68 results found
Leggatt G, Cheng G, Narain S, et al., 2023, A genotype-to-phenotype approach suggests under-reporting of single nucleotide variants in nephrocystin-1 (NPHP1) related disease (UK 100,000 Genomes Project)., Sci Rep, Vol: 13
Autosomal recessive whole gene deletions of nephrocystin-1 (NPHP1) result in abnormal structure and function of the primary cilia. These deletions can result in a tubulointerstitial kidney disease known as nephronophthisis and retinal (Senior-Løken syndrome) and neurological (Joubert syndrome) diseases. Nephronophthisis is a common cause of end-stage kidney disease (ESKD) in children and up to 1% of adult onset ESKD. Single nucleotide variants (SNVs) and small insertions and deletions (Indels) have been less well characterised. We used a gene pathogenicity scoring system (GenePy) and a genotype-to-phenotype approach on individuals recruited to the UK Genomics England (GEL) 100,000 Genomes Project (100kGP) (n = 78,050). This approach identified all participants with NPHP1-related diseases reported by NHS Genomics Medical Centres and an additional eight participants. Extreme NPHP1 gene scores, often underpinned by clear recessive inheritance, were observed in patients from diverse recruitment categories, including cancer, suggesting the possibility of a more widespread disease than previously appreciated. In total, ten participants had homozygous CNV deletions with eight homozygous or compound heterozygous with SNVs. Our data also reveals strong in-silico evidence that approximately 44% of NPHP1 related disease may be due to SNVs with AlphaFold structural modelling evidence for a significant impact on protein structure. This study suggests historical under-reporting of SNVS in NPHP1 related diseases compared with CNVs.
Need AC, Goldstein DB, 2022, Neuropsychiatric Genomics in Precision Medicine: Diagnostics, Gene discovery, and Translation, Dialogues in Clinical Neuroscience, ISSN: 1958-5969
Only a few years after its development, next generation sequencing is rapidly becoming an essential part of clinical care for patients with serious neurological conditions, especially in the diagnosis of early onset and severe presentations. Beyond this diagnostic role, there has been an explosion in definitive gene discovery in a range of neuropsychiatric diseases. This is providing new pointers to underlying disease biology, and beginning to outline a new framework for genetic stratification of neuropsychiatric disease, with clear relevance to both individual treatment optimization and clinical trial design. Here we outline these developments and chart the expected impact on the treatment of neurological, neurodevelopmental and psychiatric disease.
McGuigan A, Whitworth J, Andreou A, et al., 2022, Multilocus Inherited Neoplasia Allele Syndrome (MINAS): an update., Eur J Hum Genet, Vol: 30, Pages: 265-270
Multi-locus Inherited Neoplasia Allele Syndrome (MINAS) refers to individuals with germline pathogenic variants in two or more cancer susceptibility genes(CSGs). With increased use of exome/genome sequencing it would be predicted that detection of MINAS would become more frequent. Here we review recent progress in knowledge of MINAS. A systematic literature search for reports of individuals with germline pathogenic variants in 2 or more of 94 CSGs was performed. In addition, participants with multiple primary tumours who underwent genome sequencing as part of the Rare Disease arm of the UK 100,000 Genomes Project were interrogated to detect additional cases. We identified 385 MINAS cases (211 reported in the last 5 years, 6 from 100,000 genomes participants). Most (287/385) cases contained at least one pathogenic variant in either BRCA1 or BRCA2. 108/385 MINAS cases had multiple primary tumours at presentation and a subset of cases presented unusual multiple tumour phenotypes. We conclude that, as predicted, increasing numbers of individuals with MINAS are being have been reported but, except for individuals with BRCA1/BRCA2 MINAS, individual CSG combinations are generally rare. In many cases it appears that the clinical phenotype is that which would be expected from the effects of the constituent CSG variants acting independently. However, in some instances the presence of unusual tumour phenotypes and/or multiple primary tumours suggests that there may be complex interactions between the relevant MINAS CSGs. Systematic reporting of MINAS cases in a MINAS database (e.g. https://databases.lovd.nl/shared/diseases/04296 ) will facilitate more accurate prognostic predictions for specific CSG combinations.
