scholarly journals Rare variants in axonogenesis genes connect three families with sound–color synesthesia

2018 ◽  
Vol 115 (12) ◽  
pp. 3168-3173 ◽  
Author(s):  
Amanda K. Tilot ◽  
Katerina S. Kucera ◽  
Arianna Vino ◽  
Julian E. Asher ◽  
Simon Baron-Cohen ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Rare Variants ◽  
Autism Spectrum ◽  
Sensory Experiences ◽  
Limited Success ◽  
Whole Exome ◽  
Rare Genetic Variants ◽  
Sound Color ◽  
Stimulation Of

Synesthesia is a rare nonpathological phenomenon where stimulation of one sense automatically provokes a secondary perception in another. Hypothesized to result from differences in cortical wiring during development, synesthetes show atypical structural and functional neural connectivity, but the underlying molecular mechanisms are unknown. The trait also appears to be more common among people with autism spectrum disorder and savant abilities. Previous linkage studies searching for shared loci of large effect size across multiple families have had limited success. To address the critical lack of candidate genes, we applied whole-exome sequencing to three families with sound–color (auditory–visual) synesthesia affecting multiple relatives across three or more generations. We identified rare genetic variants that fully cosegregate with synesthesia in each family, uncovering 37 genes of interest. Consistent with reports indicating genetic heterogeneity, no variants were shared across families. Gene ontology analyses highlighted six genes—COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2—associated with axonogenesis and expressed during early childhood when synesthetic associations are formed. These results are consistent with neuroimaging-based hypotheses about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences.

scholarly journals Gene-level analysis of rare variants in 363,977 whole exome sequences reveals an association of GIGYF1 loss of function with diabetes

2021 ◽  
Author(s):  
Aimee M. Deaton ◽  
Margaret M. Parker ◽  
Lucas D. Ward ◽  
Alexander O. Flynn-Carroll ◽  
Lucas BonDurant ◽  
...  
Keyword(s):  
Rare Variants ◽  
Loss Of Function ◽  
Cholesterol Levels ◽  
Whole Exome ◽  
Increased Risk ◽  
Gene Level ◽  
Rare Genetic Variants ◽  
The Uk ◽  
Novel Associations

AbstractSequencing of large cohorts offers an unprecedented opportunity to identify rare genetic variants and to find novel contributors to human disease. We used gene-based collapsing tests to identify genes associated with glucose, HbA1c and T2D diagnosis in 363,977 exome-sequenced participants in the UK Biobank. We identified known associations with diabetes including variants in GCK, HNF1A and PDX1, genes involved in Mendelian forms of diabetes. Novel associations were identified for GIGYF1 predicted loss of function (pLOF), TNRC6B pLOF and PFAS predicted damaging missense variants. Multiple rare variants contributed to these associations, including singleton variants. The most significant novel associations were seen for GIGYF1 pLOF which associated with increased levels of glucose (0.77 mmol/L increase, p = 4.42 × 10−12) and HbA1c (4.33 mmol/mol, p = 1.28 × 10−14) as well as T2D diagnosis (OR = 4.15, p= 6.14 x10−11). GIGYF1 pLOF also associated with decreased cholesterol levels as well as an increased risk of hypothyroidism. An independent common variant association for glucose and T2D was identified at GIGYF1 which replicated in additional datasets. Our results highlight the role of GIGYF1 in regulating insulin signaling and protecting from diabetes.

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

2021 ◽  
Author(s):  
Amein Kadhem AlAli ◽  
Abdulrahman Al-Enazi ◽  
Ahmed Ammar ◽  
Mahmoud Hajj ◽  
Cyril Cyrus ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
High Rate ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants ◽  
Unknown Significance ◽  
Rare Genetic Variants

Abstract Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian Epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity amongst large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known Epilepsy related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline based variant prioritization approach in an attempt to discover putative causative variants. We identified a 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi Epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity were observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants known to be epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci have been identified which may be prioritized for further investigation.

scholarly journals Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses

2020 ◽  
Vol 9 (6) ◽  
pp. 1851
Author(s):  
Bàrbara Torrico ◽  
Ester Antón-Galindo ◽  
Noèlia Fernàndez-Castillo ◽  
Eva Rojo-Francàs ◽  
Sadaf Ghorbani ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Psychiatric Disorders ◽  
Rare Variants ◽  
Neurological Diseases ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Risk Variants ◽  
Whole Exome ◽  
Target Binding ◽  
Functional Analyses

The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10−7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia.

scholarly journals HCV and Lymphoproliferation

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Anna Linda Zignego ◽  
Carlo Giannini ◽  
Laura Gragnani
Keyword(s):  
Molecular Mechanisms ◽  
Public Health Problem ◽  
Viral Proteins ◽  
Mixed Cryoglobulinemia ◽  
Lymphoproliferative Disorders ◽  
Hcv Infection ◽  
Ideal Model ◽  
The Past ◽  
Stimulation Of

