Background: To delineate the clinical and mutational signatures of patients with CRB1-associated retinopathies.
Methods: This multicentre retrospective cohort study involved 40 patients with CRB1 mutations and 40 age-matched and gender-matched inherited retinal diseases (IRDs). The detailed phenotyping and genotyping characteristics and genotype‒phenotype correlations of the patients were analysed.
Results: The mean age of CRB1 cohort was 27.33±14.63 years. Results showed that yellowish geographic macular degeneration (66.67%), small white or yellow dots (65.6%), hyperopia (62.5%), abnormally laminated retina (61.61%), epiretinal membrane (60.6%) and nummular pigment deposits (50%) were the most common signatures in patients with CRB1 mutations. These clinical signatures were notably more prevalent among CRB1 patients than among individuals in other IRD groups (p<0.001). Early-onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA) patients are more likely to present these signatures than retinitis pigmentosa (RP) and macular dystrophy (MD) patients. Furthermore, a significant reduction in central foveal thickness coupled with pronounced thickening of the peripheral retina was observed more distinctly in patients with EOSRD/LCA (p<0.001). The choroidal thickness was not significantly altered compared to the normal controls, but was markedly reduced in the other IRD groups (p<0.001). 55 pathogenic variants were identified, 20 of which were novel. Null mutations were associated with EOSRD/LCA patients, and missense mutations were more prevalent in MD and RP patients.
Conclusions: Key clinical and mutational signatures were demonstrated in this study, providing a comprehensive update on CRB1-associated retinopathies that will aid in diagnosis and lay the foundation for future therapeutic studies.
{"title":"Clinical and mutational signatures of <i>CRB1</i>-associated retinopathies: a multicentre study.","authors":"Mo-Ying Wang, Feng-Juan Gao, Yu-Qiao Ju, Lin-Ying Guo, Cong Duan, Qing Chang, Ting Zhang, Ge-Zhi Xu, Hui Du, Yuan Zong, Xin Huang","doi":"10.1136/jmg-2024-110289","DOIUrl":"10.1136/jmg-2024-110289","url":null,"abstract":"<p><strong>Background: </strong>To delineate the clinical and mutational signatures of patients with <i>CRB1</i>-associated retinopathies.</p><p><strong>Methods: </strong>This multicentre retrospective cohort study involved 40 patients with <i>CRB1</i> mutations and 40 age-matched and gender-matched inherited retinal diseases (IRDs). The detailed phenotyping and genotyping characteristics and genotype‒phenotype correlations of the patients were analysed.</p><p><strong>Results: </strong>The mean age of <i>CRB1</i> cohort was 27.33±14.63 years. Results showed that yellowish geographic macular degeneration (66.67%), small white or yellow dots (65.6%), hyperopia (62.5%), abnormally laminated retina (61.61%), epiretinal membrane (60.6%) and nummular pigment deposits (50%) were the most common signatures in patients with <i>CRB1</i> mutations. These clinical signatures were notably more prevalent among <i>CRB1</i> patients than among individuals in other IRD groups (p<0.001). Early-onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA) patients are more likely to present these signatures than retinitis pigmentosa (RP) and macular dystrophy (MD) patients. Furthermore, a significant reduction in central foveal thickness coupled with pronounced thickening of the peripheral retina was observed more distinctly in patients with EOSRD/LCA (p<0.001). The choroidal thickness was not significantly altered compared to the normal controls, but was markedly reduced in the other IRD groups (p<0.001). 55 pathogenic variants were identified, 20 of which were novel. Null mutations were associated with EOSRD/LCA patients, and missense mutations were more prevalent in MD and RP patients.</p><p><strong>Conclusions: </strong>Key clinical and mutational signatures were demonstrated in this study, providing a comprehensive update on <i>CRB1</i>-associated retinopathies that will aid in diagnosis and lay the foundation for future therapeutic studies.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576422","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}
Kayla Horowitz, Nellie H Fotopoulos, Alana J Mistry, Justin Simo, Miranda Medeiros, Isabela D Bucco, Mia Ginsberg, Emily Dwosh, Roberta La Piana, Guy A Rouleau, Allison A Dilliott, Sali M K Farhan
Background: The findings of variants of uncertain significance (VUS) on a clinical genetic testing report pose a challenge for attending healthcare professionals (HCPs) in patient care. Here, we describe the outcomes of multidisciplinary VUS Rounds, implemented at a neurological disease tertiary care centre, which aid in interpreting and communicating VUS identified in our neurogenetics patient population.
