Elan Hahn, Chloe Mighton, Yael Fisher, Andrew Wong, Vanessa Di Gioacchino, Nicholas Watkins, Justin Mayers, Yvonne Bombard, George S Charames, Jordan Lerner-Ellis
Background: Variant classification in the setting of germline genetic testing is necessary for patients and their families to receive proper care. Variants are classified as pathogenic (P), likely pathogenic (LP), uncertain significance (VUS), likely benign (LB) and benign (B) using the standards and guidelines recommended by the American College of Medical Genetics and the Association for Molecular Pathology, with modifications for specific genes. As the literature continues to rapidly expand, and evidence continues to accumulate, prior classifications can be updated accordingly. In this study, we aim to characterise variant reclassifications in Ontario.
Methods: DNA samples from patients seen at hereditary cancer clinics in Ontario from January 2012 to April 2022 were submitted for testing. Patients met provincial eligibility criteria for testing for hereditary cancer syndromes or polycystic kidney disease. Reclassification events were determined to be within their broader category of significance (B to LB or vice versa, or P to LP or vice versa) or outside of their broader category as significance (ie, significant reclassifications from B/LB or VUS or P/LP, from P/LP to VUS or B/LB, or from VUS to any other category).
Results: Of the 8075 unique variants included in this study, 23.7% (1912) of variants were reassessed, and 7.2% (578) of variants were reclassified. Of these, 351 (60.7%) variants were reclassified outside of their broader category of significance. Overall, the final classification was significantly different for 336 (58.1%) variants. Importantly, most reclassified variants were downgraded to a more benign classification (n=245; 72.9%). Of note, most reclassified VUS was downgraded to B/LB (n=233; 84.7%).
Conclusions: The likelihood for reclassification of variants on reassessment is high. Most reclassified variants were downgraded to a more benign classification. Our findings highlight the importance of periodic variant reassessment to ensure timely and appropriate care for patients and their families.
背景:在进行种系遗传检测时,有必要对变异进行分类,以便患者及其家属得到适当的治疗。根据美国医学遗传学会(American College of Medical Genetics)和分子病理学协会(Association for Molecular Pathology)推荐的标准和指南,变异可分为致病(P)、可能致病(LP)、意义不确定(VUS)、可能良性(LB)和良性(B),并针对特定基因进行修改。随着文献的迅速扩充和证据的不断积累,以前的分类方法也会随之更新。在本研究中,我们旨在了解安大略省变异基因重新分类的特点:2012年1月至2022年4月期间在安大略省遗传性癌症诊所就诊的患者的DNA样本被提交进行检测。患者符合省级遗传性癌症综合征或多囊肾病检测资格标准。重新分类事件被确定为在其更广泛的重要类别内(B 到 LB 或反之亦然,或 P 到 LP 或反之亦然)或在其更广泛的重要类别外(即从 B/LB 或 VUS 或 P/LP,从 P/LP 到 VUS 或 B/LB,或从 VUS 到任何其他类别的重要重新分类):在纳入本研究的 8075 个独特变异体中,23.7%(1912 个)的变异体接受了重新评估,7.2%(578 个)的变异体被重新分类。其中,351 个(60.7%)变异体被重新分类,超出了其更广泛的重要类别。总体而言,336 个(58.1%)变异体的最终分类有明显不同。重要的是,大多数被重新分类的变异体被降级为更良性的分类(n=245;72.9%)。值得注意的是,大多数重新分类的 VUS 被降级为 B/LB(n=233;84.7%):结论:变异体在重新评估时被重新分类的可能性很高。结论:变异体在重新评估时被重新分类的可能性很高。大多数被重新分类的变异体都被降级为更良性的分类。我们的研究结果凸显了定期进行变异再评估的重要性,以确保为患者及其家属提供及时、适当的治疗。
{"title":"Variant classification changes over time in the clinical molecular diagnostic laboratory setting.","authors":"Elan Hahn, Chloe Mighton, Yael Fisher, Andrew Wong, Vanessa Di Gioacchino, Nicholas Watkins, Justin Mayers, Yvonne Bombard, George S Charames, Jordan Lerner-Ellis","doi":"10.1136/jmg-2023-109772","DOIUrl":"10.1136/jmg-2023-109772","url":null,"abstract":"<p><strong>Background: </strong>Variant classification in the setting of germline genetic testing is necessary for patients and their families to receive proper care. Variants are classified as pathogenic (P), likely pathogenic (LP), uncertain significance (VUS), likely benign (LB) and benign (B) using the standards and guidelines recommended by the American College of Medical Genetics and the Association for Molecular Pathology, with modifications for specific genes. As the literature continues to rapidly expand, and evidence continues to accumulate, prior classifications can be updated accordingly. In this study, we aim to characterise variant reclassifications in Ontario.