Journal of Medical Genetics最新文献

{"title":"Identification of biallelic loss-of-function <i>PREP</i> variants in three individuals with syndromic intellectual disability.","authors":"Erik Hertstein, Miriam Bertrand, Johannes Kopp, Henrike Lisa Sczakiel, Oliver Küchler, Nicolai von Kügelgen, Björn Fischer-Zirnsak, Gabriele Hildebrand, Jonas Leubner, Denise Horn, Stefan Mundlos, Tobias B Haack, Angela Kaindl, Christoph G Korenke, Felix Boschann","doi":"10.1136/jmg-2026-111501","DOIUrl":"10.1136/jmg-2026-111501","url":null,"abstract":"<p><strong>Background: </strong>Neurodevelopmental disorders are one of the most prevalent reasons for genetic testing in childhood. Despite the identification of over 1950 associated genes, many proposed candidate genes lack convincing gene-disease validity. The gene <i>PREP</i> encodes the broadly expressed prolyl endopeptidase whose exact function remains largely unknown. A homozygous <i>PREP</i> variant has been reported once as a candidate gene in two siblings with intellectual disability but no functional studies were conducted.</p><p><strong>Methods: </strong>Exome and trio genome sequencing were performed in two unrelated families as part of larger cohorts. Segregation analysis, RNA sequencing and immunoblots were performed to further examine the pathogenicity of detected <i>PREP</i> variants.</p><p><strong>Results: </strong>We report three individuals from two unrelated families who presented with intellectual disability, behavioural abnormalities, strabismus, generalised muscular hypotonia, dysmorphic facial features and epilepsy. Exome and genome sequencing identified two different homozygous rare <i>PREP</i> variants: c.1570_1573dup, p.(Asn525Thrfs*5) and c.1839-2A>G, p.?. RNA sequencing confirmed the detected intronic variant to result in two aberrant mRNA isoforms. In patient-derived cells immunoblots showed absence of PREP protein.</p><p><strong>Conclusion: </strong>Our data suggest PREP deficiency as the underlying cause of a syndromic neurodevelopmental disorder.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"605-612"},"PeriodicalIF":3.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338849","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":"Identification of Lynch syndrome among people newly diagnosed with endometrial cancer: a prospective audit.","authors":"Jean-Ellen Johnson, Sarah Milliken, James Bolton, D Gareth Evans, Fiona Lalloo, Emma J Davidson","doi":"10.1136/jmg-2026-111578","DOIUrl":"10.1136/jmg-2026-111578","url":null,"abstract":"<p><strong>Background: </strong>Since 2020, the UK National Institute for Health and Care Excellence (NICE) recommends screening for Lynch syndrome in all people newly diagnosed with endometrial cancer. Screening involves tumour testing for loss of the mismatch repair (MMR) proteins using immunohistochemistry (IHC), <i>MLH1</i> methylation testing and germline sequencing for Lynch syndrome according to a diagnostic algorithm. Here we review adherence to NICE guidance at a gynaecological cancer centre in North-West England.</p><p><strong>Methods: </strong>We conducted a prospective audit of Lynch syndrome screening for consecutive patients newly diagnosed with endometrial cancer discussed at the gynaecological oncology multidisciplinary (MDT) meeting. We recorded adherence with the NICE recommended diagnostic algorithm, testing turnaround times and the impact of gynaecology-led genetic testing (mainstreaming) on diagnostic intervals.</p><p><strong>Results: </strong>Between November 2021 and November 2023, 421 new endometrial cancer patients were discussed at MDT. Overall, 96.9% (408/421) underwent IHC and 26.0% (106/408) were MMR deficient, mostly due to <i>MLH1</i> hypermethylation (17.4%, 71/408). In total, 7.1% (29/408) had MMR deficiency not due to <i>MLH1</i> hypermethylation (25/408 had <i>MSH2/MSH6/PMS2</i> loss and 4/408 were non-hypermethylated) that required germline testing for Lynch syndrome, and 3.2% (13/408) had Lynch syndrome. Only 19/27 (70.4%) with positive tumour triage underwent Lynch syndrome testing (four declined and four died before testing). The median time from tumour MMR IHC results to germline test result was 121 days (IQR 103, 133) with gynaecology-led testing compared with 278 days (IQR 183, 476) with testing organised by clinical genetics.