Methods: VUS Rounds brought together genetic counsellors, molecular geneticists and scientists to evaluate VUS against genomic and phenotypic evidence and assign an internal temperature classification of 'VUS Hot', 'True VUS' or 'VUS Cold', corresponding to potential pathogenicity. Biweekly meetings were held among the committee to deliberate variant classifications, determine additional clinical management actions and discuss nuances of VUS result communication.
Results: In total, 143 VUS identified in 72 individuals with neurological disease were curated between October 2022 and December 2023. Of these, 12.6% were classified as VUS Hot, carried by 22.2% of the individuals, allowing for prioritisation of additional evaluation to determine potential pathogenicity of the variants, such as clinical follow-up or segregation analysis. In contrast, 45.4% of VUS were Cold and could be eliminated from further consideration in the carrier's care. We thoroughly evaluated the various evidence that contributed to our VUS classifications and resulting clinical actions.
Conclusions: The assessment of VUS leveraging multidisciplinary collaboration allowed us to delineate required follow-up analyses for our neurology patient population. Integration of VUS Rounds into healthcare practices ensures equitable knowledge dissemination among HCPs and effective incorporation of uncertain genetic results into patient care.
{"title":"Enhancing variant of uncertain significance (VUS) interpretation in neurogenetics: collaborative experiences from a tertiary care centre.","authors":"Kayla Horowitz, Nellie H Fotopoulos, Alana J Mistry, Justin Simo, Miranda Medeiros, Isabela D Bucco, Mia Ginsberg, Emily Dwosh, Roberta La Piana, Guy A Rouleau, Allison A Dilliott, Sali M K Farhan","doi":"10.1136/jmg-2024-110122","DOIUrl":"https://doi.org/10.1136/jmg-2024-110122","url":null,"abstract":"<p><strong>Background: </strong>The findings of variants of uncertain significance (VUS) on a clinical genetic testing report pose a challenge for attending healthcare professionals (HCPs) in patient care. Here, we describe the outcomes of multidisciplinary VUS Rounds, implemented at a neurological disease tertiary care centre, which aid in interpreting and communicating VUS identified in our neurogenetics patient population.</p><p><strong>Methods: </strong>VUS Rounds brought together genetic counsellors, molecular geneticists and scientists to evaluate VUS against genomic and phenotypic evidence and assign an internal temperature classification of 'VUS Hot', 'True VUS' or 'VUS Cold', corresponding to potential pathogenicity. Biweekly meetings were held among the committee to deliberate variant classifications, determine additional clinical management actions and discuss nuances of VUS result communication.</p><p><strong>Results: </strong>In total, 143 VUS identified in 72 individuals with neurological disease were curated between October 2022 and December 2023. Of these, 12.6% were classified as VUS Hot, carried by 22.2% of the individuals, allowing for prioritisation of additional evaluation to determine potential pathogenicity of the variants, such as clinical follow-up or segregation analysis. In contrast, 45.4% of VUS were Cold and could be eliminated from further consideration in the carrier's care. We thoroughly evaluated the various evidence that contributed to our VUS classifications and resulting clinical actions.</p><p><strong>Conclusions: </strong>The assessment of VUS leveraging multidisciplinary collaboration allowed us to delineate required follow-up analyses for our neurology patient population. Integration of VUS Rounds into healthcare practices ensures equitable knowledge dissemination among HCPs and effective incorporation of uncertain genetic results into patient care.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639215","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}
Vahid Akbari, Sarah Dada, Yaoqing Shen, Katherine Dixon, Duha Hejla, Andrew Galbraith, Sanaa Choufani, Rosanna Weksberg, Cornelius F Boerkoel, Laura Stewart, William T Gibson, Steven J M Jones