</p><p><strong>Methods: </strong>DNA samples from patients seen at hereditary cancer clinics in Ontario from January 2012 to April 2022 were submitted for testing. Patients met provincial eligibility criteria for testing for hereditary cancer syndromes or polycystic kidney disease. Reclassification events were determined to be within their broader category of significance (B to LB or vice versa, or P to LP or vice versa) or outside of their broader category as significance (ie, significant reclassifications from B/LB or VUS or P/LP, from P/LP to VUS or B/LB, or from VUS to any other category).</p><p><strong>Results: </strong>Of the 8075 unique variants included in this study, 23.7% (1912) of variants were reassessed, and 7.2% (578) of variants were reclassified. Of these, 351 (60.7%) variants were reclassified outside of their broader category of significance. Overall, the final classification was significantly different for 336 (58.1%) variants. Importantly, most reclassified variants were downgraded to a more benign classification (n=245; 72.9%). Of note, most reclassified VUS was downgraded to B/LB (n=233; 84.7%).</p><p><strong>Conclusions: </strong>The likelihood for reclassification of variants on reassessment is high. Most reclassified variants were downgraded to a more benign classification. Our findings highlight the importance of periodic variant reassessment to ensure timely and appropriate care for patients and their families.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"788-793"},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160573","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}
Jing Yang, Ya-Nan Zhang, Ren-Xue Wang, Chen-Zhi Hao, Yiling Qiu, Hao Chi, Wei-Sha Luan, HongYi Tang, Xiu-Juan Zhang, XuXu Sun, Jonathan A Sheps, Victor Ling, Muqing Cao, Jian-She Wang
Background and aims: Variants in ZFYVE19 underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to elucidate the pathogenic mechanism.
Methods: Zfyve19 knockout (Zfyve19-/- ) mice were generated and exposed to different liver toxins. Their livers were characterised at the tissue, cellular and molecular levels. Findings were compared with those in wild-type mice and in ZFYVE19-deficient patients. ZFYVE19 knockout and knockdown retinal pigment epithelial-1 cells and mouse embryonic fibroblasts were generated to study cell division and cell death.
Results: The Zfyve19-/- mice were normal overall, particularly with respect to hepatobiliary features. However, when challenged with α-naphthyl isothiocyanate, Zfyve19-/- mice developed changes resembling those in ZFYVE19-deficient patients, including elevated serum liver injury markers, increased numbers of bile duct profiles with abnormal cholangiocyte polarity and biliary fibrosis. Failure of cell division, centriole and cilia abnormalities, and increased cell death were observed in knockdown/knockout cells. Increased cell death and altered mRNA expression of cell death-related signalling pathways was demonstrated in livers from Zfyve19-/- mice and patients. Transforming growth factor-β (TGF-β) and Janus kinase-Signal Transducer and Activator of Transcription 3 (JAK-STAT3) signalling pathways were upregulated in vivo, as were chemokines such as C-X-C motif ligands 1, 10 and 12.
Conclusions: Our findings demonstrated that ZFYVE19 deficiency is a ciliopathy with novel histological features. Failure of cell division with ciliary abnormalities and cell death activates macrophages and may thus lead to biliary fibrosis via TGF-β pathway in the disease.