Hepatitis C virus (HCV) infection is a serious public health problem because of its worldwide diffusion and sequelae. It is not only a hepatotropic but also a lymphotropic agent and is responsible not only for liver injury—potentially evolving to cirrhosis and hepatocellular carcinoma—but also for a series of sometimes severely disabling extrahepatic diseases and, in particular, B-cell lymphoproliferative disorders. These latter range from benign, but prelymphomatous conditions, like mixed cryoglobulinemia, to frank lymphomas. Analogously withHelicobacter pylorirelated lymphomagenesis, the study of the effects of viral eradication confirmed the etiopathogenetic role of HCV and showed it is an ideal model for better understanding of the molecular mechanisms involved. Concerning these latter, several hypotheses have been proposed over the past two decades which are not mutually exclusive. These hypotheses have variously emphasized the important role played by sustained stimulation of the immune system by HCV, infection of the lymphatic cells, viral proteins, chromosomal aberrations, cytokines, or microRNA molecules. In this paper we describe the main hypotheses that have been proposed with the corresponding principal supporting data.

scholarly journals Rare CYLD Variants in Chinese Patients With Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaojing Gu ◽  
Yongping Chen ◽  
Qianqian Wei ◽  
Yanbing Hou ◽  
Bei Cao ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Rare Variants ◽  
Chinese Patients ◽  
Causative Gene ◽  
Missense Variants ◽  
Whole Exome ◽  
Sporadic Als ◽  
Als Patients ◽  
Lateral Sclerosis

Background: CYLD Lysine 63 Deubiquitinase gene (CYLD) was recently identified to be a novel causative gene for frontal temporal dementia (FTD)-amyotrophic lateral sclerosis (ALS). In the current study, we aimed to (1) systematically screen the mutations of CYLD in a large cohort of Chinese ALS patients, (2) study the genotype–phenotype correlation, and (3) explore the role of CYLD in ALS via rare variants burden analysis.Methods: A total of 978 Chinese sporadic ALS (sALS) patients and 46 familial ALS (fALS) patients were sequenced with whole-exome sequencing and analyzed rare variants in CYLD with minor allele frequency <0.1%.Results: In total, seven rare missense variants in CYLD have been identified in 7 (0.72%) patients among 978 sALS patients. Two (4.3%) rare missense variants were identified among the 46 fALS cases, in which one patient was diagnosed as having comorbidity of ALS and progressive supranuclear palsy (PSP). Moreover, the burden analysis indicated no enrichment of rare variants in CYLD among patients with ALS.Conclusion: In conclusion, our study extended the genotype and phenotype of CYLD in ALS, but the pathogenicity of these variants needs to be further verified. Moreover, burden analysis argued against the role of CYLD in the pathogenesis of ALS. More studies from different ethnicities would be needed.

scholarly journals Lnc-EPB41-Protein Interactions Associated with Congenital Pouch Colon

Biomolecules ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. 95 ◽  
Author(s):  
Sonal Gupta ◽  
Nidhi Gupta ◽  
Pradeep Tiwari ◽  
Saji Menon ◽  
Praveen Mathur ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Rare Variants ◽  
Clinical Genetic ◽  
Northwestern India ◽  
Whole Exome ◽  
Congenital Pouch Colon ◽  
Pouch Colon ◽  
Non Coding Rnas ◽  
Polymerase Chain

Congenital Pouch Colon (CPC) is a rare anorectal anomaly common to northwestern India, specifically Rajasthan. Despite efforts to understand the clinical genetic makeup of CPC, no attempt on identifying non-coding RNAs was done. We have earlier reported CPC’s rare variants from whole exome sequencing (WES) across 18 affected samples in a total of 64 subjects. A Smith–Waterman algorithm was used to infer a couple of lncRNAs from WES samples of CPC with predictions from the Noncode database. Further screening and quantification using polymerase chain reaction (PCR), we ascertained interactions using Micro Scale Thermophoresis (MST). We report the role of lnc-EPB41-1-1 shown to be promiscuously interacting with KIF13A substantiating their role in regulation.

scholarly journals Database for Gene Variants and Metabolic Networks Implicated in Familial Gastroschisis

Data ◽  
2019 ◽  
Vol 4 (3) ◽  
pp. 97 ◽  
Author(s):  
Víctor M. Salinas-Torres ◽  
Hugo L. Gallardo-Blanco ◽  
Rafael A. Salinas-Torres ◽  
Laura E. Martínez de Villarreal
Keyword(s):  
Metabolic Networks ◽  
Body Wall ◽  
Molecular Mechanisms ◽  
Machine Learning Techniques ◽  
Gene Variants ◽  
Gene Variation ◽  
Technological Advances ◽  
Learning Techniques ◽  
Whole Exome