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are imprinting disorders caused by genetic or epigenetic aberrations of 15q11.2-q13. Their clinical testing is often multitiered; diagnostic testing begins with methylation-specific multiplex ligation-dependent probe amplification or methylation-sensitive PCR and then proceeds to molecular subtyping to determine the mechanism and recurrence risk. Currently, correct classification of a proband's PWS/AS subtype often requires parental samples, a costly process for families and health systems. The use of nanopore sequencing for molecular diagnosis of PWS and AS has been explored by Yamada et al; however, to confirm heterodisomy parental data were still required. Here, we investigate genome-wide nanopore sequencing in a larger cohort of PWS (18) and AS (6) as a singular test to detect the molecular subtype, without parental data. We accurately subtyped these cases including uniparental heterodisomy, mixed iso-/heterodisomy, type 1 and 2 deletions, microdeletion and UBE3A indels. One PWS case with a previously unresolved diagnosis subtyped as maternal isodisomy. This work highlights the application of long-read sequencing and other imprinted regions outside of the PWS/AS critical region to resolve the molecular diagnosis and subtyping of PWS and AS without parental data. The work also outlines an approach to generically detect heterodisomy through the interrogation of distant imprinted regions.
{"title":"Long-read sequencing for detection and subtyping of Prader-Willi and Angelman syndromes.","authors":"Vahid Akbari, Sarah Dada, Yaoqing Shen, Katherine Dixon, Duha Hejla, Andrew Galbraith, Sanaa Choufani, Rosanna Weksberg, Cornelius F Boerkoel, Laura Stewart, William T Gibson, Steven J M Jones","doi":"10.1136/jmg-2024-110115","DOIUrl":"https://doi.org/10.1136/jmg-2024-110115","url":null,"abstract":"<p><p>Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are imprinting disorders caused by genetic or epigenetic aberrations of 15q11.2-q13. Their clinical testing is often multitiered; diagnostic testing begins with methylation-specific multiplex ligation-dependent probe amplification or methylation-sensitive PCR and then proceeds to molecular subtyping to determine the mechanism and recurrence risk. Currently, correct classification of a proband's PWS/AS subtype often requires parental samples, a costly process for families and health systems. The use of nanopore sequencing for molecular diagnosis of PWS and AS has been explored by Yamada <i>et al</i>; however, to confirm heterodisomy parental data were still required. Here, we investigate genome-wide nanopore sequencing in a larger cohort of PWS (18) and AS (6) as a singular test to detect the molecular subtype, without parental data. We accurately subtyped these cases including uniparental heterodisomy, mixed iso-/heterodisomy, type 1 and 2 deletions, microdeletion and <i>UBE3A</i> indels. One PWS case with a previously unresolved diagnosis subtyped as maternal isodisomy. This work highlights the application of long-read sequencing and other imprinted regions outside of the PWS/AS critical region to resolve the molecular diagnosis and subtyping of PWS and AS without parental data. The work also outlines an approach to generically detect heterodisomy through the interrogation of distant imprinted regions.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622214","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}
Marina Eskin-Schwartz, Shaikah Seraidy, Eyal Paz, Maism Molhem, Emmanuelle Ranza, Stylianos E Antonarakis, Xavier Blanc, Kristin Herman, William S Benko, Stephanie Libzon, Liat Ben Sira, Aviva Fattal-Valevski, Vadim Dolgin, Ohad S Birk, Amit Kessel, Peter Bross, Celeste Weiss, Abdussalam Azem, Ayelet Zerem
Introduction: Hypomyelinating leukodystrophies are a group of genetic disorders, characterised by severe permanent myelin deficiency. Their clinical features include developmental delay with or without neuroregression, nystagmus, central hypotonia, progressing to spasticity and ataxia. HSPD1 encodes the HSP60 chaperonin protein, mediating ATP-dependent folding of imported proteins in the mitochondrial matrix. Pathogenic variants in HSPD1 have been related to a number of neurological phenotypes, including the dominantly inherited pure hereditary spastic paraplegia (MIM 605280) and the recessively inherited hypomyelinating leukodystrophy 4 (MIM 612233). Subsequently, an additional phenotype of hypomyelinating leukodystrophy has been reported due to de novo heterozygous HSPD1 variants.In the current work, we expand the clinical and genetic spectrum of this hypomyelinating disorder by describing a cohort of three patients, being heterozygous for HSPD1 variants involving residue Ala536 of HSP60 (the novel p.Ala536Pro variant and the previously reported p.Ala536Val).