{"title":"ZFYVE19 deficiency: a ciliopathy involving failure of cell division, with cell death.","authors":"Jing Yang, Ya-Nan Zhang, Ren-Xue Wang, Chen-Zhi Hao, Yiling Qiu, Hao Chi, Wei-Sha Luan, HongYi Tang, Xiu-Juan Zhang, XuXu Sun, Jonathan A Sheps, Victor Ling, Muqing Cao, Jian-She Wang","doi":"10.1136/jmg-2023-109779","DOIUrl":"10.1136/jmg-2023-109779","url":null,"abstract":"<p><strong>Background and aims: </strong>Variants in <i>ZFYVE19</i> underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to elucidate the pathogenic mechanism.</p><p><strong>Methods: </strong><i>Zfyve19</i> knockout (<i>Zfyve19<sup>-/-</sup></i> ) mice were generated and exposed to different liver toxins. Their livers were characterised at the tissue, cellular and molecular levels. Findings were compared with those in wild-type mice and in ZFYVE19-deficient patients. <i>ZFYVE19</i> knockout and knockdown retinal pigment epithelial-1 cells and mouse embryonic fibroblasts were generated to study cell division and cell death.</p><p><strong>Results: </strong>The <i>Zfyve19<sup>-/-</sup></i> mice were normal overall, particularly with respect to hepatobiliary features. However, when challenged with α-naphthyl isothiocyanate, <i>Zfyve19<sup>-/-</sup></i> mice developed changes resembling those in ZFYVE19-deficient patients, including elevated serum liver injury markers, increased numbers of bile duct profiles with abnormal cholangiocyte polarity and biliary fibrosis. Failure of cell division, centriole and cilia abnormalities, and increased cell death were observed in knockdown/knockout cells. Increased cell death and altered mRNA expression of cell death-related signalling pathways was demonstrated in livers from <i>Zfyve19<sup>-/-</sup></i> mice and patients. Transforming growth factor-β (TGF-β) and Janus kinase-Signal Transducer and Activator of Transcription 3 (JAK-STAT3) signalling pathways were upregulated in vivo, as were chemokines such as C-X-C motif ligands 1, 10 and 12.</p><p><strong>Conclusions: </strong>Our findings demonstrated that ZFYVE19 deficiency is a ciliopathy with novel histological features. Failure of cell division with ciliary abnormalities and cell death activates macrophages and may thus lead to biliary fibrosis via TGF-β pathway in the disease.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"750-758"},"PeriodicalIF":3.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11287636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179442","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}
Bree E Martin, Tristan Sands, Louise Bier, Amanda Bergner, Amelia K Boehme, Natalie Lippa
Background: Studies indicate that variants of uncertain significance are more common in non-European populations due to lack of a diversity in population databases. This difference has not been explored in epilepsy, which is increasingly found to be genetic in paediatric populations, and has precision medicine applications. This study examines the differences in the frequency of uncertain next-generation sequencing (NGS) results among a paediatric epilepsy cohort between ancestral groups historically under-represented in biomedical research (UBR) and represented in biomedical research (RBR).
Methods: A retrospective chart review of patients with epilepsy seen at Columbia University Irving Medical Center (CUIMC). One hundred seventy-eight cases met the following criteria: (1) visited any provider within the Pediatric Neurology Clinic at CUIMC, (2) had an ICD code indicating a diagnosis of epilepsy, (3) underwent NGS testing after March 2015 and (4) had self-reported ancestry that fit into a single dichotomous category of either historically represented or under-represented in biomedical research.
Results: UBR cases had significantly higher rates of uncertain results when compared with RBR cases (79.2% UBR, 20.8% RBR; p value=0.002). This finding remained true after controlling for potential confounding factors, including sex, intellectual disability or developmental delay, epilepsy type, age of onset, number of genes tested and year of testing.
Conclusion: Our results add to the literature that individuals who are of ancestries historically under-represented in genetics research are more likely to receive uncertain genetic results than those of represented majority ancestral groups and establishes this finding in an epilepsy cohort.
