Viviana Tritto, Paola Bettinaglio, Eleonora Mangano, Claudia Cesaretti, Federica Marasca, Chiara Castronovo, Roberta Bordoni, Cristina Battaglia, Veronica Saletti, Valeria Ranzani, Beatrice Bodega, Marica Eoli, Federica Natacci, Paola Riva
NF1 microdeletion syndrome, accounting for 5-11% of NF1 patients, is caused by a deletion in the NF1 region and it is generally characterized by a severe phenotype. Although 70% of NF1 microdeletion patients presents the same 1.4 Mb type-I deletion, some patients may show additional clinical features. Therefore, the contribution of several pathogenic mechanisms, besides haploinsufficiency of some genes within the deletion interval, is expected and needs to be defined. We investigated an altered expression of deletion flanking genes by qPCR in patients with type-1 NF1 deletion, compared to healthy donors, possibly contributing to the clinical traits of NF1 microdeletion syndrome...
June 14, 2024: Human Genetics
Kexin Zhang, Shengxiong Wang, Ying Qiu, Baoling Bai, Qin Zhang, Xianghui Xie
Hypospadias refers to the abnormal position of the male urethral orifice, which not only leads to urination disorder but also causes sexual dysfunction in adulthood. However, the complex and diverse pathogenic factors of hypospadias are still unclear. To study the pathogenesis and prognosis of hypospadias, we counted the serological indexes of children with hypospadias, and found that sSBP, TC and LDL increased in children with mild, moderate and severe hypospadias. Subsequently, we used quantitative proteomics to find differential proteins in mild, moderate and severe hypospadias...
June 8, 2024: Human Genetics
Jun Chen, Licong Shen, Tingting Wu, Yongwen Yang
Endometriosis is characterized by the ectopic proliferation of endometrial cells, posing considerable diagnostic and therapeutic challenges. Our study investigates AGPAT4's involvement in endometriosis pathogenesis, aiming to unveil new therapeutic targets. Our investigation by analyzing eQTL data from GWAS for preliminary screening. Subsequently, within the GEO dataset, we utilized four machine learning algorithms to precisely identify risk-associated genes. Gene validity was confirmed through five Mendelian Randomization methods...
June 8, 2024: Human Genetics
Weiwei Shi, Jiahui Song, January Mikolaj Weiner, Avneesh Chopra, Henrik Dommisch, Dieter Beule, Arne S Schaefer
The long noncoding RNA CDKN2B-AS1 harbors a major coronary artery disease risk haplotype, which is also associated with progressive forms of the oral inflammatory disease periodontitis as well as myocardial infarction (MI). Despite extensive research, there is currently no broad consensus on the function of CDKN2B-AS1 that would explain a common molecular role of this lncRNA in these diseases. Our aim was to investigate the role of CDKN2B-AS1 in gingival cells to better understand the molecular mechanisms underlying the increased risk of progressive periodontitis...
June 4, 2024: Human Genetics
Pallawi Kumari, Manmeet Kaur, Kiran Dindhoria, Bruce Ashford, Shanika L Amarasinghe, Amarinder Singh Thind
Long-read single-cell transcriptomics (scRNA-Seq) is revolutionizing the way we profile heterogeneity in disease. Traditional short-read scRNA-Seq methods are limited in their ability to provide complete transcript coverage, resolve isoforms, and identify novel transcripts. The scRNA-Seq protocols developed for long-read sequencing platforms overcome these limitations by enabling the characterization of full-length transcripts. Long-read scRNA-Seq techniques initially suffered from comparatively poor accuracy compared to short read scRNA-Seq...
