Hussam Al-Kateb, P Y Billie Au, Siren Berland, Benjamin Cogne, Florence Demurger, Joel Fluss, Bertrand Isidor, L Matthew Frank, Konstantinos Varvagiannis, David A Koolen, Marie McDonald, Sarah Montgomery, Stéphanie Moortgat, Marie Deprez, Deniz Karadurmus, Julie Paulsen, André Reis, Melissa Rieger, Georgia Vasileiou, Marcia Willing, Marwan Shinawi
Calmodulin-binding transcriptional activator 1 (CAMTA1) is highly expressed in the brain and plays a role in cell cycle regulation, cell differentiation, regulation of long-term memory, and initial development, maturation, and survival of cerebellar neurons. The existence of human neurological phenotypes, including cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA), associated with CAMTA1 variants, has further supported its role in brain functions. In this study, we phenotypically and molecularly characterize the largest cohort of individuals (n = 26) with 23 novel CAMTA1 variants (frameshift-7, nonsense-6, splicing-1, initiation codon-1, missense-5, and intragenic deletions-3) and compare the findings with all previously reported cases (total = 53)...
December 3, 2023: Clinical Genetics
Claudia Strafella, Luca Colantoni, Domenica Megalizzi, Giulia Trastulli, Emma Proietti Piorgo, Guido Primiano, Cristina Sancricca, Giulia Ricci, Gabriele Siciliano, Carlo Caltagirone, Massimiliano Filosto, Giorgio Tasca, Enzo Ricci, Raffaella Cascella, Emiliano Giardina
Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disease, although 10%-30% of cases are sporadic. However, this percentage may include truly de novo patients (carrying a reduced D4Z4 allele that is not present in either of the parents) and patients with apparently sporadic disease resulting from mosaicism, non-penetrance, or complex genetic situations in either patients or parents. In this study, we characterized the D4Z4 Reduced Alleles (DRA) and evaluated the frequency of truly de novo cases in FSHD1 in a cohort of DNA samples received consecutively for FSHD-diagnostic from 100 Italian families...
December 2, 2023: Clinical Genetics
Yingchao Zhou, Gang Luo, Ai Zhang, Shuai Gao, Yaqi Tang, Zhanhui Du, Silin Pan
Familial hypercholesterolemia (FH) is defined as a monogenic disease, characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels. FH remains underdiagnosed and undertreated in Chinese. We whole-genome sequenced 6820 newborns from Qingdao of China to investigate the FH-related gene (LDLR, APOB, PCSK9) mutation types, carrier ratio and genotype-phenotype correlation. In this study, the prevalence of FH in Qingdao of China was 0.47% (95% CI: 0.32%-0.66%). The plasma lipid levels of FH-related gene mutation carriers begin to increase as early as infant...
November 29, 2023: Clinical Genetics
Amit Jairaman, Vaishnavi Ashok Badiger, Spoorthy Raj, Karthik Vijay Nair, Suma Balan, Dhanya Lakshmi Narayanan
The evolutionarily conserved mevalonate pathway plays an important role in the synthesis of cholesterol and isoprenoid compounds. Mevalonate kinase (MVK) and phosphomevalonate kinase (PMVK) enzymes regulate key rate-limiting steps in this pathway by sequentially phosphorylating mevalonic acid to yield downstream metabolites that regulate protein prenylation and cell signaling. Biallelic pathogenic variants in MVK cause a spectrum of rare autoinflammatory disorders that encompass milder forms of hyper-IgD syndrome (HIDS) at one end and the more severe mevalonic aciduria on the other...
November 28, 2023: Clinical Genetics
Qian Li, Wenbo Li, Kaiyue Hu, Yaqian Wang, Yang Li, Jiawei Xu
Autism spectrum disorder (ASD) is a highly variable neurodevelopmental disorder that typically manifests childhood, characterized by a triad of symptoms: impaired social interaction, communication difficulties, and restricted interests with repetitive behaviors. De novo variants in related genes can cause ASD. We present the case of a 6-year-old Chinese boy with autistic behavior, including language communication impairments, intellectual disabilities, stunted development, and irritability in social interactions...
November 28, 2023: Clinical Genetics
Prajna Udupa, Akshaykumar Nanaji Shrikondawar, Akash Ranjan, Debasish Kumar Ghosh
Osteogenesis imperfecta (OI) is a group of genetic disorders of bone formation characterized by soft and shorter brittle bones in affected individuals. OI is generally considered a collagenopathy resulting from abnormal expression of type I collagen. As assay system to detect the cellular level and quality of type I collagen would help in rapid and correct detection of OI from the diagnostic perspectives. Here, we report an immunofluorescence assay for detection of type I collagen in fibroblast models of OI and represented them into two broad categories based on the expression level and aggregation characteristics of pro-α1(I)...