Methods: Clinical and radiological evaluation; whole exome sequencing, in vitro reconstitution assay and patient fibroblast cell lysate analysis.
Results: Clinical manifestation was of early-onset nystagmus, tremor and hypotonia evolving into spasticity and ataxia and childhood-onset neuroregression in one case. Brain MRI studies revealed diffuse hypomyelination.The 3D protein structure showed these variants to lie in spatial proximity to the previously reported Leu47Val variant, associated with a similar clinical phenotype. In vitro reconstitution assay and patient fibroblast cell lysate analysis demonstrated that these mutants display aberrant chaperonin protein complex assembly.
Discussion: We provide evidence that impaired oligomerisation of the chaperonin complex might underlie this HSPD1-related phenotype, possibly through exerting a dominant negative effect.
{"title":"Heterozygous de novo variants in <i>HSPD1</i> cause hypomyelinating leukodystrophy through impaired HSP60 oligomerisation.","authors":"Marina Eskin-Schwartz, Shaikah Seraidy, Eyal Paz, Maism Molhem, Emmanuelle Ranza, Stylianos E Antonarakis, Xavier Blanc, Kristin Herman, William S Benko, Stephanie Libzon, Liat Ben Sira, Aviva Fattal-Valevski, Vadim Dolgin, Ohad S Birk, Amit Kessel, Peter Bross, Celeste Weiss, Abdussalam Azem, Ayelet Zerem","doi":"10.1136/jmg-2024-109862","DOIUrl":"https://doi.org/10.1136/jmg-2024-109862","url":null,"abstract":"<p><strong>Introduction: </strong>Hypomyelinating leukodystrophies are a group of genetic disorders, characterised by severe permanent myelin deficiency. Their clinical features include developmental delay with or without neuroregression, nystagmus, central hypotonia, progressing to spasticity and ataxia. <i>HSPD1</i> encodes the HSP60 chaperonin protein, mediating ATP-dependent folding of imported proteins in the mitochondrial matrix. Pathogenic variants in <i>HSPD1</i> have been related to a number of neurological phenotypes, including the dominantly inherited pure hereditary spastic paraplegia (MIM 605280) and the recessively inherited hypomyelinating leukodystrophy 4 (MIM 612233). Subsequently, an additional phenotype of hypomyelinating leukodystrophy has been reported due to de novo heterozygous <i>HSPD1</i> variants.In the current work, we expand the clinical and genetic spectrum of this hypomyelinating disorder by describing a cohort of three patients, being heterozygous for <i>HSPD1</i> variants involving residue Ala536 of HSP60 (the novel p.Ala536Pro variant and the previously reported p.Ala536Val).</p><p><strong>Methods: </strong>Clinical and radiological evaluation; whole exome sequencing, in vitro reconstitution assay and patient fibroblast cell lysate analysis.</p><p><strong>Results: </strong>Clinical manifestation was of early-onset nystagmus, tremor and hypotonia evolving into spasticity and ataxia and childhood-onset neuroregression in one case. Brain MRI studies revealed diffuse hypomyelination.The 3D protein structure showed these variants to lie in spatial proximity to the previously reported Leu47Val variant, associated with a similar clinical phenotype. In vitro reconstitution assay and patient fibroblast cell lysate analysis demonstrated that these mutants display aberrant chaperonin protein complex assembly.</p><p><strong>Discussion: </strong>We provide evidence that impaired oligomerisation of the chaperonin complex might underlie this HSPD1-related phenotype, possibly through exerting a dominant negative effect.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582367","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}
Cathy D Vocke, Christopher J Ricketts, Svetlana Pack, Mark Raffeld, Stephen Hewitt, Alexandra P Lebensohn, Lidenys O'Brien, Rabindra Gautam, Krista Reynolds, Laura S Schmidt, Kristin Choo, Alex Kenigsberg, Sandeep Gurram, Emily Y Chew, Naris Nilubol, Prashant Chittaboina, Maria J Merino, Mark W Ball, W Marston Linehan
