Journal of Medical Genetics最新文献

{"title":"Cystic fibrosis carrier screening in Australia: comparing sequencing and targeted panels across diverse ancestries.","authors":"Eric Lee, Kaylee Orton","doi":"10.1136/jmg-2024-110365","DOIUrl":"10.1136/jmg-2024-110365","url":null,"abstract":"<p><strong>Background: </strong>Targeted cystic fibrosis (CF) carrier screening panels may lack sensitivity in non-European ancestry groups. This study aims to evaluate the sensitivity of various panels in Australian CF carriers identified through sequencing.</p><p><strong>Methods: </strong>The following panels were evaluated in 869 CF carriers: Asuragen, Elucigene, Devyser, American College of Medical Genetics and Genomics and Victorian Clinical Genetics Services. Ancestry-specific CF carrier frequencies from population databases and Bayesian analysis were used to estimate post-test residual carrier risks.</p><p><strong>Results: </strong>When variants with varying clinical consequences (VCC) were not considered, mean test sensitivity was highest in the Northern Europe group (95.6%) and lowest in the Southern Asia group (64.0%). The post-test residual carrier risk in the Northern Europe group was approximately 1 in 546, with only the Southern Asia group having a higher residual carrier risk of 1 in 179.</p><p><strong>Conclusion: </strong>The Southern Asia group exhibited the lowest test sensitivity and the highest post-test residual carrier risk, surpassing that of the Northern Europe group. The inclusion or exclusion of VCC significantly impacted the calculated test sensitivities. Further research is suggested to better characterise <i>CFTR</i> variants in non-European ancestry groups and to determine which VCC, if any, should be included in carrier screening reports.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"219-226"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Congenital urinary tract anomalies are a variable finding associated with nevoid basal cell carcinoma syndrome.","authors":"Isha Harshe, Talia Donenberg, Marie Jeanjean, Jesus Ramirez Castano, Frankie Fann, Stephanie Feupe Fotsing, Jamie D Weyandt, Xiaolin Hu, Aditi Dhir, Nicholas A Borja","doi":"10.1136/jmg-2024-110340","DOIUrl":"10.1136/jmg-2024-110340","url":null,"abstract":"<p><strong>Introduction: </strong>Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disorder classically associated with multiple basal cell carcinomas, odontogenic keratocysts and skeletal anomalies. However, its significant phenotypic heterogeneity often delays the diagnosis. Here, we undertake the first comprehensive characterisation of NBCCS and congenital urinary tract anomalies.</p><p><strong>Methods: </strong>Clinical evaluation followed by genetic testing was performed on a proband with congenital hydronephrosis due to ureteropelvic obstruction. Then, a cohort of patients with molecularly confirmed NBCCS evaluated at a single institution was analysed, followed by a comprehensive review of the literature.</p><p><strong>Results: </strong>The novel, non-canonical splice-site variant c.349+4 delA in <i>PTCH1</i> was detected in a proband, with RNA analysis confirming exon 2 skipping. Of the additional nine NBCCS cases examined at our institution, a second proband with a nonsense variant in <i>PTCH1</i> was identified with renal agenesis and a bladder diverticulum. A literature review then yielded 11 case reports of patients with congenital urinary tract anomalies, most frequently renal agenesis.</p><p><strong>Discussion: </strong>Congenital urinary tract anomalies are a variable finding in NBCCS. Renal ultrasound may be warranted at the time of initial diagnosis, if not previously performed. Moreover, <i>PTCH1</i> should be included in multigene panels that assess for congenital urinary tract disorders.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"176-179"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>PURA</i>-related neurodevelopmental disorders: a systematic review on genotype-phenotype correlations.","authors":"Noritaka Taniguchi, Keisuke Watanuki, Daisuke Nakato, Toshiki Takenouchi, Kenjiro Kosaki, Hiroshi Koga","doi":"10.1136/jmg-2024-110379","DOIUrl":"10.1136/jmg-2024-110379","url":null,"abstract":"<p><strong>Introduction: </strong>Genotype-phenotype correlations in <i>PURA</i>-related neurodevelopmental disorders (<i>PURA</i>-NDDs) remain unclear. This systematic review aimed to clarify these correlations.