Clinical Genetics最新文献

{"title":"A Novel Case of Biallelic MLH3 Variants in a Patient With Rectal Cancer and Polyps","authors":"Katrine M. Johannesen,&nbsp;John Gásdal Karstensen,&nbsp;Andreas Ørslev Rasmussen,&nbsp;Emma Adine Hoxer Scott,&nbsp;Ulf Birkedal,&nbsp;Thomas v. O. Hansen,&nbsp;Casper Steenholdt,&nbsp;Anne Marie Jelsig","doi":"10.1111/cge.14689","DOIUrl":"10.1111/cge.14689","url":null,"abstract":"<div>\u0000 \u0000 <p>An increasing number of autosomal recessive forms of adenomatous polyposis have been described, but some in very few cases. Here, we describe a rare case of biallelic germline pathogenic variants in the <i>MLH3</i> gene, implicating it as a potential cause of early colorectal cancer. The patient, a 47-year-old woman, presented with rectal bleeding, leading to the discovery of a malignant rectal tumor and adenomas during colonoscopy. Histopathological examination confirmed adenocarcinoma without microsatellite instability, and genetic testing identified two likely pathogenic frameshift variants in <i>MLH3</i> located in trans. These findings contribute to the expanding knowledge of <i>MLH3</i>-related polyposis and colorectal cancer and underscore the need for further research into the gene's broader implications, including its potential role in cancer and infertility pathways.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 4","pages":"480-482"},"PeriodicalIF":2.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Underpinnings of Oligoasthenoteratozoospermia","authors":"Yanting Feng,&nbsp;Wensheng Liu,&nbsp;Junbo Dong,&nbsp;Fei Lu,&nbsp;Chunyan Wu,&nbsp;Qingting Shao,&nbsp;Aizhu Duan,&nbsp;Xinjie Yang,&nbsp;Ruipeng Sun,&nbsp;Yanwei Sha,&nbsp;Shihao Wu,&nbsp;Xiaoli Wei","doi":"10.1111/cge.14652","DOIUrl":"10.1111/cge.14652","url":null,"abstract":"<div>\u0000 \u0000 <p>Oligoasthenoteratozoospermia (OAT) is a frequent but severe type of male infertility. As one of the most multifaceted male infertility resulting from sperm problems, its genetic etiology remains unknown in most cases. In this review, we systematically sort out the latest literature on clinical reports and animal models leading to OAT, summarise the expression profiles of causative genes for OAT, and highlight the important role of the protein transport system during spermiogenesis, spermatid cell-specific genes, Golgi and acrosome-related genes, manchette-related genes, HTCA-related genes, and axoneme-related genes in OAT development. These causative genes would be instrumental in genetic etiological screening, genetic counseling, and pre-implantation genetic testing of patients with clinical OAT.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 3","pages":"243-260"},"PeriodicalIF":2.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the Genetic and Epidemiological Landscape of Inherited Retinal Diseases (IRDs) in a Cohort of Eastern Iranian Patients","authors":"Reza Mousavi Ardehaie,&nbsp;Atieh Eslahi,&nbsp;Masoome Alerasool,&nbsp;Elham Khani Rad,&nbsp;Nasser Shoeibi,&nbsp;Mohammad Reza Sedaghat,&nbsp;Amir Avan,&nbsp;Alireza Pasdar,&nbsp;Majid Mojarrad","doi":"10.1111/cge.14662","DOIUrl":"https://doi.org/10.1111/cge.14662","url":null,"abstract":"<div>\u0000 \u0000 <p>Inherited retinal diseases (IRDs) may have significant diagnostic challenges due to their genetic complexity and diverse inheritance patterns. Advanced genotyping tools like exome sequencing (ES) offer promising opportunities for identifying causative variants and improving disease management. This retrospective study was aimed to present prevalent pathogenic and novel variants in patients diagnosed with IRDs using ES. We investigated 154 patients diagnosed clinically with IRDs, of which non-syndromic IRDs were more prevalent than syndromic form (~56% vs. ~44%). Out of 154 unrelated patients, 133 (~86%) were genetically resolved, where retinitis pigmentosa was the most common subtype (26% of all resolved patients). Fifty-three previously known and also 56 novel variants across known IRD genes were identified. Autosomal recessive inheritance predominated in both resolved forms (112/133, 84.21%), with 46 novel variants. This could be due to high rate of consanguinity in the studied families (114/133 patients, 85.71%). The two previously reported ancestral founder pathogenic variants in <i>TMEM67</i> (c.725A &gt; G) and <i>BBS2</i> (c.471G &gt; A) genes, as well as the most common variant in <i>AIPL1</i> gene (c.834G &gt; A), were also prevalent in our patients. Interestingly, identical novel compound heterozygote of the <i>CEP290</i> gene (c.3167C &gt; A and c.7024C &gt; T) were identified in two unrelated cases. This retrospective study was the first attempt in terms of sample size and diversity to add more to our current knowledge of the genetic makeup of IRDs in a population from the East of Iran. Our findings can facilitate genetic counselling and subtype classification of IRDs, especially in challenging cases.