Lam M, Chen C-Y, Ge T, et al., 2021, Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics, NEUROPSYCHOPHARMACOLOGY, Vol: 46, Pages: 1788-1801, ISSN: 0893-133X
Zou X, Koh GCC, Nanda AS, et al., 2021, A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage, NATURE CANCER, Vol: 2
Sato MS, Kyriakopoulos M, James A, et al., 2020, Hemizygous mutations in <i>L1CAM</i> in two unrelated male probands with childhood onset psychosis, PSYCHIATRIC GENETICS, Vol: 30, Pages: 73-82, ISSN: 0955-8829
Freeman TM, Wang D, Harris J, et al., 2020, Genomic loci susceptible to systematic sequencing bias in clinical whole genomes, GENOME RESEARCH, Vol: 30, Pages: 415-426, ISSN: 1088-9051
Cacheiro P, Munoz-Fuentes V, Murray SA, et al., 2020, Human and mouse essentiality screens as a resource for disease gene discovery, NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723
Wheway G, Ambrose JC, Baple EL, et al., 2019, Opportunities and Challenges for Molecular Understanding of Ciliopathies-The 100,000 Genomes Project (vol 10, 127, 2019), FRONTIERS IN GENETICS, Vol: 10
Lam M, Hill WD, Trampush JW, et al., 2019, Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 105, Pages: 334-350, ISSN: 0002-9297
Davies G, Lam M, Harris SE, et al., 2019, Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function (vol 9, 2098, 2018), NATURE COMMUNICATIONS, Vol: 10, ISSN: 2041-1723
Shashi V, Schoch K, Spillmann R, et al., 2019, A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative, GENETICS IN MEDICINE, Vol: 21, Pages: 161-172, ISSN: 1098-3600
Lam M, Trampush JW, Yu J, et al., 2018, Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018), TWIN RESEARCH AND HUMAN GENETICS, Vol: 21, Pages: 394-397, ISSN: 1832-4274
Liu N, Schoch K, Luo X, et al., 2018, Functional variants in <i>TBX2</i> are associated with a syndromic cardiovascular and skeletal developmental disorder, HUMAN MOLECULAR GENETICS, Vol: 27, Pages: 2454-2465, ISSN: 0964-6906
Savage JE, Jansen PR, Stringer S, et al., 2018, Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence, Nature Genetics, Vol: 50, Pages: 912-919, ISSN: 1061-4036
Intelligence is highly heritable1 and a major determinant of human health and well-being. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer’s disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Davies G, Lam M, Harris SE, et al., 2018, Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function, Nature Communications, Vol: 9, ISSN: 2041-1723
General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16–102) and find 148 genome-wide significant independent loci (P < 5 × 10−8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
Savage JE, Jansen PR, Stringer S, et al., 2018, GWAS meta-analysis (N=279,930) identifies new genes and functional links to general cognitive ability, Publisher: BIOMED CENTRAL LTD, ISSN: 1473-9542
Sato MS, Need AC, 2018, Genetics of Childhood-Onset Psychosis, Publisher: BIOMED CENTRAL LTD, ISSN: 1473-9542
Lam M, Trampush JW, Yu J, et al., 2017, Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets., Cell Reports, Vol: 21, Pages: 2597-2613, ISSN: 2211-1247
Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.
Trampush JW, Yang MLZ, Yu J, et al., 2017, GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium (vol 22, pg 336, 2017), Molecular Psychiatry, Vol: 22, Pages: 1651-1652, ISSN: 1359-4184
Trampush J, Zhan Yang ML, Yu J, et al., 2017, GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: A report from the COGENT consortium, Molecular Psychiatry, Vol: 22, Pages: 336-345, ISSN: 1476-5578
The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single nucleotide polymorphisms with minor allele frequency≥1%) to general cognitive function in a sample of 35,298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). Additionally, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genomewide significance level (P<5⨯10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1, and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e. = .01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight, and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.
Need AC, Shashi V, Schoch K, et al., 2016, The importance of dynamic reanalysis In diagnostic whole exome sequencing, Journal of Medical Genetics, Vol: 54, Pages: 155-156, ISSN: 1468-6244
Shashi V, Pena LD, Kim K, et al., 2016, De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype, American Journal of Human Genetics, Vol: 99, Pages: 991-999, ISSN: 1537-6605
The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder. In this study, we performed whole-exome sequencing in six unrelated probands with developmental delay, macrocephaly, and dysmorphic features. All six had de novo truncating variants in ASXL2. A careful review enabled the recognition of a specific phenotype consisting of macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, hypotonia, and developmental disabilities. Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the ASXL2-associated condition from ASXL1- and ASXL3-related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities. We were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated ASXL2 transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in ASXL2 underlie a neurodevelopmental syndrome with a clinically recognizable phenotype. This report expands the germline disorders that are linked to the ASXL genes.
Shashi V, Xie P, Schoch K, et al., 2015, The <i>RBMX</i> gene as a candidate for the Shashi X-linked intellectual disability syndrome, CLINICAL GENETICS, Vol: 88, Pages: 386-390, ISSN: 0009-9163
Zhu X, Petrovski S, Xie P, et al., 2015, Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios, Genetics in Medicine, Vol: 17, Pages: 774-781, ISSN: 1530-0366
Purpose:Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene–disease associations.Methods:We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients.Results:We obtained a genetic diagnosis for 29 (24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice (P = 3.4 × 10−8). This enrichment is only partially explained by mutations found in known disease-causing genes.Conclusion:This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications.
Enns GM, Shashi V, Bainbridge M, et al., 2014, Mutations in <i>NGLY1</i> cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway, GENETICS IN MEDICINE, Vol: 16, Pages: 751-758, ISSN: 1098-3600
Need AC, Goldstein DB, 2014, Schizophrenia Genetics Comes of Age, NEURON, Vol: 83, Pages: 760-763, ISSN: 0896-6273
Nutt DJ, Need AC, 2014, Where now for schizophrenia research?, EUROPEAN NEUROPSYCHOPHARMACOLOGY, Vol: 24, Pages: 1181-1187, ISSN: 0924-977X
Zhu X, Need AC, Petrovski S, et al., 2014, One gene, many neuropsychiatric disorders: lessons from Mendelian diseases, NATURE NEUROSCIENCE, Vol: 17, Pages: 773-781, ISSN: 1097-6256
Tiwari AK, Need AC, Lohoff FW, et al., 2014, Exome sequence analysis of Finnish patients with clozapine-induced agranulocytosis, MOLECULAR PSYCHIATRY, Vol: 19, Pages: 403-405, ISSN: 1359-4184
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