</p><p><strong>Methods: </strong>Searches of PubMed and Embase were conducted on 8 August 2024 to identify studies that had investigated genetically diagnosed <i>PURA-</i>NDDs (5q31.3 deletion syndrome and PURA syndrome). All types and languages of studies were included. Study quality was assessed using a 20-item criterion checklist. Genetic and clinical data were extracted from each article and genotype-phenotype correlations were explored.</p><p><strong>Results: </strong>Our analysis included 46 studies encompassing 230 patients with <i>PURA</i>-NDDs (5q31.3 deletion syndrome 18 (8%) and PURA syndrome 212 (92%)). Patients with 5q31.3 deletion syndrome exhibited more congenital defects (50% vs 12%, p<0.0001), respiratory difficulties (94% vs 63%, p=0.013) and walking disability (94% vs 55%, p=0.0026) than patients with PURA syndrome. In PURA syndrome, protein-truncating (nonsense or frameshift) variants were associated with more speech deficits (93% vs 80%, p=0.014) than non-protein-truncating (missense or in-frame) variants. <i>PURA</i> variant location had no effect on congenital defect occurrence or neurodevelopmental outcome. Overall, respiratory difficulties, walking disability and speech deficits were more commonly observed in the following order: 5q31.3 deletion (94%, 94% and 100%, respectively), multiple PUR-repeat deletions (68%, 60% and 95%, respectively), single PUR-repeat deletion or alteration (61%, 53% and 85%, respectively), and deletion or alteration located outside PUR repeats (38%, 33% and 43%, respectively).</p><p><strong>Conclusion: </strong>The clinical severity of <i>PURA</i>-NDDs appears to be associated with the deletion/alteration size including PUR repeats rather than the location of <i>PURA</i> variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"191-198"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homozygous loss of function variant in <i>LMNB2</i> gene causes major brain malformation and perinatal death.","authors":"Camille Desgrouas, Igor Deryabin, Clémence Duvillier, Diane Frankel, Elise Kaspi, Thibaud Quibel, Gabriel Le Goff, Mathieu Cerino, Jérémie Mortreux, Bénédicte Gérard, Rodolphe Dard, Catherine Badens","doi":"10.1136/jmg-2024-110549","DOIUrl":"https://doi.org/10.1136/jmg-2024-110549","url":null,"abstract":"<p><p>Lamins play a major role in the mechanical stability of cell nuclei, the organisation of chromatin and the DNA replication, transcription and repair. The expression profiles of A-type and B-type lamins vary depending on developmental stages, cell types and tissues. Lamin B2 is expressed very early in embryogenesis, especially in the central nervous system, where it is essential for neuronal migration and brain development. Pathogenic missense variants in lamin B2 have been linked to conditions such as lipodystrophy, progressive myoclonic epilepsy and primary microcephaly. Here, we report clinical data and molecular findings for two related newborns carrying a homozygous loss-of-function variant in the <i>LMNB2</i> gene. Both newborns died in the perinatal period and exhibited a similar phenotype at birth, including severe brain development abnormalities, which closely mirror findings observed in several <i>Lmnb2</i>-deficient mouse models. Western blot and immunofluorescence cell labelling performed on the patient's fibroblasts obtained at birth confirmed the complete absence of lamin B2 and revealed an increase in lamin B1, together with alterations in alpha-tubulin and vimentin organisation. This novel clinical form of laminopathy associated with lamin B2 deficiency expands the molecular causes of brain development abnormalities to <i>LMNB2</i> gene variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Li-Fraumeni syndrome: a germline <i>TP53</i> splice variant reveals a novel physiological alternative transcript.","authors":"Jeanne Louis, Marion Rolain, Corentin Levacher, Karen Baudry, Pascal Pujol, Philippe Ruminy, Stéphanie Baert Desurmont, Jacqueline Bou, Emilie Bouvignies, Sophie Coutant, Edwige Kasper, Gwendoline Lienard, Stéphanie Vasseur, Myriam Vezain, Claude Houdayer, Françoise Charbonnier, Gaëlle Bougeard","doi":"10.1136/jmg-2024-110449","DOIUrl":"10.1136/jmg-2024-110449","url":null,"abstract":"<p><strong>Background: </strong>Li-Fraumeni syndrome (LFS) predisposes individuals to a wide range of cancers from childhood onwards, underscoring the crucial need for accurate interpretation of germline <i>TP53</i> variants for optimal clinical management of patients and families. Several unclassified variants, particularly those potentially affecting splicing, require specialised testing. One such example is the NM_000546.6:c.1101-2A>C (rs587781664) variant, located at the splice acceptor site of the last intron of <i>TP53</i>, identified in a female patient with breast cancer diagnosed in her 20s.