Gastroschisis is one of the most prevalent human birth defects concerning the ventral body wall development. Recent research has given a better understanding of gastroschisis pathogenesis through the identification of multiple novel pathogenetic pathways implicated in ventral body wall closure. Deciphering the underlying genetic factors segregating among familial gastroschisis allows better detection of novel susceptibility variants than the screening of pooled unrelated cases and controls, whereas bioinformatic-aided analysis can help to address new insights into human biology and molecular mechanisms involved in gastroschisis. Technological advances in DNA sequencing (Next Generation Sequencing), computing power, and machine learning techniques provide opportunities to the scientific communities to assess significant gaps in research and clinical practice. Thus, in an effort to study the role of gene variation in gastroschisis, we employed whole exome sequencing in a Mexican family with recurrence for gastroschisis. Stringent bioinformatic analyses were implemented to identify and predict pathogenetic networks comprised of potential gastroschisis predispositions. This is the first database for gene variants and metabolic networks implicated in familial gastroschisis. The dataset provides information on gastroschisis annotated genes, gene variants, and metabolic networks and constitutes a useful source to enhance further investigations in gastroschisis.

Novel Rare SORL1 Variants in Early-Onset Dementia

2021 ◽  
pp. 1-10
Author(s):  
Anita Korpioja ◽  
Johanna Krüger ◽  
Susanna Koivuluoma ◽  
Katri Pylkäs ◽  
Virpi Moilanen ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Early Onset ◽  
Rare Variants ◽  
Late Onset ◽  
Age At Onset ◽  
Early Onset Dementia ◽  
Missense Variants ◽  
Whole Exome ◽  
Increased Risk

Background: Rare variants of SORL1 have been associated with an increased risk of early-onset or late-onset Alzheimer’s disease (AD). However, a lot remains to be clarified about their significance in the pathogenesis of the disease. Objective: To evaluate the role of SORL1 variants among Finnish patients with early-onset AD (EOAD). Methods: The rare SORL1variants were screened in a cohort of 115 Finnish EOAD patients (mean age at onset 58.3 years, range 46–65 years) by using the whole-exome sequencing. Results: We found one novel nonsense variant (p.Gln290 *) and eight missense variants in SORL1. This is the first study reporting the SORL1 variants p.Lys80Arg, p.Ala789Val and p.Arg866Gln in EOAD patients. Furthermore, two of these three missense variants were overrepresented in EOAD patients compared to gnomAD non-neuro Finnish samples. Conclusion: This study strengthens the earlier findings, that the rare variants in SORL1 are associated with EOAD.

Rare Variants Analysis of Lysosomal Related Genes in Early-Onset and Familial Parkinson’s Disease in a Chinese Cohort

2021 ◽  
pp. 1-11
Author(s):  
Yong-Ping Chen ◽  
Xiao-Jing Gu ◽  
Wei Song ◽  
Yan-Bing Hou ◽  
Ru-Wei Ou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
Rare Variants ◽  
Lysosomal Storage ◽  
Asian Populations ◽  
Whole Exome ◽  
Gene Level ◽  
Chinese Cohort

Background: Genetic studies have indicated that variants in several lysosomal genes are risk factors for idiopathic Parkinson’s disease (PD). However, the role of lysosomal genes in PD in Asian populations is largely unknown. Objective: This study aimed to analyze rare variants in lysosomal related genes in Chinese population with early-onset and familial PD. Methods: In total, 1,136 participants, including 536 and 600 patients with sporadic early-onset PD (SEOPD) and familial PD, respectively, underwent whole-exome sequencing to assess the genetic etiology. Rare variants in PD were investigated in 67 candidate lysosomal related genes (LRGs), including 15 lysosomal function-related genes and 52 lysosomal storage disorder genes. Results: Compared with the autosomal dominant PD (ADPD) or SEOPD cohorts, a much higher proportion of patients with multiple rare damaging variants of LRGs were found in the autosomal recessive PD (ARPD) cohort. At a gene level, rare damaging variants in GBA and MAN2B1 were enriched in PD, but in SCARB2, MCOLN1, LYST, VPS16, and VPS13C were much less in patients. At an allele level, GBA p. Leu483Pro was found to increase the risk of PD. Genotype-phenotype correlation showed no significance in the clinical features among patients carrying a discrepant number of rare variants in LRGs. Conclusion: Our study suggests rare variants in LRGs might be more important in the pathogenicity of ARPD cases compared with ADPD or SEOPD. We further confirm rare variants in GBA are involve in PD pathogenecity and other genes associated with PD identified in this study should be supported with more evidence.

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