von Hippel-Lindau (VHL) is an autosomal-dominant hereditary tumour susceptibility disease associated with pathogenic germline variants in the VHL tumour suppressor gene. VHL patients are at increased risk of developing multiple benign and malignant tumours. Current CLIA-based genetic tests demonstrate a very high detection rate of germline VHL variants in patients with clinical manifestations of VHL. In this report, we describe a large family with canonical VHL manifestations, for which no germline alteration had been detected by conventional germline testing. We identified a novel 291 kb chromosomal inversion involving chromosome 3p in affected family members. This inversion disrupts the VHL gene between exon 2 and exon 3 and is thereby responsible for the disease observed in this family.
{"title":"A novel pathogenic germline chromosome 3 inversion in von Hippel-Lindau disease.","authors":"Cathy D Vocke, Christopher J Ricketts, Svetlana Pack, Mark Raffeld, Stephen Hewitt, Alexandra P Lebensohn, Lidenys O'Brien, Rabindra Gautam, Krista Reynolds, Laura S Schmidt, Kristin Choo, Alex Kenigsberg, Sandeep Gurram, Emily Y Chew, Naris Nilubol, Prashant Chittaboina, Maria J Merino, Mark W Ball, W Marston Linehan","doi":"10.1136/jmg-2024-110202","DOIUrl":"10.1136/jmg-2024-110202","url":null,"abstract":"<p><p>von Hippel-Lindau (VHL) is an autosomal-dominant hereditary tumour susceptibility disease associated with pathogenic germline variants in the <i>VHL</i> tumour suppressor gene. VHL patients are at increased risk of developing multiple benign and malignant tumours. Current CLIA-based genetic tests demonstrate a very high detection rate of germline <i>VHL</i> variants in patients with clinical manifestations of VHL. In this report, we describe a large family with canonical VHL manifestations, for which no germline alteration had been detected by conventional germline testing. We identified a novel 291 kb chromosomal inversion involving chromosome 3p in affected family members. This inversion disrupts the <i>VHL</i> gene between exon 2 and exon 3 and is thereby responsible for the disease observed in this family.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1026-1030"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11503160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348350","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}
Brian C Kavanaugh, Jennifer Elacio, Carrie R Best, Danielle G St Pierre, Matthew F Pescosolido, Qing Ouyang, John Biedermann, Rebecca S Bradley, Judy S Liu, Richard N Jones, Eric M Morrow
Objectives: Mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome (CS). Here, in the largest study to date, we examine genetic diversity and clinical progression in CS into adulthood.
Method: Data were collected as part of the International Christianson Syndrome and NHE6 (SLC9A6) Gene Network Study. 44 individuals with 31 unique NHE6 mutations, age 2-32 years, were followed prospectively, herein reporting baseline, 1 year follow-up and retrospective natural history.
Results: We present data on the CS phenotype with regard to physical growth and adaptive and motor regression across the lifespan including information on mortality. Longitudinal data on body weight and height were examined using a linear mixed model. The rate of growth across development was slow and resulted in prominently decreased age-normed height and weight by adulthood. Adaptive functioning was longitudinally examined; a majority of adult participants (18+ years) lost gross and fine motor skills over a 1 year follow-up. Previously defined core diagnostic criteria for CS (present in>85%)-namely non-verbal status, intellectual disability, epilepsy, postnatal microcephaly, ataxia, hyperkinesia-were universally present in age 6-16; however, an additional core feature of high pain tolerance was added (present in 91%). While neurologic examinations were consistent with cerebellar dysfunction, importantly, a majority of individuals (>50% older than 10) also had corticospinal tract abnormalities. Three participants died during the period of the study.