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 3","pages":"300-310"},"PeriodicalIF":2.9,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143112605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss-of-Function of CLMP Is Associated With Congenital Short Bowel Syndrome and Impaired Intestinal Development","authors":"Shanshan Chen,&nbsp;Juan Xu,&nbsp;Yongtao Xiao,&nbsp;Hui Cai,&nbsp;Jie Zhou,&nbsp;Wei Cai,&nbsp;Ying Wang","doi":"10.1111/cge.14678","DOIUrl":"https://doi.org/10.1111/cge.14678","url":null,"abstract":"<div>\u0000 \u0000 <p>Coxsackie and adenovirus receptor-like membrane protein (CLMP) mutation is identified as a genetic risk factor of congenital short bowel syndrome (CSBS). However, the specific pathogenic mechanism remains unclear. This study aimed to explore the clinical manifestations, genetic characteristics, and molecular mechanisms underlying CSBS caused by CLMP mutations. Whole-exome sequencing was performed to determine the pathogenic gene mutations in children with CSBS and their family members. In addition, a zebrafish model was established by microinjecting morpholinos into zebrafish embryos to investigate the role of <i>clmp</i> in intestinal embryonic development. This was investigated by measuring the length of zebrafish, evaluating gastrointestinal motility, and performing qRT-PCR assays. Two children with CSBS had CLMP mutations, one with a c.244C&gt;T (p.R82*) mutation and exons 3–5 deletion, and the other with a c.23T&gt;A (p.L8*) mutation and exons 3–5 deletion. After knocking down <i>clmp</i> expression in zebrafish embryos, the intestinal length and the gastrointestinal motility decreased. Furthermore, the expression of smooth muscle-associated genes decreased significantly. Additionally, <i>clmp</i> mRNA partially rescued zebrafish defects caused by <i>clmp</i> morpholino knockdown. <i>Clmp</i> knockdown decreased intestinal transport dynamics and expression of smooth muscle-related genes in zebrafish. CLMP is expected to be a potential gene therapeutic target for CSBS.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 4","pages":"413-424"},"PeriodicalIF":2.9,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Splice Site Variant in SENP7 Results in a Severe Form of Arthrogryposis.","authors":"Udhaya Kotecha, Euri S Kim, Parth S Shah, Nidhi Shah, Vandana A Gupta","doi":"10.1111/cge.14698","DOIUrl":"https://doi.org/10.1111/cge.14698","url":null,"abstract":"<p><p>Arthrogryposis multiplex congenita (AMC) is a heterogeneous disorder associated with 1/3000 to 1/5000 live births. We report a consanguineous family with multiple affected members with AMC and identified a recessive mutation in the highly conserved splice donor site, resulting in the mis-splicing of the affected exons. SENP7 is a deSUMOylase that is critical for sarcomere assembly and skeletal muscle contraction by regulating the transcriptional program in the skeletal muscle. This is a reported case of an affected family with a noncoding, splice site SENP7 variant, expanding the spectrum of SENP7 as a causative gene in rare cases of lethal AMC.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved Diagnostic Yield in Recessive Intellectual Disability Utilizing Systematic Whole Exome Sequencing Data Reanalysis.","authors":"Zohreh Fattahi, Ebrahim Shokouhian, Fatemeh Peymani, Mojgan Babanejad, Maryam Beheshtian, Masoud Edizadeh, Negar Molaei, Parnian Alagha, Fatemeh Ghodratpour, Fatemeh Keshavarzi, Masoumeh Goleyjani Moghadam, Sanaz Arzhangi, Kimia Kahrizi, Hossein Najmabadi","doi":"10.1111/cge.14692","DOIUrl":"https://doi.org/10.1111/cge.14692","url":null,"abstract":"<p><p>Recent advances in next generation sequencing (NGS) have positioned whole exome sequencing (WES) as an efficient first-tier method in genetic diagnosis. However, despite the diagnostic yield of 35%-50% in intellectual disability (ID) many patients still remain undiagnosed due to inherent limitations and bioinformatic short-comings. In this study, we reanalyzed WES data from 159 Iranian families showing recessively inherited ID. The reanalysis was conducted with an initial clinical re-evaluation of the patients and their families, followed by data