</p><p><strong>Conclusion: </strong>The prevalence of Lynch syndrome in our unselected endometrial cancer population was 3.2% but not everyone at risk was tested. Some declined germline Lynch syndrome testing due to a lack of at-risk family members and delay getting their genetic appointment. A significant minority died before they could be offered or receive Lynch syndrome testing. We recommend gynaecology-led germline testing and referral to clinical genetics only patients with confirmed Lynch syndrome. This approach would ease the burden of an already overstretched genetics service while promptly identifying Lynch syndrome in high-risk patients. This in turn enables timely colorectal cancer surveillance and cascade testing of at-risk family members.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"554-560"},"PeriodicalIF":3.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148054796","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":"Interpreting <i>TP53</i> variants: somatic mosaicism and <i>ERCC6L2</i>-driven clonal evolution.","authors":"Amalie Noergaard Andersson, Anna Byrjalsen, Ida Elisabeth Viller Tuxen, Mette Klarskov Andersen, Thomas van Overeem Hansen, Karin A W Wadt","doi":"10.1136/jmg-2025-111449","DOIUrl":"10.1136/jmg-2025-111449","url":null,"abstract":"<p><p>We present two illustrative cases highlighting diagnostic, surveillance and management complexities of <i>TP53</i> pathogenic variants (PVs). Case 1 describes a 24-year-old female with early-onset breast cancer and a somatic mosaic <i>TP53</i> PV with a variant allele frequency of 19% in blood, initially missed by panel sequencing. Case 2 concerns a 59-year-old female with multiple primary tumours and two identical <i>TP53</i> variants detected in two different tissues which initially suggested somatic mosaicism but were consistent with a myelodysplastic syndrome-related clone secondary to homozygous germline <i>ERCC6L2</i>-associated bone marrow failure. These cases highlight the importance of accurately interpreting <i>TP53</i> variants for correct clinical decision-making. Contextual factors such as age, phenotype, family history and tissue testing must guide diagnosis, treatment and surveillance.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"569-572"},"PeriodicalIF":3.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148211266","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":"Identification of a novel intergenic <i>EPCAM-MSH2</i> deletion causing EPCAM-associated Lynch syndrome by long-read nanopore sequencing.","authors":"Luiza Steffens Reinhardt, Alexander Coster, Sean M Burnard, Caitlin S Romanis, Andrew Ziolkowski, Gordana Pecenpetelovska, Andrea Mathe, Amelia Hedley, Vicki E Maltby, Jeannette Lechner-Scott, Katie Ashton, Kelly A Avery-Kiejda, Rodney J Scott","doi":"10.1136/jmg-2026-111541","DOIUrl":"10.1136/jmg-2026-111541","url":null,"abstract":"<p><p>Epithelial cell adhesion molecule (<i>EPCAM</i>)-associated Lynch syndrome arises from deletions at the 3'-end of <i>EPCAM</i> that disrupt transcriptional termination, generate read-through transcripts and cause epigenetic silencing of MSH2 in EPCAM-expressing tissues. However, the clinical significance of deletions confined to the <i>EPCAM-MSH2</i> intergenic region remains uncertain without in-depth investigation.We investigated a family with a strong history of Lynch syndrome-related cancers in whom diagnostic testing by short-read sequencing identified a heterozygous deletion spanning the <i>EPCAM-MSH2</i> intergenic region that was initially classified as a variant of uncertain significance. The variant was further characterised using long-read Oxford Nanopore sequencing with adaptive sampling and methylation profiling.Long-read sequencing defined precise breakpoints, and tumour analysis demonstrated <i>MSH2</i> promoter hypermethylation with complete loss of MSH2 protein expression in the absence of germline promoter methylation. The molecular phenotype closely mirrored the recognised mechanism for 3'-end <i>EPCAM</i> deletions, whereby aberrant <i>EPCAM</i> transcription interferes with <i>MSH2</i> promoter regulation in a tissue-specific manner.These findings support reclassification of this variant to likely pathogenic and establish a diagnosis of <i>EPCAM</i>-associated Lynch syndrome. This report provides the first evidence that intergenic <i>EPCAM-MSH2</i> deletions are associated with <i>MSH2</i> epimutations and highlights the diagnostic utility of long-read sequencing for noncoding structural variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"591-595"},"PeriodicalIF":3.