Conclusions: In this large and longitudinal study of CS, we begin to define the trajectory of symptoms and the adult phenotype thereby identifying critical targets for treatment.
{"title":"Christianson syndrome across the lifespan: genetic mutations and longitudinal study in children, adolescents, and adults.","authors":"Brian C Kavanaugh, Jennifer Elacio, Carrie R Best, Danielle G St Pierre, Matthew F Pescosolido, Qing Ouyang, John Biedermann, Rebecca S Bradley, Judy S Liu, Richard N Jones, Eric M Morrow","doi":"10.1136/jmg-2024-109973","DOIUrl":"10.1136/jmg-2024-109973","url":null,"abstract":"<p><strong>Objectives: </strong>Mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome (CS). Here, in the largest study to date, we examine genetic diversity and clinical progression in CS into adulthood.</p><p><strong>Method: </strong>Data were collected as part of the International Christianson Syndrome and <i>NHE6</i> (<i>SLC9A6</i>) Gene Network Study. 44 individuals with 31 unique <i>NHE6</i> mutations, age 2-32 years, were followed prospectively, herein reporting baseline, 1 year follow-up and retrospective natural history.</p><p><strong>Results: </strong>We present data on the CS phenotype with regard to physical growth and adaptive and motor regression across the lifespan including information on mortality. Longitudinal data on body weight and height were examined using a linear mixed model. The rate of growth across development was slow and resulted in prominently decreased age-normed height and weight by adulthood. Adaptive functioning was longitudinally examined; a majority of adult participants (18+ years) lost gross and fine motor skills over a 1 year follow-up. Previously defined core diagnostic criteria for CS (present in>85%)-namely non-verbal status, intellectual disability, epilepsy, postnatal microcephaly, ataxia, hyperkinesia-were universally present in age 6-16; however, an additional core feature of high pain tolerance was added (present in 91%). While neurologic examinations were consistent with cerebellar dysfunction, importantly, a majority of individuals (>50% older than 10) also had corticospinal tract abnormalities. Three participants died during the period of the study.</p><p><strong>Conclusions: </strong>In this large and longitudinal study of CS, we begin to define the trajectory of symptoms and the adult phenotype thereby identifying critical targets for treatment.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1031-1039"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11503119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140312","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}
Background: GlcNAc2-epimerase (GNE) myopathy is a rare autosomal recessive disorder caused by pathogenic variants in the GNE gene, which is essential for the sialic acid biosynthesis pathway.
Objective: This multi-centre study aimed to delineate the clinical phenotype and GNE variant spectrum in Chinese patients, enhancing our understanding of the genetic diversity and clinical manifestation across different populations.
Methods: We retrospectively analysed GNE variants from 113 patients, integrating these data with external GNE variants from online databases for a global perspective, examining their consequences, distribution, ethnicity and severity.
Results: This study revealed 97 distinct GNE variants, including 35 (36.08%) novel variants. Two more patients with deep intronic variant c.862+870C>T were identified, while whole genome sequencing (WGS) uncovered another two novel intronic variants: c.52-8924G>T and c.1505-12G>A. Nanopore long reads sequencing (LRS) and further PCR analysis verified a 639 bp insertion at chr9:36249241. Missense variants predominantly located in the epimerase/kinase domain coding region, indicating the impairment of catalytic function as a key pathogenic consequence. Comparative studies with Japanese, Korean and Jewish, our cohorts showed later onset ages by 2 years. The high allele frequency of the non-catalytic GNE variant, c.620A>T, might underlie the milder phenotype of Chinese patients.
Conclusions: Comprehensive techniques such as WGS and Nanopore LRS warrants the identifying of GNE variants. Patients with the non-catalytic GNE variant, c.620A>T, had a milder disease progression and later wheelchair use.