{"title":"Comparing the frequency of variants of uncertain significance (VUS) between ancestry groups in a paediatric epilepsy cohort.","authors":"Bree E Martin, Tristan Sands, Louise Bier, Amanda Bergner, Amelia K Boehme, Natalie Lippa","doi":"10.1136/jmg-2023-109450","DOIUrl":"10.1136/jmg-2023-109450","url":null,"abstract":"<p><strong>Background: </strong>Studies indicate that variants of uncertain significance are more common in non-European populations due to lack of a diversity in population databases. This difference has not been explored in epilepsy, which is increasingly found to be genetic in paediatric populations, and has precision medicine applications. This study examines the differences in the frequency of uncertain next-generation sequencing (NGS) results among a paediatric epilepsy cohort between ancestral groups historically under-represented in biomedical research (UBR) and represented in biomedical research (RBR).</p><p><strong>Methods: </strong>A retrospective chart review of patients with epilepsy seen at Columbia University Irving Medical Center (CUIMC). One hundred seventy-eight cases met the following criteria: (1) visited any provider within the Pediatric Neurology Clinic at CUIMC, (2) had an ICD code indicating a diagnosis of epilepsy, (3) underwent NGS testing after March 2015 and (4) had self-reported ancestry that fit into a single dichotomous category of either historically represented or under-represented in biomedical research.</p><p><strong>Results: </strong>UBR cases had significantly higher rates of uncertain results when compared with RBR cases (79.2% UBR, 20.8% RBR; p value=0.002). This finding remained true after controlling for potential confounding factors, including sex, intellectual disability or developmental delay, epilepsy type, age of onset, number of genes tested and year of testing.</p><p><strong>Conclusion: </strong>Our results add to the literature that individuals who are of ancestries historically under-represented in genetics research are more likely to receive uncertain genetic results than those of represented majority ancestral groups and establishes this finding in an epilepsy cohort.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"645-651"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059629","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}
Umut Altunoglu, Adrian Palencia-Campos, Nilay Güneş, Gozde Tutku Turgut, Julian Nevado, Pablo Lapunzina, Maria Valencia, Asier Iturrate, Ghada Otaify, Rasha Elhossini, Adel Ashour, Asmaa K Amin, Rania F Elnahas, Elisa Fernandez-Nuñez, Carmen-Lisset Flores, Pedro Arias, Jair Tenorio, Carlos Israel Chamorro Fernández, Yeliz Güven, Elif Özsu, Beray Selver Eklioğlu, Marisol Ibarra-Ramirez, Birgitte Rode Diness, Birute Burnyte, Houda Ajmi, Zafer Yüksel, Ruken Yıldırım, Edip Ünal, Ebtesam Abdalla, Mona Aglan, Hulya Kayserili, Beyhan Tuysuz, Victor Ruiz-Pérez
Background: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum.
Methods: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays.
Main results: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC.
Conclusions: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.
{"title":"Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.","authors":"Umut Altunoglu, Adrian Palencia-Campos, Nilay Güneş, Gozde Tutku Turgut, Julian Nevado, Pablo Lapunzina, Maria Valencia, Asier Iturrate, Ghada Otaify, Rasha Elhossini, Adel Ashour, Asmaa K Amin, Rania F Elnahas, Elisa Fernandez-Nuñez, Carmen-Lisset Flores, Pedro Arias, Jair Tenorio, Carlos Israel Chamorro Fernández, Yeliz Güven, Elif Özsu, Beray Selver Eklioğlu, Marisol Ibarra-Ramirez, Birgitte Rode Diness, Birute Burnyte, Houda Ajmi, Zafer Yüksel, Ruken Yıldırım, Edip Ünal, Ebtesam Abdalla, Mona Aglan, Hulya Kayserili, Beyhan Tuysuz, Victor Ruiz-Pérez","doi":"10.1136/jmg-2023-109546","DOIUrl":"10.1136/jmg-2023-109546","url":null,"abstract":"<p><strong>Background: </strong>Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in <i>EVC</i> or <i>EVC2</i>. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum.</p><p><strong>Methods: </strong>We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays.</p><p><strong>Main results: </strong>We identified pathogenic variants in <i>EVC/EVC2</i> in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in <i>WDR35</i> and a de novo heterozygous frameshift variant in <i>GLI3</i>, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel <i>EVC2</i> C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC.</p><p><strong>Conclusions: </strong>This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the <i>EVC</i>/<i>EVC2</i> mutational landscape and add <i>GLI3</i> to the list of genes associated with EvC-like phenotypes.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"633-644"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140293764","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}
Yalan Wan, Chao Zhou, Xingzhi Chang, Liwen Wu, Yilei Zheng, Jiaxi Yu, Li Bai, Mingyue Luan, Meng Yu, Qi Wang, Wei Zhang, Yun Yuan, Jianwen Deng, Zhaoxia Wang
Background: Congenital myopathies are a clinical, histopathological and genetic heterogeneous group of inherited muscle disorders that are defined on peculiar architectural abnormalities in the muscle fibres. Although there have been at least 33 different genetic causes of the disease, a significant percentage of congenital myopathies remain genetically unresolved. The present study aimed to report a novel TUBA4A variant in two unrelated Chinese patients with sporadic congenital myopathy.