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175839","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":"Updated ENIGMA recommendations for reporting germline variants in cancer susceptibility genes and their translation into twenty languages.","authors":"Arcangela De Nicolo, Diana M Eccles, Kirsimari Aaltonen, Pia Alhopuro, Sarah Louise Ariansen, Michela Biancolella, Sandrine M Caputo, Olivier Caron, Pietro Cavalli, Jianbang Chiang, Kathleen B M Claes, Edgar Christian S Cuaresma, Miguel de la Hoya, Antoine De Pauw, Orland Díez, Mev Domínguez-Valentin, Hans Ehrencrona, Magnhild K Fjeldvær, Florentia Fostira, Marie Belle D Francia, Javier Galego-Carro, Encarna B Gómez García, Nur Tiara Hassan, Jan Hauke, Akira Hirasawa, Xin Huang, Elaine Marisse H Ilagan-Cargullo, Issei Imoto, Sowmya Jonnagadla, Manasadevi Karthikeyan, Petra Kleiblova, Irene Konstantopoulou, Artur Kowalik, Anders Kvist, Fabienne Lesueur, Shao-Tzu Li, Adrià López-Fernández, Eva Machackova, Alexandra Martins, Arjen R Mensenkamp, Yukihide Momozawa, Gemma Montalban, Alvaro N A Monteiro, Heli Nevanlinna, Joanne Ngeow, Edenir Inez Palmero, Inge Sokilde Pedersen, Frances Victoria F Que, Marta Santamariña, Elizabeth Santana Dos Santos, Christian F Singer, Monika Siołek, Angela R Solano, Jana Soukupova, Priyadharshini D/O Suresh, Magdalena Szczepaniak, Yen Y Tan, Soo Hwang Teo, Emma Tham, Mads Thomassen, Georgios Tsaousis, Thomas van Overeem Hansen, Ana Vega, Eladio A Velasco-Sampedro, Teresia Wangensteen, Barbara Wappenschmidt, Drakoulis Yannoukakos, Sook-Yee Yoon, Amanda B Spurdle, Paolo Radice","doi":"10.1136/jmg-2026-111498","DOIUrl":"10.1136/jmg-2026-111498","url":null,"abstract":"<p><p>Genetic testing for cancer susceptibility underpins precision cancer prevention and care. Gaps in the healthcare providers' genetic literacy and an ambiguous lexicon for variant description may hinder proper delivery and clinical application of consistently trustworthy test results. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) international consortium supports controlled terminology and recommends a framework for reporting germline variants in cancer susceptibility genes, using breast cancer as an exemplar. Moving forward towards terminological coherence across disciplines and borders, the ENIGMA Clinical Working Group launched a multinational effort to release consortium-approved translations of the published recommendations. The herein reported Vocabulary Translation Project offered an opportunity to reappraise and align the reference text to the recent <i>BRCA1</i> and <i>BRCA2</i> specifications to the American College of Medical Genetics and Genomics/Association for Molecular Pathology rules by the ENIGMA Variant Curation Expert Panel and to highlight country-specific differences in breast cancer risk assessment and management. The updated recommendations and their 20 translations are now provided as easy to handle documents, covering 11 of the most widely spoken languages in the world. They will contribute to minimised erroneous inferences, more informed decision-making, improved health outcomes and equity in the use of genetic testing for cancer predisposition and in translational oncology.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"548-553"},"PeriodicalIF":3.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147941704","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":"Decreasing diffuse gastric cancer risk in individuals with germline <i>CDH1</i> pathogenic variants. What about prophylactic total gastrectomy?","authors":"Giovanni Corso, Carlo La Vecchia","doi":"10.1136/jmg-2026-111577","DOIUrl":"10.1136/jmg-2026-111577","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"589-590"},"PeriodicalIF":3.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148054767","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":"Location matters: topography of germline <i>CEBPA</i> variants predicts variable outcomes in familial acute myeloid leukaemia-a rare disease perspective.","authors":"Jinjun Yang, Xiaoqian Duan, Min Zhu, Yu Wu","doi":"10.1136/jmg-2026-111543","DOIUrl":"10.1136/jmg-2026-111543","url":null,"abstract":"<p><strong>Background: </strong>Familial acute myeloid leukaemia (AML) with germline <i>CEBPA</i> (CCAAT/enhancer-binding protein alpha) variants is a distinct hereditary entity, yet clinically meaningful genotype-phenotype correlations remain incompletely defined.