{"title":"Novel variants and genotype-phenotype correlation in a multicentre cohort of GNE myopathy in China.","authors":"Kexin Jiao, Jialong Zhang, Qiuxiang Li, Xiaoqing Lv, Yanyan Yu, Bochen Zhu, Huahua Zhong, Xu'en Yu, Jia Song, Qing Ke, Fangyuan Qian, Xinghua Luan, Xiaojie Zhang, Xueli Chang, Liang Wang, Meirong Liu, Jihong Dong, Zhangyu Zou, Bitao Bu, Haishan Jiang, LingChun Liu, Yue Li, Dongyue Yue, Xuechun Chang, Yongsheng Zheng, Ningning Wang, Mingshi Gao, Xingyu Xia, Nachuan Cheng, Tao Wang, Su-Shan Luo, Jianying Xi, Jie Lin, Jiahong Lu, Chongbo Zhao, Huan Yang, Pengfei Lin, Daojun Hong, Zhe Zhao, Zhiqiang Wang, Wenhua Zhu","doi":"10.1136/jmg-2024-110149","DOIUrl":"10.1136/jmg-2024-110149","url":null,"abstract":"<p><strong>Background: </strong>GlcNAc2-epimerase (GNE) myopathy is a rare autosomal recessive disorder caused by pathogenic variants in the <i>GNE</i> gene, which is essential for the sialic acid biosynthesis pathway.</p><p><strong>Objective: </strong>This multi-centre study aimed to delineate the clinical phenotype and <i>GNE</i> variant spectrum in Chinese patients, enhancing our understanding of the genetic diversity and clinical manifestation across different populations.</p><p><strong>Methods: </strong>We retrospectively analysed <i>GNE</i> variants from 113 patients, integrating these data with external <i>GNE</i> variants from online databases for a global perspective, examining their consequences, distribution, ethnicity and severity.</p><p><strong>Results: </strong>This study revealed 97 distinct <i>GNE</i> variants, including 35 (36.08%) novel variants. Two more patients with deep intronic variant c.862+870C>T were identified, while whole genome sequencing (WGS) uncovered another two novel intronic variants: c.52-8924G>T and c.1505-12G>A. Nanopore long reads sequencing (LRS) and further PCR analysis verified a 639 bp insertion at chr9:36249241. Missense variants predominantly located in the epimerase/kinase domain coding region, indicating the impairment of catalytic function as a key pathogenic consequence. Comparative studies with Japanese, Korean and Jewish, our cohorts showed later onset ages by 2 years. The high allele frequency of the non-catalytic <i>GNE</i> variant, c.620A>T, might underlie the milder phenotype of Chinese patients.</p><p><strong>Conclusions: </strong>Comprehensive techniques such as WGS and Nanopore LRS warrants the identifying of <i>GNE</i> variants. Patients with the non-catalytic <i>GNE</i> variant, c.620A>T, had a milder disease progression and later wheelchair use.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1053-1061"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348353","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}
Joery den Hoed, Hirokazu Hashimoto, Mubeen Khan, Fleur Semmekrot, Katherine A Bosanko, Chihiro Abe-Hatano, Eiji Nakagawa, Hanka Venselaar, Nada Quercia, Lauren Chad, Hiroshi Kurosaka, Stephane Rondeau, Simon E Fisher, Shinya Yamamoto, Yuri A Zarate
SATB2-associated syndrome (SAS) is caused by pathogenic variants in SATB2, which encodes an evolutionarily conserved transcription factor. Despite the broad range of phenotypic manifestations and variable severity related to this syndrome, haploinsufficiency has been assumed to be the primary molecular explanation.In this study, we describe eight individuals with SATB2 variants that affect p.Gly392 (four women, age range 2-16 years; p.Gly392Arg, p.Gly392Glu and p.Gly392Val). Of these, individuals with p.Gly392Arg substitutions were found to have more severe neurodevelopmental phenotypes based on an established rubric scoring system when compared with individuals with p.Gly392Glu, p.Gly392Val and other previously reported causative SATB2 missense variants. Consistent with the observations at the phenotypic level, using human cell-based and model organism functional data, we documented that while all three described p.Gly392 variants affect the same residue and seem to all have a partial loss-of-function effect, some effects on SATB2 protein function appear to be variant-specific. Our results indicate that genotype-phenotype correlations in SAS are more complex than originally thought, and variant-specific genotype-phenotype correlations are needed.