Methods: A comprehensive strategy combining laser capture microdissection, proteomics and whole-exome sequencing was performed to identify the candidate genes. In addition, the available clinical data, myopathological changes, the findings of electrophysiological examinations and thigh muscle MRIs were also reviewed. A cellular model was established to assess the pathogenicity of the TUBA4A variant.
Results: We identified a recurrent novel heterozygous de novo c.679C>T (p.L227F) variant in the TUBA4A (NM_006000), encoding tubulin alpha-4A, in two unrelated patients with clinicopathologically diagnosed sporadic congenital myopathy. The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F mutant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.
Conclusion: Our findings expanded the phenotypic and genetic manifestations of TUBA4A as well as tubulinopathies, and added a new type of congenital myopathy to be taken into consideration in the differential diagnosis.
{"title":"Novel <i>TUBA4A</i> variant causes congenital myopathy with focal myofibrillar disorganisation.","authors":"Yalan Wan, Chao Zhou, Xingzhi Chang, Liwen Wu, Yilei Zheng, Jiaxi Yu, Li Bai, Mingyue Luan, Meng Yu, Qi Wang, Wei Zhang, Yun Yuan, Jianwen Deng, Zhaoxia Wang","doi":"10.1136/jmg-2023-109786","DOIUrl":"10.1136/jmg-2023-109786","url":null,"abstract":"<p><strong>Background: </strong>Congenital myopathies are a clinical, histopathological and genetic heterogeneous group of inherited muscle disorders that are defined on peculiar architectural abnormalities in the muscle fibres. Although there have been at least 33 different genetic causes of the disease, a significant percentage of congenital myopathies remain genetically unresolved. The present study aimed to report a novel <i>TUBA4A</i> variant in two unrelated Chinese patients with sporadic congenital myopathy.</p><p><strong>Methods: </strong>A comprehensive strategy combining laser capture microdissection, proteomics and whole-exome sequencing was performed to identify the candidate genes. In addition, the available clinical data, myopathological changes, the findings of electrophysiological examinations and thigh muscle MRIs were also reviewed. A cellular model was established to assess the pathogenicity of the <i>TUBA4A</i> variant.</p><p><strong>Results: </strong>We identified a recurrent novel heterozygous de novo c.679C>T (p.L227F) variant in the <i>TUBA4A</i> (NM_006000), encoding tubulin alpha-4A, in two unrelated patients with clinicopathologically diagnosed sporadic congenital myopathy. The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F mutant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.</p><p><strong>Conclusion: </strong>Our findings expanded the phenotypic and genetic manifestations of <i>TUBA4A</i> as well as tubulinopathies, and added a new type of congenital myopathy to be taken into consideration in the differential diagnosis.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"626-632"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139983116","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}
Background: As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases.
Methods: We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines.
Results: A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases.
Conclusion: A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.
{"title":"Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases.","authors":"Kensuke Goto, Yoshito Koyanagi, Masato Akiyama, Yusuke Murakami, Masatoshi Fukushima, Kohta Fujiwara, Hanae Iijima, Mitsuyo Yamaguchi, Mikiko Endo, Kazuki Hashimoto, Masataka Ishizu, Toshiaki Hirakata, Kei Mizobuchi, Masakazu Takayama, Junya Ota, Ai Fujita Sajiki, Taro Kominami, Hiroaki Ushida, Kosuke Fujita, Hiroki Kaneko, Shinji Ueno, Takaaki Hayashi, Chikashi Terao, Yoshihiro Hotta, Akira Murakami, Kazuki Kuniyoshi, Shunji Kusaka, Yuko Wada, Toshiaki Abe, Toru Nakazawa, Yasuhiro Ikeda, Yukihide Momozawa, Koh-Hei Sonoda, Koji M Nishiguchi","doi":"10.1136/jmg-2023-109750","DOIUrl":"10.1136/jmg-2023-109750","url":null,"abstract":"<p><strong>Background: </strong>As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases.</p><p><strong>Methods: </strong>We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines.</p><p><strong>Results: </strong>A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with <i>EYS</i> accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases.</p><p><strong>Conclusion: </strong>A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"613-620"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140158311","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}
Background: The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy.
Methods: Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy.
Results: Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth.
Conclusion: ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.