November 28, 2023: Clinical Genetics
Keqiang Liu, Ru Chen, Minzhong Zhang, Yiming Gong, Yong Wang, Wei Cai
The Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene was first identified as a cause of lethal congenital contracture syndrome (OMIM 607598), while a recent study reported six additional patients carrying ERBB3 variants which exhibited distinct clinical features with evident intestinal dysmotility (OMIM 243180). The potential connection between these phenotypes remains unknown, and the ERBB3-related phenotype spectrum needs to be better characterized. Here, we described a patient presenting with a multisystemic syndrome including skip segment Hirschsprung disease, bilateral clubfoot deformity, and cardiac defect...
November 27, 2023: Clinical Genetics
Changying Li, Ruixiao Zhang, Fengjiao Pan, Qing Xin, Xiaomeng Shi, Wencong Guo, Dan Qiao, Zhi Wang, Yiyin Zhang, Xuyan Liu, Yan Zhang, Leping Shao
Cystinosis is a severe, monogenic systemic disease caused by variants in CTNS gene. Currently, there is growing evidence that exonic variants in many diseases can affect pre-mRNA splicing. The impact of CTNS gene exonic variants on splicing regulation may be underestimated due to the lack of routine studies at the RNA level. Here, we analyzed 59 exonic variants in the CTNS gene using bioinformatics tools and identified candidate variants that may induce splicing alterations by minigene assays. We identified six exonic variants that induce splicing alterations by disrupting the ratio of exonic splicing enhancers/exonic splicing silencers (ESEs/ESSs) or by interfering with the recognition of classical splice sites, or both...
November 27, 2023: Clinical Genetics
Sabrina V Southwick, Ian M MacFarlane, Catherine Long, Nishitha R Pillai, Rebecca Tryon
Professional guidelines generally caution against carrier testing in minors, though prior research indicates parents request and providers sometimes facilitate testing for unaffected siblings of a child affected by a genetic disorder. We investigated the perspectives of genetic counselors in North America regarding carrier testing prior to adolescence. Practicing genetic counselors (n = 177) responded to an electronic survey assessing their willingness to facilitate testing in four hypothetical scenarios and their evaluation of parental motivations...
November 23, 2023: Clinical Genetics
Jordi Pijuan, Alba Vilanova-Adell, Dídac Casas-Alba, Jaume Campistol, Janet Hoenicka, Francesc Palau
We studied a patient with a severe phenotype carrying two GNB5 variants: c.514delT from the unaffected heterozygous mother and c.628-6G>A from the unaffected homozygous father. Functional genomics studies showed that parents express 50% (nonsense-mediated decay, NMD) of the RNA/protein while the patient does not produce enough protein for normal development.
November 22, 2023: Clinical Genetics
Silvia Cannova, Camilla Meossi, Federico Grilli, Donatella Milani, Federica Alberti, Claudia Cesaretti, Paola Giovanna Marchisio, Francesca Crosti, Lidia Pezzani
We report the case of a 12-year-old girl and her father who both had marked postnatal tall stature, camptodactyly and clinodactyly, scoliosis and juvenile-onset hearing loss. The CATSHL (CAmptodactyly - Tall stature - Scoliosis - Hearing Loss syndrome) syndrome was suspected, and molecular analysis revealed a hitherto unreported, monoallelic variant c.1861C>T (p.Arg621Cys) in FGFR3. This variant affects the same residue, but is different than, the variant p.Arg621His reported in the two families with dominant CATSHL described so far...
November 22, 2023: Clinical Genetics
Fareeda M Barzak, Anita Lu, Alexa R Geltzeiler, Elizabeth C Ledgerwood, Wendy K Chung, Catherine L Day
A key signalling pathway required for clearance of viruses from host cells relies on the receptor protein, retinoic acid-inducible gene I (RIG-I). The activity of RIG-I is tightly controlled, and once bound to viral dsRNA, addition of lysine 63-linked ubiquitin chains activates signalling. Meanwhile, the addition of lysine 48-linked ubiquitin chains to RIG-I is required to terminate signalling when the infection has been resolved. Really interesting new gene (RING) finger protein 125 (RNF125) is the E3 ligase responsible for addition of the ubiquitin chains that terminate signalling, with disruption of its function associated with Tenorio syndrome...
November 20, 2023: Clinical Genetics
Jiaqi Ji, Xinlong Shi
Gene mutations could predict the tumor progression and prognosis, which are us to predict CLNM in patients with cN0 PTC, however, these results are not consistent. This meta-analysis tried to identify gene mutations which could predict CLNM in patients with cN0 PTC. A systematic search was performed for identifying relevant literature published prior to July 2023 in three search engines: PubMed, EMBASE and Web of Science. Studies that investigated the gene mutations for CLNM in patients with cN0 PTC were included in our meta-analysis...