May 24, 2024: Human Genetics
Niels Vos, Sadegheh Haghshenas, Liselot van der Laan, Perle K M Russel, Kathleen Rooney, Michael A Levy, Raissa Relator, Jennifer Kerkhof, Haley McConkey, Saskia M Maas, Lisenka E L M Vissers, Bert B A de Vries, Rolph Pfundt, Mariet W Elting, Johanna M van Hagen, Nienke E Verbeek, Marjolijn C J Jongmans, Phillis Lakeman, Lynne Rumping, Danielle G M Bosch, Antonio Vitobello, Christel Thauvin-Robinet, Laurence Faivre, Sophie Nambot, Aurore Garde, Marjolaine Willems, David Genevieve, Gaël Nicolas, Tiffany Busa, Annick Toutain, Marion Gérard, Varoona Bizaoui, Bertrand Isidor, Giuseppe Merla, Maria Accadia, Charles E Schwartz, Katrin Ounap, Mariëtte J V Hoffer, Marjan M Nezarati, Marie-José H van den Boogaard, Matthew L Tedder, Curtis Rogers, Alfredo Brusco, Giovanni B Ferrero, Marta Spodenkiewicz, Richard Sidlow, Alessandro Mussa, Slavica Trajkova, Emma McCann, Henry J Mroczkowski, Sandra Jansen, Laura Donker-Kaat, Floor A M Duijkers, Kyra E Stuurman, Marcel M A M Mannens, Mariëlle Alders, Peter Henneman, Susan M White, Bekim Sadikovic, Mieke M van Haelst
Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome...
May 24, 2024: Human Genetics
Elisabetta Di Fede, Antonella Lettieri, Esi Taci, Silvia Castiglioni, Stefano Rebellato, Chiara Parodi, Elisa Adele Colombo, Paolo Grazioli, Federica Natacci, Paola Marchisio, Lidia Pezzani, Grazia Fazio, Donatella Milani, Valentina Massa, Cristina Gervasini
Histone deacetylases (HDACs) are enzymes pivotal for histone modification (i.e. acetylation marks removal), chromatin accessibility and gene expression regulation. Class I HDACs (including HDAC1, 2, 3, 8) are ubiquitously expressed and they often participate in multi-molecular protein complexes. To date, three neurodevelopmental disorders caused by mutations in genes encoding for HDACs (HDAC4, HDAC6 and HDAC8) and thus belonging to the group of chromatinopathies, have been described. We performed whole exome sequencing (WES) for a patient (#249) clinically diagnosed with the chromatinopathy Rubinstein-Taybi syndrome (RSTS) but negative for mutations in RSTS genes, identifying a de novo frameshift variant in HDAC2 gene...
May 16, 2024: Human Genetics
Lama AlAbdi, Teresa Neuhann, Eva-Christina Prott, Ulrike Schön, Firdous Abdulwahab, Eissa Faqeih, Fowzan S Alkuraya
Germline gain of function variants in the oncogene ABL1 cause congenital heart defects and skeletal malformations (CHDSKM) syndrome. Whether a corresponding ABL1 deficiency disorder exists in humans remains unknown although developmental defects in mice deficient for Abl1 support this notion. Here, we describe two multiplex consanguineous families, each segregating a different homozygous likely loss of function variant in ABL1. The associated phenotype is multiple congenital malformations and distinctive facial dysmorphism that are opposite in many ways to CHDSKM...
May 14, 2024: Human Genetics
Brett M Colbert, Cris Lanting, Molly Smeal, Susan Blanton, Derek M Dykxhoorn, Pei-Ciao Tang, Richard L Getchell, Hedwig Velde, Mirthe Fehrmann, Ryan Thorpe, Prem Chapagain, Heidy Elkhaligy, Hannie Kremer, Helger Yntema, Lonneke Haer-Wigman, Shelby Redfield, Tieqi Sun, Saskia Bruijn, Astrid Plomp, Thadé Goderie, Jiddeke van de Kamp, Rolien H Free, Jolien Klein Wassink-Ruiter, Josine Widdershoven, Els Vanhoutte, Liselotte Rotteveel, Marjolein Kriek, Marieke van Dooren, Lies Hoefsloot, Heriette H W de Gier, Amanda Schaefer, Diana Kolbe, Hela Azaiez, Grace Rabie, Armal Aburayyan, Mariana Kawas, Moien Kanaan, Jourdan Holder, Shin-Ichi Usami, Zhengyi Chen, Pu Dai, Jeffrey Holt, Rick Nelson, Byung Yoon Choi, Eliot Shearer, Richard J H Smith, Ronald Pennings, Xue Zhong Liu
TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes...
April 30, 2024: Human Genetics
Bianca E Russell, Wen-Hann Tan
No abstract text is available yet for this article.