reanalysis using two updated bioinformatic pipelines. In the first phase, the BWA-GATK pipeline was utilized for alignment and variant calling, with subsequent variant annotation by the ANNOVAR tool. This approach yielded causative variants in 17 families (10.6%). Among these, six genes (MAZ, ACTR5, AKTIP, MIX23, SERPINB12, and CDC25B) were identified as novel candidates potentially associated with ID, supported by bioinformatics functional annotation and segregation analysis. In the second phase, families with negative results were reassessed using the Illumina DRAGEN Bio-IT platform for variant-calling, and Ilyome, a newly developed web-based tool, for annotation. The second phase identified likely pathogenic variants in two additional families, increasing the total diagnostic yield to 11.9% which is consistent with other studies conducted on cohorts of patients with ID. In conclusion, identification of co-segregating variants in six novel candidate genes in this study, emphasizes once more on the potential of WES reanalysis to uncover previously unknown gene-disease associations. Notably, it demonstrates that systematic reanalysis of WES data using updated bioinformatic tools and a thorough review of the literature for new gene-disease associations while performing phenotypic re-evaluation, can improve diagnostic outcome of WES in recessively inherited ID. Consequently, if performed within a 1-3 year period, it can reduce the number of cases that may require other costly diagnostic methods such as whole genome sequencing.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Phenotypes and Genotype-Phenotype Correlations in a Large Clinical Cohort of Patients With Kleefstra Syndrome.","authors":"Zoë J Frazier, Seyda Kilic, Hailey Osika, Alisa Mo, Meg Quinn, Sonia Ballal, Tamar Katz, A Eliot Shearer, Max A Horlbeck, Lynn S Pais, Kira A Dies, Anne O'Donnell-Luria, Joe Kossowsky, Jonathan O Lipton, Tjitske Kleefstra, Siddharth Srivastava","doi":"10.1111/cge.14697","DOIUrl":"https://doi.org/10.1111/cge.14697","url":null,"abstract":"<p><p>Kleefstra syndrome (KLEFS) is a genetic neurodevelopmental disorder caused by haploinsufficiency of EHMT1. The full spectrum of clinical features and genotype-phenotype correlations is currently not fully understood. We performed a retrospective chart review of patients with KLEFS evaluated at the Boston Children's Hospital Kleefstra Clinic. There were 65 individuals (40 females, 25 males, mean age 9.3 years). 17% had large 9q34 deletions (≥ 1 Mb), 29% had small 9q34 deletions (< 1 Mb), and 54% had sequence variants. Global developmental delay (GDD) or intellectual disability (ID) was present in 77%. Behavioral disorders, such as autism spectrum disorder (38%), were common. Epilepsy affected 15%. Systemic health issues included structural cardiac defects (40%), hearing loss (32%), and constipation (31%). Novel features including subgroups with significant motor impairment (24%) and refractory epilepsy (9%), as well as small numbers with opsoclonus-like eye movements (n = 2), thrombocytopenia (n = 2), progressive cerebral atrophy (n = 1), and adrenal carcinoma (n = 1). 9q34 deletion subgroups had higher rates of GDD/ID (p = 0.037), significant motor impairment (p = 0.01), epilepsy (p = 0.004), and cortical visual impairment (p = 0.003) compared to the subgroup with sequence variants. This information may be used to improve clinical care as well as inform research and future therapeutic initiatives.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Portuguese Society of Ophthalmology and Portuguese Society of Human Genetics Joint Clinical Practice Guidelines for Genetic Testing in Inherited Retinal Dystrophies.","authors":"João Pedro Marques, Célia Azevedo Soares, Ana Luísa Carvalho, Sérgio Estrela-Silva, Luísa Coutinho Santos, Lina Ramos, Eduardo Silva","doi":"10.1111/cge.14691","DOIUrl":"https://doi.org/10.1111/cge.14691","url":null,"abstract":"<p><p>The Portuguese Society of Ophthalmology and the Portuguese Society of Human Genetics developed clinical practice guidelines to streamline genetic testing for inherited retinal dystrophies (IRDs), underlining the critical role of molecular diagnosis in enhancing patient care. Genetic testing is pivotal in diagnosis, genetic counselling, prognosis and access to clinical trials, and new gene-specific therapies. These guidelines recommend genetic testing in all IRD patients and provide a detailed assessment of available testing methods, ensuring that genetic counselling is integrated into ophthalmic care. Essential to this