背景:ZFHX3基因在胚胎发育、细胞增殖、神经元分化和神经元死亡中发挥着重要作用。本研究旨在探讨 ZFHX3 基因变异与癫痫之间的关系:方法:对378名部分性(局灶性)癫痫患者进行了全外显子组测序。采用果蝇 Zfh2 基因敲除模型验证 ZFHX3 与癫痫的关系:结果:在8例无关病例中发现了ZFHX3复合杂合变体。多重/特异性统计分析显示,病例队列中 ZFHX3 变体的负担明显较高。在 Zfh2 基因敲除的苍蝇中,癫痫样行为的发生率和持续时间明显高于对照组。Zfh2基因敲除的苍蝇表现出更多的兴奋性神经元点燃。所有患者都出现了部分性癫痫发作。C端/N端变异的五名患者表现为轻度部分性癫痫。另外三名患者中,一名经常出现非惊厥性癫痫状态,两名出现早期痉挛。这三名患者也有神经发育异常,被诊断为发育性癫痫性脑病(DEE),但在接受抗癫痫药物治疗而不使用促肾上腺皮质激素/类固醇后,癫痫不再发作。对时间表达(遗传依赖阶段)的分析表明,ZFHX3同源物在胚胎期高度表达,出生后则急剧下降:结论:ZFHX3 是儿童部分性癫痫和 DEE 的新型致病基因。结论:ZFHX3 是儿童部分性癫痫和 DEE 的新致病基因,婴儿痉挛症患者在不使用促肾上腺皮质激素/类固醇治疗后癫痫不再发作,这意味着基因诊断在精确治疗中具有重要意义。遗传依赖阶段让人们了解了疾病演变过程的内在机制。
{"title":"<i>ZFHX3</i> variants cause childhood partial epilepsy and infantile spasms with favourable outcomes.","authors":"Ming-Feng He, Li-Hong Liu, Sheng Luo, Juan Wang, Jia-Jun Guo, Peng-Yu Wang, Qiong-Xiang Zhai, Su-Li He, Dong-Fang Zou, Xiao-Rong Liu, Bing-Mei Li, Hai-Yan Ma, Jing-Da Qiao, Peng Zhou, Na He, Yong-Hong Yi, Wei-Ping Liao","doi":"10.1136/jmg-2023-109725","DOIUrl":"10.1136/jmg-2023-109725","url":null,"abstract":"<p><strong>Background: </strong>The <i>ZFHX3</i> gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between <i>ZFHX3</i> variants and epilepsy.</p><p><strong>Methods: </strong>Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A <i>Drosophila Zfh2</i> knockdown model was used to validate the association between <i>ZFHX3</i> and epilepsy.</p><p><strong>Results: </strong>Compound heterozygous <i>ZFHX3</i> variants were identified in eight unrelated cases. The burden of <i>ZFHX3</i> variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In <i>Zfh2</i> knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The <i>Zfh2</i> knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that <i>ZFHX3</i> orthologous were highly expressed in the embryonic stage and decreased dramatically after birth.</p><p><strong>Conclusion: </strong><i>ZFHX3</i> is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"652-660"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175022","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}
Terri Patricia McVeigh, Kevin J Monahan, Joseph Christopher, Nick West, Malcolm Scott, Jennie Murray, Helen Hanson
Background: Mismatch repair deficiency (dMMR) is a characteristic feature of cancers linked to Lynch syndrome. However, in most cases, it results from sporadic somatic events rather than hereditary factors. The term 'Lynch-like syndrome' (LLS) has been used to guide colorectal cancer surveillance for relatives of individuals with a dMMR tumour when somatic and germline genomic testing is uninformative. As the assessment of mismatch repair through immunohistochemistry and/or microsatellite instability is increasingly applied across various tumour types for treatment planning, dMMR is increasingly detected in tumours where suspicion of hereditary aetiology is low. Our objective was to establish current practices and develop national guidance for investigating, and managing relatives of, patients with cancers demonstrating unexplained dMMR.
Methods: This was achieved through a virtual consensus meeting involving key stakeholders from the UK, through premeeting surveys, structured discussions and in-meeting polling to formulate best practice guidance.