</p><p><strong>Methods: </strong>We integrated cases from our institution with all published pedigrees of germline <i>CEBPA</i>-mutated AML and analysed 56 affected patients from 40 families, including one newly identified pedigree harbouring a novel TAD2 (transactivation domain 2) variant (p.C133Ter).</p><p><strong>Results: </strong>Variant localisation significantly influenced disease phenotype and outcome. Compared with non-TAD2 variants, TAD2 variants were associated with older age at AML onset (40 years vs 21 years, p<0.001), a higher burden of cooperating somatic variants (64.3% vs 27.3%, p=0.023) and lower complete remission rates after induction therapy (69.2% vs 95.3%, p=0.022). TAD2 involvement conferred inferior overall survival (p<0.001) and progression-free survival (p=0.025). In univariate analyses, TAD2 variants emerged as adverse prognostic factors for 2-year overall survival (OR=0.06, 95% CI 0.01 to 0.34, p=0.002) and progression-free survival (OR=0.07, 95% CI 0.01 to 0.35, p=0.003).</p><p><strong>Conclusions: </strong>Although germline <i>CEBPA</i>-mutated AML is generally regarded as favourable-risk, TAD2-involving variants may define a biologically and clinically high-risk subset, supporting variant topography as a clinically actionable prognostic marker.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"596-604"},"PeriodicalIF":3.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148054804","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":"Biallelic pathogenic variants in <i>FLNB</i> are associated with paediatric steroid-resistant nephrotic syndrome via podocyte cytoskeletal dysfunction.","authors":"Yueheng Gan, Xueying Yang, Han Chan, Shuyan Yang, Haiping Yang, Qiu Li","doi":"10.1136/jmg-2025-111444","DOIUrl":"10.1136/jmg-2025-111444","url":null,"abstract":"<p><strong>Background: </strong>Steroid-resistant nephrotic syndrome (SRNS) is a severe paediatric kidney disease and a leading cause of end-stage kidney disease in children, with a high genetic contribution. While over 80 monogenic causes of SRNS have been identified, a significant proportion of affected patients still lack a clear genetic diagnosis, indicating that additional causative genes remain to be discovered.</p><p><strong>Methods: </strong>Through whole-exome sequencing of a paediatric SRNS cohort, we identified three probands carrying biallelic <i>FLNB</i> pathogenic variants. Sanger sequencing was performed for familial cosegregation verification and ACMG classification. Expression of Filamin B, Nephrin and Synaptopodin in renal tissues was assessed by immunohistochemistry/immunofluorescence. Wild-type and patient-derived variant <i>FLNB</i> plasmids were constructed and transfected into HEK293T cells and immortalised human podocytes (HPCs). The effects of these variants on protein expression, localisation and cytoskeletal organisation were assessed by western blotting and immunofluorescence. <i>FLNB</i> expression in HPCs was silenced using shRNA to evaluate the impact on podocyte marker proteins, cytoskeletal integrity and migratory capacity. A zebrafish <i>flnb</i> knockdown model was employed to validate its effects on renal development.</p><p><strong>Results: </strong>All three probands presented with isolated SRNS without skeletal developmental abnormalities, and renal tissues showed significantly reduced Filamin B protein expression. In vitro, p.L117P and p.M1803L variants led to markedly reduced protein expression, while p.R470L and p.K2586R induced perinuclear aggregation of Filamin B accompanied by F-actin rearrangement. <i>FLNB</i> silencing led to downregulation of Nephrin and Synaptopodin, cytoskeletal disorganisation and impaired cell migration. Zebrafish <i>flnb</i> knockdown exhibited pericardial oedema, defective nephron development and abnormal podocyte foot processes.</p><p><strong>Conclusion: </strong>We report for the first time that biallelic <i>FLNB</i> pathogenic variants are associated with paediatric SRNS by disrupting Filamin B expression, cytoskeletal integrity and podocyte function, providing evidence that <i>FLNB</i> is a novel monogenic cause of SRNS.