails.

Am J Hum Genet 2019 Mar 26;104(3):520-529. Epub 2019 Feb 26.

Department of Clinical Genetics, Erasmus Medical Center, University Medical Center, 3015 GD Rotterdam, the Netherlands.

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging tRNA molecules with cognate amino acids. Consistent with the essential function and ubiquitous expression of ARSs, mutations in 32 of the 37 ARS-encoding loci cause severe, early-onset recessive phenotypes. Previous genetic and functional data suggest a loss-of-function mechanism; however, our understanding of the allelic and locus heterogeneity of ARS-related disease is incomplete. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407526PMC
March 2019
1 Read