Results: We identified variability in the availability of diagnostic technologies across specialist centres. It was agreed that equitable access to baseline testing is required, acknowledging the need for a pragmatic approach to investigating dMMR cancers not traditionally associated with Lynch syndrome. Factors such as family history, age, tumour type, protein loss pattern and extent of the investigation were deemed crucial in guiding family management. The term 'unexplained dMMR' was recommended over LLS.
Conclusion: Decisions regarding investigations and future cancer risk management in patients and relatives should be nuanced, considering factors like clinical suspicion of hereditary predisposition to allocate limited resources efficiently and avoid unnecessary investigations in low-suspicion families.
{"title":"Extent of investigation and management of cases of 'unexplained' mismatch repair deficiency (u-dMMR): a UK Cancer Genetics Group consensus.","authors":"Terri Patricia McVeigh, Kevin J Monahan, Joseph Christopher, Nick West, Malcolm Scott, Jennie Murray, Helen Hanson","doi":"10.1136/jmg-2024-109886","DOIUrl":"10.1136/jmg-2024-109886","url":null,"abstract":"<p><strong>Background: </strong>Mismatch repair deficiency (dMMR) is a characteristic feature of cancers linked to Lynch syndrome. However, in most cases, it results from sporadic somatic events rather than hereditary factors. The term 'Lynch-like syndrome' (LLS) has been used to guide colorectal cancer surveillance for relatives of individuals with a dMMR tumour when somatic and germline genomic testing is uninformative. As the assessment of mismatch repair through immunohistochemistry and/or microsatellite instability is increasingly applied across various tumour types for treatment planning, dMMR is increasingly detected in tumours where suspicion of hereditary aetiology is low. Our objective was to establish current practices and develop national guidance for investigating, and managing relatives of, patients with cancers demonstrating unexplained dMMR.</p><p><strong>Methods: </strong>This was achieved through a virtual consensus meeting involving key stakeholders from the UK, through premeeting surveys, structured discussions and in-meeting polling to formulate best practice guidance.</p><p><strong>Results: </strong>We identified variability in the availability of diagnostic technologies across specialist centres. It was agreed that equitable access to baseline testing is required, acknowledging the need for a pragmatic approach to investigating dMMR cancers not traditionally associated with Lynch syndrome. Factors such as family history, age, tumour type, protein loss pattern and extent of the investigation were deemed crucial in guiding family management. The term 'unexplained dMMR' was recommended over LLS.</p><p><strong>Conclusion: </strong>Decisions regarding investigations and future cancer risk management in patients and relatives should be nuanced, considering factors like clinical suspicion of hereditary predisposition to allocate limited resources efficiently and avoid unnecessary investigations in low-suspicion families.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"707-715"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140293763","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}
Wen Wen, Zhengye Zhao, Zhifa Zheng, Sen Zhao, Hengqiang Zhao, Xi Cheng, Huakang Du, Ziquan Li, Shengru Wang, Guixing Qiu, Zhihong Wu, Terry Jianguo Zhang, Nan Wu
Background: Adolescent idiopathic scoliosis (AIS), the predominant genetic-influenced scoliosis, results in spinal deformities without vertebral malformations. However, the molecular aetiology of AIS remains unclear.
Methods: Using genome/exome sequencing, we studied 368 patients with severe AIS (Cobb angle >40°) and 3794 controls from a Han Chinese cohort. We performed gene-based and pathway-based weighted rare variant association tests to assess the mutational burden of genes and established biological pathways. Differential expression analysis of muscle tissues from 14 patients with AIS and 15 controls was served for validation.
Results: SLC16A8, a lactate transporter linked to retinal glucose metabolism, was identified as a novel severe AIS-associated gene (p=3.08E-06, false discovery rate=0.009). Most AIS cases with deleterious SLC16A8 variants demonstrated early onset high myopia preceding scoliosis. Pathway-based burden test also revealed a significant enrichment in multiple carbohydrate metabolism pathways, especially galactose metabolism. Patients with deleterious variants in these genes demonstrated a significantly larger spinal curve. Genes related to catabolic processes and nutrient response showed divergent expression between AIS cases and controls, reinforcing our genomic findings.
Conclusion: This study uncovers the pivotal role of genetic variants in carbohydrate metabolism in the development of AIS, unveiling new insights into its aetiology and potential treatment.