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"578-588"},"PeriodicalIF":3.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148054789","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":"PRS-BC₃₁₃ integration for tailored breast cancer prevention in female patients and their healthy relatives.","authors":"Rosanna H E Krakowsky, Stephan Drukewitz, Alexandra Händel, John Wiedenhöft, Bahriye Aktas, Johannes R Lemke, Vincent Strehlow, Julia Hentschel","doi":"10.1136/jmg-2025-111211","DOIUrl":"10.1136/jmg-2025-111211","url":null,"abstract":"<p><p>Precise breast cancer risk assessment (BCR) is essential for personalised prevention in women with a family history of hereditary breast and ovarian cancer (HBOC). The CanRisk model integrates monogenic variants with reproductive, lifestyle and familial factors and can be extended by Polygenic Risk Scores (PRS). We evaluated the impact of PRS-BC₃₁₃ in three groups: (1) healthy carriers of (likely) pathogenic variants (LP/P), (2) affected LP/P carriers and (3) healthy female relatives from variant-negative HBOC families.In healthy LP/P carriers, median 10-year breast cancer (BC) risk remained stable, while individual estimates ranged from+25% to -16% compared with calculations without PRS. Among affected LP/P carriers, contralateral BC risk shifted by+24% to -11%, indicating PRS effects even in high-risk individuals.In healthy relatives, applying the recently introduced German threshold of an 8% BC risk between ages 40 and 50 years resulted in escalation to intensified surveillance in ~6% (5/86) (2.4-14%, Wilson binomial CI with Yates' correction) and de-escalation in ~1% (1/86) (0.061-7.2%).Here, we provide new evidence of PRS clinical impact under the updated German threshold.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"561-568"},"PeriodicalIF":3.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175899","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":"Founder variant in <i>OTOG</i> causing non-syndromic sensorineural hearing loss in Irish traveller population.","authors":"Aoife Flynn, Rebecca Finnegan, Aisling Stafford, Ivan Keogh, Andrew Green, Sally Ann Lynch, Nicholas M Allen, Aisling Lyons, Kathleen Mary Gorman","doi":"10.1136/jmg-2026-111607","DOIUrl":"https://doi.org/10.1136/jmg-2026-111607","url":null,"abstract":"<p><p>Deafness is a common multifactorial sensory disorder with numerous underlying causes (genetic, environmental) and a broad range of impact on humans. To date, 156 non-syndromic hearing loss-associated genes have been identified (DFN) and 75%-80% follow a recessive inheritance pattern (DFNB). <i>OTOG</i> (MIM: 604487, chr11:17,547,259-17,646044, GrCh38) encodes otogelin, a non-collagenous protein specific to the inner ear tectorial membrane. Biallelic pathogenic variants in <i>OTOG</i> result in mild to moderate autosomal recessive non-syndromic SNHL (DNF18B). To date, only 41 families (63 individuals) have been reported in the literature.We report an additional seven families from the Irish Traveller population (16 individuals), with a recurrent homozygous variant in <i>OTOG</i> (c.3700C>T; p.Arg1234*) causing non-syndromic early-onset SNHL. The median current age is 9.5 years (IQR: 5.75-14.5 years). Two-thirds (n=11) were identified after failing newborn hearing screening, with others referred due to speech delay. All individuals have mild to moderate SNHL, with a characteristic U-shaped or 'cookie bite' audiogram. Similar to previously reported cases of <i>OTOG-</i>associated SNHL, in our cohort, SNHL was non-progressive even in our adult patients. There were no features of vestibular dysfunction or neurodevelopmental impairment.We reviewed all reported cases to date, in addition to our families (n=79). We demonstrate that protein-truncating variants are scattered throughout the length of the OTOG protein. However, pathogenic missense variants occur only in key domains such as vWD and trypsin inhibitor-like cysteine-rich domains.This report highlights a founder variant in <i>OTOG</i> within the Irish Traveller population. Clinicians should ensure that this is requested in all infants who fail newborn screening from this ethnicity.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818605","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}