April 26, 2024: Human Genetics
Vu Viet Hoang Pham, Toni Rose Jue, Jessica Lilian Bell, Fabio Luciani, Filip Michniewicz, Giuseppe Cirillo, Linda Vahdat, Chelsea Mayoh, Orazio Vittorio
Copper is a vital micronutrient involved in many biological processes and is an essential component of tumour cell growth and migration. Copper influences tumour growth through a process called cuproplasia, defined as abnormal copper-dependent cell-growth and proliferation. Copper-chelation therapy targeting this process has demonstrated efficacy in several clinical trials against cancer. While the molecular pathways associated with cuproplasia are partially known, genetic heterogeneity across different cancer types has limited the understanding of how cuproplasia impacts patient survival...
April 20, 2024: Human Genetics
Sophia Kerns, Katherine A Owen, Dana Schwalbe, Amrie C Grammer, Peter E Lipsky
Systemic Lupus Erythematosus (SLE) is an autoimmune disease with heterogeneous manifestations, including neurological and psychiatric symptoms. Genetic association studies in SLE have been hampered by insufficient sample size and limited power compared to many other diseases. Multiple Sclerosis (MS) is a chronic relapsing autoimmune disease of the central nervous system (CNS) that also manifests neurological and immunological features. Here, we identify a method of leveraging large-scale genome wide association studies (GWAS) in MS to identify novel genetic risk loci in SLE...
April 12, 2024: Human Genetics
Noam Hadar, Vadim Dolgin, Katya Oustinov, Yuval Yogev, Tomer Poleg, Amit Safran, Ofek Freund, Nadav Agam, Matan M Jean, Regina Proskorovski-Ohayon, Ohad Wormser, Max Drabkin, Daniel Halperin, Marina Eskin-Schwartz, Ginat Narkis, Sufa Sued-Hendrickson, Ilana Aminov, Maya Gombosh, Sarit Aharoni, Ohad S Birk
With the increasing importance of genomic data in understanding genetic diseases, there is an essential need for efficient and user-friendly tools that simplify variant analysis. Although multiple tools exist, many present barriers such as steep learning curves, limited reference genome compatibility, or costs. We developed VARista, a free web-based tool, to address these challenges and provide a streamlined solution for researchers, particularly those focusing on rare monogenic diseases. VARista offers a user-centric interface that eliminates much of the technical complexity typically associated with variant analysis...
April 12, 2024: Human Genetics
Johannes Kopp, Leonard A Koch, Hristiana Lyubenova, Oliver Küchler, Manuel Holtgrewe, Andranik Ivanov, Christele Dubourg, Erika Launay, Sebastian Brachs, Stefan Mundlos, Nadja Ehmke, Dominik Seelow, Mélanie Fradin, Uwe Kornak, Björn Fischer-Zirnsak
Generalized lipodystrophy is a feature of various hereditary disorders, often leading to a progeroid appearance. In the present study we identified a missense and a frameshift variant in a compound heterozygous state in SUPT7L in a boy with intrauterine growth retardation, generalized lipodystrophy, and additional progeroid features. SUPT7L encodes a component of the transcriptional coactivator complex STAGA. By transcriptome sequencing, we showed the predicted missense variant to cause aberrant splicing, leading to exon truncation and thereby to a complete absence of SUPT7L in dermal fibroblasts...
April 9, 2024: Human Genetics
Wenqiang Zhang, Jingwei Zhu, Xuan Wu, Tianle Feng, Wei Liao, Xuan Li, Jianci Chen, Li Zhang, Chenghan Xiao, Huijie Cui, Chao Yang, Peijing Yan, Yutong Wang, Mingshuang Tang, Lin Chen, Yunjie Liu, Yanqiu Zou, Xueyao Wu, Ling Zhang, Chunxia Yang, Yuqin Yao, Jiayuan Li, Zhenmi Liu, Xia Jiang, Ben Zhang
While carotid intima-media thickness (cIMT) as a noninvasive surrogate measure of atherosclerosis is widely considered a risk factor for stroke, the intrinsic link underlying cIMT and stroke has not been fully understood. We aimed to evaluate the clinical value of cIMT in stroke through the investigation of phenotypic and genetic relationships between cIMT and stroke. We evaluated phenotypic associations using observational data from UK Biobank (N = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (N = 45,185) and any stroke (AS, Ncase /Ncontrol =40,585/406,111)...