{"title":"Rare variant association analyses reveal the significant contribution of carbohydrate metabolic disturbance in severe adolescent idiopathic scoliosis.","authors":"Wen Wen, Zhengye Zhao, Zhifa Zheng, Sen Zhao, Hengqiang Zhao, Xi Cheng, Huakang Du, Ziquan Li, Shengru Wang, Guixing Qiu, Zhihong Wu, Terry Jianguo Zhang, Nan Wu","doi":"10.1136/jmg-2023-109667","DOIUrl":"10.1136/jmg-2023-109667","url":null,"abstract":"<p><strong>Background: </strong>Adolescent idiopathic scoliosis (AIS), the predominant genetic-influenced scoliosis, results in spinal deformities without vertebral malformations. However, the molecular aetiology of AIS remains unclear.</p><p><strong>Methods: </strong>Using genome/exome sequencing, we studied 368 patients with severe AIS (Cobb angle >40°) and 3794 controls from a Han Chinese cohort. We performed gene-based and pathway-based weighted rare variant association tests to assess the mutational burden of genes and established biological pathways. Differential expression analysis of muscle tissues from 14 patients with AIS and 15 controls was served for validation.</p><p><strong>Results: </strong><i>SLC16A8</i>, a lactate transporter linked to retinal glucose metabolism, was identified as a novel severe AIS-associated gene (p=3.08E-06, false discovery rate=0.009). Most AIS cases with deleterious <i>SLC16A8</i> variants demonstrated early onset high myopia preceding scoliosis. Pathway-based burden test also revealed a significant enrichment in multiple carbohydrate metabolism pathways, especially galactose metabolism. Patients with deleterious variants in these genes demonstrated a significantly larger spinal curve. Genes related to catabolic processes and nutrient response showed divergent expression between AIS cases and controls, reinforcing our genomic findings.</p><p><strong>Conclusion: </strong>This study uncovers the pivotal role of genetic variants in carbohydrate metabolism in the development of AIS, unveiling new insights into its aetiology and potential treatment.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"666-676"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140898208","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}
Claire E L Smith, Virginie Laugel-Haushalter, Ummey Hany, Sunayna Best, Rachel L Taylor, James A Poulter, Saskia B Wortmann, Rene G Feichtinger, Johannes A Mayr, Suhaila Al Bahlani, Georgios Nikolopoulos, Alice Rigby, Graeme C Black, Christopher M Watson, Sahar Mansour, Chris F Inglehearn, Alan J Mighell, Agnès Bloch-Zupan
Background: Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic PLXND1 and PLXNA1 variants have so far been associated with Mendelian genetic disease.
Methods: Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice.
Results: Rare biallelic pathogenic variants in plexin B2 (PLXNB2), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. Plxnb2 expression was detected in differentiating ameloblasts.
Conclusion: We identify rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in Plxnb2 knockout mice, and, together with the rarity of human PLXNB2 variants, may explain why pathogenic variants in PLXNB2 have not been reported previously.
{"title":"Biallelic variants in Plexin B2 (<i>PLXNB2</i>) cause amelogenesis imperfecta, hearing loss and intellectual disability.","authors":"Claire E L Smith, Virginie Laugel-Haushalter, Ummey Hany, Sunayna Best, Rachel L Taylor, James A Poulter, Saskia B Wortmann, Rene G Feichtinger, Johannes A Mayr, Suhaila Al Bahlani, Georgios Nikolopoulos, Alice Rigby, Graeme C Black, Christopher M Watson, Sahar Mansour, Chris F Inglehearn, Alan J Mighell, Agnès Bloch-Zupan","doi":"10.1136/jmg-2023-109728","DOIUrl":"10.1136/jmg-2023-109728","url":null,"abstract":"<p><strong>Background: </strong>Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic <i>PLXND1</i> and <i>PLXNA1</i> variants have so far been associated with Mendelian genetic disease.</p><p><strong>Methods: </strong>Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice.</p><p><strong>Results: </strong>Rare biallelic pathogenic variants in plexin B2 (<i>PLXNB2</i>), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. <i>Plxnb2</i> expression was detected in differentiating ameloblasts.</p><p><strong>Conclusion: </strong>We identify rare biallelic pathogenic variants in <i>PLXNB2</i> as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in <i>Plxnb2</i> knockout mice, and, together with the rarity of human <i>PLXNB2</i> variants, may explain why pathogenic variants in <i>PLXNB2</i> have not been reported previously.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"689-698"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065220","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}