November 20, 2023: Clinical Genetics
Fadwa Jreijiri, Emma Cavarocchi, Amir Amiri-Yekta, Caroline Cazin, Seyedeh-Hanieh Hosseini, Elma El Khouri, Catherine Patrat, Nicolas Thierry-Mieg, Pierre F Ray, Emmanuel Dulioust, Marjorie Whitfield, Aminata Touré
Sperm flagella share an evolutionary conserved microtubule-based structure with motile cilia expressed at the surface of several cell types, such as the airways epithelial cells. As a result, male infertility can be observed as an isolated condition or a syndromic trait, illustrated by Primary Cilia Dyskinesia (PCD). We report two unrelated patients showing multiple morphological abnormalities of the sperm flagella (MMAF) and carrying distinct homozygous truncating variants in the PCD-associated gene CCDC65...
November 17, 2023: Clinical Genetics
Ming-Ming Ni, Ju-Fei Yang, Jing Miao, Jin Xu
Anthracyclines remain the cornerstone of numerous chemotherapeutic protocols, with beneficial effects against haematological malignancies and solid tumours. Unfortunately, the clinical usefulness of anthracyclines is compromised by the development of cardiotoxic side effects, leading to dose limitations or treatment discontinuation. There is no absolute linear correlation between the incidence of cardiotoxicity and the threshold dose, suggesting that genetic factors may modify the association between anthracyclines and cardiotoxicity risk...
November 14, 2023: Clinical Genetics
Zine-Eddine Kherraf, Anne-Laure Barbotin, Guillaume Martinez, Aurélien Mazet, Caroline Cazin, Charles Coutton, Christophe Arnoult, Nicolas Thierry-Mieg, Nathalie Rives, Aurélie Rives-Feraille, Pierre F Ray
Motile cilia and flagella are closely related organelles structured around a highly conserved axoneme whose formation and maintenance involve proteins from hundreds of genes. Defects in many of these genes have been described to induce primary ciliary dyskinesia (PCD) mainly characterized by chronic respiratory infections, situs inversus and/or infertility. In men, cilia/flagella-related infertility is usually caused by asthenozoospermia due to multiple morphological abnormalities of the sperm flagella (MMAF)...
November 11, 2023: Clinical Genetics
Yi Yang, Man Qin, Yuming Zhao, Xin Wang
Amelogenesis imperfecta (AI) represents a group of clinically and genetically heterogeneous disorders that affect enamel formation and mineralization. Although AI is commonly considered a monogenic disorder, digenic inheritance is rarely reported. In this study, we recruited two nonconsanguineous Chinese families exhibiting diverse phenotypes of enamel defects among affected family members. Digenic variants were discovered in both probands. In family 1, the proband inherited a paternal frameshift variant in LAMA3 (NM_198129...
November 8, 2023: Clinical Genetics
Sunu Kim, Carly Pistawka, Sylvie Langlois, Horacio Osiovich, Alice Virani, Vanessa Kitchin, Alison M Elliott
Genetic and genomic technologies can effectively diagnose numerous genetic disorders. Patients benefit when genetic counselling accompanies genetic testing and international guidelines recommend pre- and post-test genetic counselling with genome-wide sequencing. However, there is a gap in knowledge regarding the unique genetic counselling considerations with different types of genetic testing in the Neonatal Intensive Care Unit (NICU) and the Pediatric Intensive Care Unit (PICU). This scoping review was conducted to identify the gaps in care with respect to genetic counselling for infants/pediatric patients undergoing genetic and genomic testing in NICUs and PICUs and understand areas in need of improvement in order to optimize clinical care for patients, caregivers, and healthcare providers...
November 6, 2023: Clinical Genetics
Claire Perret, Carole Proust, Ulrike Esslinger, Flavie Ader, Jan Haas, Jean-François Pruny, Richard Isnard, Pascale Richard, David-Alexandre Trégouët, Philippe Charron, François Cambien, Eric Villard
Dilated cardiomyopathy (DCM) is a heart disease characterized by left ventricular dilatation and systolic dysfunction. In 30% of cases, pathogenic variants, essentially private to each patient, are identified in at least one of almost 50 reported genes. Thus, while costly, exons capture-based Next Generation Sequencing (NGS) of a targeted gene panel appears as the best strategy to genetically diagnose DCM. Here, we report a NGS strategy applied to pools of 8 DNAs from DCM patients and validate its robustness for rare variants detection at 4-fold reduced cost...
October 30, 2023: Clinical Genetics
Alejandro Parra, Patricia Pascual, Mario Cazalla, Pedro Arias, Natalia Gallego-Zazo, Esteban A San-Martín, Cristina Silván, Fernando Santos-Simarro, Julián Nevado, Jair Tenorio-Castano, Pablo Lapunzina
DDX3X is a multifunctional ATP-dependent RNA helicase involved in several processes of RNA metabolism and in other biological pathways such as cell cycle control, innate immunity, apoptosis and tumorigenesis. Variants in DDX3X have been associated with a developmental disorder named intellectual developmental disorder, X-linked syndromic, Snijders Blok type (MRXSSB, MIM #300958) or DDX3X neurodevelopmental disorder (DDX3X-NDD). DDX3X-NDD is mainly characterized by intellectual disability, brain abnormalities, hypotonia and behavioral problems...
October 30, 2023: Clinical Genetics
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