</p><p><strong>Methods: </strong>To interpret this variant, which has been classified as a variant of uncertain significance (VUS), we developed specific assays including a p53 functional assay, RT-QMPSF, Splice and Expression Analyses by exon Ligation and High-Throughput Sequencing and long RT-droplet digital PCR.</p><p><strong>Results: </strong>We demonstrated a loss of p53 transcriptional activity, and a half reduction in TP53 mRNA expression. Additionally, we detected the use of a novel alternative last exon downstream of exon 11, which we have named exon 12. This transcript, typically detectable at low levels in most individuals, was found to be more highly expressed in the c.1101-2A>C carrier, predominantly transcribed from the mutant allele due to the disruption of the splice acceptor site in intron 10.</p><p><strong>Conclusion: </strong>By combining these approaches, we successfully reclassified this intronic VUS as 'pathogenic', enabling appropriate genetic counselling for the patient and her family. Additionally, we identified a novel TP53 alternative transcript that is expressed in both physiological and pathological contexts, with heightened expression in the patient with LFS. This discovery provides a basis for further investigation into the role of TP53 isoforms in LFS oncogenesis.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"160-168"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Under-recognised neurocognitive deficits in adults and adolescents with tuberous sclerosis complex.","authors":"Mélissa Boisclair, Laury-Anne Blondeau, Florence Bouchard, Rose-Marie Drouin-Engler, Jimmy Li, Samuel Bertrand, Fayçal Zine-Eddine, Laurent Létourneau-Guillon, Catherine Larochelle, Philippe Major, Olivier Boucher, Mark R Keezer","doi":"10.1136/jmg-2024-110388","DOIUrl":"10.1136/jmg-2024-110388","url":null,"abstract":"<p><strong>Background: </strong>Tuberous sclerosis complex (TSC) is a genetic disease characterised by the growth of benign tumours. The Tuberous sclerosis Associated Neuropsychiatric Disorders (TAND) Checklist is used to identify patient-reported neurocognitive deficits. Patients may, however, under-recognise mild cognitive impairment. We aimed to determine the frequency of abnormal scores on three objective tests of cognitive function in people with and without diagnosed intellectual disability and examine associations between scores on these tests with self-reported TAND Checklist symptoms.</p><p><strong>Methods: </strong>We conducted a cross-sectional study where people with TSC (PwTSC; n=46) completed the TAND Checklist and three cognitive tests: Symbol Digit Modalities Test (SDMT), Montreal Cognitive Assessment test and Trail Making Test-Parts A and B. We examined associations between cognitive test scores and the TAND Checklist using Pearson's correlations (95% CI). Receiver operating characteristics (ROC) curves were plotted to determine the screening accuracy of each measure in identifying physician-diagnosed neurocognitive disorders.</p><p><strong>Results: </strong>There were minimal correlations between the cognitive test scores and the TAND Checklist. More than 20% of PwTSC reported no cognitive issues on the TAND Checklist but had abnormal performance on at least one cognitive test. The ROC curves demonstrated similar results, with areas under the curve of 0.93 (95% CI 0.79 to 1.00) for the SDMT but only 0.70 (95% CI 0.45 to 0.95) for the TAND Checklist.</p><p><strong>Conclusion: </strong>Objective tests of cognitive function are useful in identifying unrecognised neurocognitive deficits in PwTSC. Deficits likely have multifactorial origins, including undiagnosed intellectual disability and the impact of chronic epilepsy.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"169-175"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Foecal incontinence disorders in Wolfram syndrome: a new manifestation.","authors":"Christophe Orssaud","doi":"10.1136/jmg-2024-110233","DOIUrl":"10.1136/jmg-2024-110233","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"107-108"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling non-coding <i>DMD</i> variants: synergising RNA sequencing and DNA sequencing for enhanced molecular diagnosis.","authors":"Yinghong Pan, Babi Ramesh Reddy Nallamilli, Ruby Liu, Naga Guruju, Daniel Lesperance, Zeqiang Ma, Abhinav Mathur, Kayla Banks, Ann S Martin, Rolando García, Fen Guo, Madhuri Hegde","doi":"10.1136/jmg-2024-110152","DOIUrl":"10.1136/jmg-2024-110152","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in the <i>DMD</i> gene are associated with dystrophinopathy including Duchenne and Becker muscular dystrophy (DMD/BMD). Targeted <i>DMD</i> gene, gene panels, exomes and genome sequencing have advanced genetic diagnostics, yet some cases remain elusive.