process is the inclusion of at least one genetic counselling session to effectively communicate and discuss implications of test results with patients and families/carers. Key recommendations include cascade testing to identify at-risk family members and standardisation of variant classification according to international criteria to ensure consistency in diagnosis and care. Ophthalmological follow-up is generally prescribed at intervals of 1-2 years for adults and 6 months for paediatric patients, to monitor disease progression and complications. Paediatric considerations are addressed, reflecting the complexities and ethical concerns associated with testing minors. These guidelines aim to elevate diagnostic accuracy, guide therapeutic decisions and ultimately improve patient outcomes, marking a significant advance in the genetic management of IRDs.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.","authors":"Cindy Colson, Marine Tessarech, Elise Boucher-Brischoux, Odile Boute-Benejean, Catherine Vincent-Delorme, Clémence Vanlerberghe, Simon Boussion, Justine Le Cunff, Bénédicte Duban-Bedu, Laurence Faivre, Christel Thauvin, Christophe Philippe, Ange-Line Bruel, Frédéric Tran Mau-Them, Clara Houdayer, Gaetan Lesca, Audrey Putoux, Jonathan Lévy, Olivier Patat, Marlène Rio, Jamal Ghoumid, Thomas Smol","doi":"10.1111/cge.14688","DOIUrl":"https://doi.org/10.1111/cge.14688","url":null,"abstract":"<p><p>Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP) is a rare autosomal dominant syndrome caused by pathogenic variants in the BRPF1 gene, which is critical for chromatin regulation. This study expands the clinical and molecular spectrum of IDDDFP by analysing 29 new patients from 20 families with confirmed BRPF1 variants. Our cohort presented with a wide range of clinical features including developmental delay, intellectual disability (ID) and characteristic dysmorphic facial features such as ptosis, blepharophimosis and a broad nasal bridge. New phenotypic features identified include palpebral oedema, laterally elongated eyebrows, low hanging columella and hypertrichosis. Neuropsychological assessment reveals a predominance of mild to moderate ID, with cognitive profiles showing variability in verbal and visual processing. Structural abnormalities such as agenesis of the corpus callosum and ocular defects were noted, consistent with previous studies but with some differences. Familial analysis revealed variability in clinical expression. Our findings highlight the diverse clinical manifestations of BRPF1-related disorders and suggest that comprehensive ophthalmological evaluation is essential for the management of these patients.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Value of ROH Metrics for Predicting Morbidity: Insights From a Large Cohort Analysis of Chromosomal Microarray.","authors":"Lena Sagi-Dain, Michal Levy, Reut Matar, Sarit Kahana, Ifaat Agmon-Fishman, Cochava Klein, Merav Gurevitch, Lina Basel-Salmon, Idit Maya","doi":"10.1111/cge.14686","DOIUrl":"https://doi.org/10.1111/cge.14686","url":null,"abstract":"<p><p>This retrospective cohort study aimed to define the optimal Regions of Homozygosity (ROH) size cut-offs for prediction of morbidity, based on 13 483 Chromosomal Microarray Analyses (CMA). Receiver operating characteristic (ROC) curves were generated, and area under the curve (AUC) was used to assess the predictive capability of total ROH percentage (TRPS), ROH number and ROH segment size in distinguishing between healthy (n=6,196) and affected (n=6,839) cohorts. The metrics were examined for telomeric and interstitial segments, distinct TRPS categories, and across different ancestral origins. ROH segments were identified in 13 035 samples (96.7%), encompassing 66 710 ROH segments. Significant differences in TRPS and ROH segment size were observed between healthy and affected cohorts (p=0.012 and p < 0.001, respectively). However, no clinically significant thresholds could be established based on ROC curves for TRPS and ROH number per sample, as well as for ROH size (AUC 0.64, 0.55, and 0.62, respectively, Figure 1). The same was noted for telomeric versus interstitial locations, various origins, and subcategories of TRPS. In conclusion, this study highlights the complexity of ROH interpretation and emphasizes the importance of tailored reporting strategies in clinical practice. Our findings underscore the need for context-specific reporting guidelines and further research, particularly in consanguineous populations.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}