April 5, 2024: Human Genetics
Ahmed N Sahly, Juan Sierra-Marquez, Stefanie Bungert-Plümke, Arne Franzen, Lina Mougharbel, Saoussen Berrahmoune, Christelle Dassi, Chantal Poulin, Myriam Srour, Raul E Guzman, Kenneth A Myers
CLCN4-related disorder is a rare X-linked neurodevelopmental condition with a pathogenic mechanism yet to be elucidated. CLCN4 encodes the vesicular 2Cl- /H+ exchanger ClC-4, and CLCN4 pathogenic variants frequently result in altered ClC-4 transport activity. The precise cellular and molecular function of ClC-4 remains unknown; however, together with ClC-3, ClC-4 is thought to have a role in the ion homeostasis of endosomes and intracellular trafficking. We reviewed our research database for patients with CLCN4 variants and epilepsy, and performed thorough phenotyping...
April 5, 2024: Human Genetics
Maolin Ding, Ken Chen, Yuedong Yang, Huiying Zhao
Genetic diseases are mostly implicated with genetic variants, including missense, synonymous, non-sense, and copy number variants. These different kinds of variants are indicated to affect phenotypes in various ways from previous studies. It remains essential but challenging to understand the functional consequences of these genetic variants, especially the noncoding ones, due to the lack of corresponding annotations. While many computational methods have been proposed to identify the risk variants. Most of them have only curated DNA-level and protein-level annotations to predict the pathogenicity of the variants, and others have been restricted to missense variants exclusively...
April 4, 2024: Human Genetics
Cristian Riccio, Max L Jansen, Linlin Guo, Andreas Ziegler
Large-scale association analyses using whole-genome sequence data have become feasible, but understanding the functional impacts of these associations remains challenging. Although many tools are available to predict the functional impacts of genetic variants, it is unclear which tool should be used in practice. This work provides a practical guide to assist in selecting appropriate tools for variant annotation. We conducted a MEDLINE search up to November 10, 2023, and included tools that are applicable to a broad range of phenotypes, can be used locally, and have been recently updated...
April 4, 2024: Human Genetics
Alejandro Ferrer, Patrick Duffy, Rory J Olson, Michael A Meiners, Laura Schultz-Rogers, Erica L Macke, Stephanie Safgren, Joel A Morales-Rosado, Margot A Cousin, Gavin R Oliver, David Rider, Megan Williams, Pavel N Pichurin, David R Deyle, Eva Morava, Ralitza H Gavrilova, Radhika Dhamija, Klass J Wierenga, Brendan C Lanpher, Dusica Babovic-Vuksanovic, Charu Kaiwar, Carolyn R Vitek, Tammy M McAllister, Myra J Wick, Lisa A Schimmenti, Konstantinos N Lazaridis, Filippo Pinto E Vairo, Eric W Klee
Most rare disease patients (75-50%) undergoing genomic sequencing remain unsolved, often due to lack of information about variants identified. Data review over time can leverage novel information regarding disease-causing variants and genes, increasing this diagnostic yield. However, time and resource constraints have limited reanalysis of genetic data in clinical laboratories setting. We developed RENEW, (REannotation of NEgative WES/WGS) an automated reannotation procedure that uses relevant new information in on-line genomic databases to enable rapid review of genomic findings...
March 27, 2024: Human Genetics
Md Moksedul Momin, Xuan Zhou, Elina Hyppönen, Beben Benyamin, S Hong Lee
While cholesterol is essential, a high level of cholesterol is associated with the risk of cardiovascular diseases. Genome-wide association studies (GWASs) have proven successful in identifying genetic variants that are linked to cholesterol levels, predominantly in white European populations. However, the extent to which genetic effects on cholesterol vary across different ancestries remains largely unexplored. Here, we estimate cross-ancestry genetic correlation to address questions on how genetic effects are shared across ancestries...
March 27, 2024: Human Genetics
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