</p><p><strong>Methods: </strong>We performed total RNA sequencing (RNAseq) on muscle biopsy from 13 male patients with a clinical diagnosis of DMD/BMD. Splice aberration events are evaluated using the Integrative Genomics Viewers. Targeted DNA sequencing result was used/re-analysed to confirm complex rearrangement events identified.</p><p><strong>Results: </strong>RNAseq identified aberration splicing or expression events in the <i>DMD</i> gene of 12 cases. Splice-altering intronic single nucleotide variant events including c.7309+5G>T, c.7309+5G>A, c.3276+1G>A and c.3603+820G>T were identified in four cases. Splice-altering events were also detected in one case with small indel c.94-38_94del and two cases with intragenic deletions (exons 51-52 and 45-47 deletions). Furthermore, complex DNA rearrangements inducing aberration splicing/expression events were identified in five cases involving exons 44-45, 55-56, 2-79, 45-79 or 68-79, which were concordant with their DNA sequencing reanalysis results. Some cases with exon deletions have presented non-canonical transcripts expression. The RNAseq result showing aberrant splicing/expression in different exon regions in most of these cases corresponded with their immunohistochemical dystrophin staining results and/or clinical symptoms.</p><p><strong>Conclusion: </strong>Our data demonstrated RNAseq is a powerful tool to provide functional data for <i>DMD</i> splice aberration events, especially when integrating with immunohistochemical testing and DNA sequencing, for elucidating the pathogenicity of <i>DMD</i> variants and achieving a precise genetic diagnosis in patients with DMD/BMD clinical presentation but without definitive diagnoses after routine genetic testing.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"97-106"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Portraying the full picture of Neurofibromatosis-Noonan syndrome: a systematic review of literature.","authors":"Omeyma Trimeche, Rania Sakka, Ekram Hajji, Abdelmouhaymen Missaoui, Bilel Ben Amor, Ines Bayar, Sana Abid, Hela Marmouch, Hanen Sayedi, Ines Khochtali","doi":"10.1136/jmg-2024-110253","DOIUrl":"10.1136/jmg-2024-110253","url":null,"abstract":"<p><strong>Background and aims: </strong>Neurofibromatosis-Noonan syndrome (NFNS) is an extremely rare genetic entity combining the clinical phenotype of two conditions: neurofibromatosis type 1 syndrome (NF1) and Noonan syndrome (NS). Nevertheless, many inconsistencies reside in our understanding of this condition, mainly its clinical features and genetic background. Through this systematic review, we aim to shed light on the epidemiological features, the broad clinical spectrum, the underlying genetic defects and the associated comorbidities of NFNS.</p><p><strong>Methods: </strong>Medline, Scopus and Google Scholar were searched for publications on the clinical and genetic features of patients with NFNS. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed and the study protocol was registered in PROSPERO.</p><p><strong>Results: </strong>Of 951 records screened, 42 were eligible. The mean age at diagnosis was 14.7 years ranging from 0 to 69 years. As for the circumstance of discovery of NFNS, it was dominated by family investigation followed by neurofibromas, facial dysmorphia and short stature (SS). Prematurity was noted in 40.9% of cases. The hallmark features of NFNS at diagnosis were 'café au lait' macules, typical facial dysmorphia of NS, postnatal SS, pectus abnormalities, broad neck and lentigines. Macrocephaly, scoliosis and cardiopathies occurred in 26%, 42.4% and 36.9% of cases, respectively. Tumours were found in 18.4% of cases. As for the genetic foundation of NFNS, <i>NF1</i> gene mutations were depicted in 87.5% of individuals.</p><p><strong>Conclusions: </strong>Based on our findings, we emphasise on the importance of searching for NS features in patients with NF1 since the prognosis, comorbidities and consequently management could be altered.</p><p><strong>Prospero registration number: </strong>42024522238.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"109-116"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Commentary on <i>Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank</i>.","authors":"Pål Møller, Toni T Seppälä, Mev Dominguez-Valentin, Julian Sampson","doi":"10.1136/jmg-2024-110385","DOIUrl":"10.1136/jmg-2024-110385","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"53"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}