{"title":"Pathogenic <i>SATB2</i> missense variants affecting p.Gly392 have variable functional implications and result in diverse clinical phenotypes.","authors":"Joery den Hoed, Hirokazu Hashimoto, Mubeen Khan, Fleur Semmekrot, Katherine A Bosanko, Chihiro Abe-Hatano, Eiji Nakagawa, Hanka Venselaar, Nada Quercia, Lauren Chad, Hiroshi Kurosaka, Stephane Rondeau, Simon E Fisher, Shinya Yamamoto, Yuri A Zarate","doi":"10.1136/jmg-2024-110015","DOIUrl":"10.1136/jmg-2024-110015","url":null,"abstract":"<p><p><i>SATB2</i>-associated syndrome (SAS) is caused by pathogenic variants in <i>SATB2</i>, which encodes an evolutionarily conserved transcription factor. Despite the broad range of phenotypic manifestations and variable severity related to this syndrome, haploinsufficiency has been assumed to be the primary molecular explanation.In this study, we describe eight individuals with <i>SATB2</i> variants that affect p.Gly392 (four women, age range 2-16 years; p.Gly392Arg, p.Gly392Glu and p.Gly392Val). Of these, individuals with p.Gly392Arg substitutions were found to have more severe neurodevelopmental phenotypes based on an established rubric scoring system when compared with individuals with p.Gly392Glu, p.Gly392Val and other previously reported causative <i>SATB2</i> missense variants. Consistent with the observations at the phenotypic level, using human cell-based and model organism functional data, we documented that while all three described p.Gly392 variants affect the same residue and seem to all have a partial loss-of-function effect, some effects on SATB2 protein function appear to be variant-specific. Our results indicate that genotype-phenotype correlations in SAS are more complex than originally thought, and variant-specific genotype-phenotype correlations are needed.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1062-1067"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348354","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}
Miriam J Smith, Cristina Perez-Becerril, Mwee van der Meer, George J Burghel, Sarah J Waller, Megan Carney, Sancha Bunstone, Katherine Fryer, Naomi L Bowers, Claire L Hartley, Philip T Smith, Scott A Rutherford, Simon R Freeman, Simon K W Lloyd, Omar N Pathmanaban, Andrew Thomas King, Dorothy Halliday, Chris Duff, D Gareth Evans
Background: Most schwannomas are isolated tumours occurring in otherwise healthy people. However, bilateral vestibular schwannomas (BVS) or multiple non-vestibular schwannomas indicate an underlying genetic predisposition. This is most commonly NF2-related schwannomatosis (SWN), but when BVS are absent, this can also indicate SMARCB1-related or LZTR1-related SWN.
Methods: We assessed the variant detection rates for the three major SWN genes (NF2, LZTR1 and SMARCB1) in 154 people, from 150 families, who had at least one non-vestibular schwannoma, but who did not meet clinical criteria for NF2-related SWN at the time of genetic testing.
Results: We found that 17 (11%) people from 13 families had a germline SMARCB1 variant and 19 (12%) unrelated individuals had a germline LZTR1 variant. 19 people had an NF2 variant, but 18 of these were mosaic and 17 were only detected when 2 tumours were available for testing. The overall detection rate was 25% using blood alone, but increased to 36% when tumour analysis was included. Another 12 people had a germline variant of uncertain significance (VUS).
Conclusions: There were similar proportions of LZTR1, SMARCB1 or mosaic NF2. However, since an NF2 variant was detected in tumours from 103 people, it is likely that further cases of mosaicism would be detected if more people had additional tumours available for analysis. In addition, if further evidence becomes available to show that the VUSs are pathogenic, this would significantly increase the proportion of people with a genetic diagnosis. Our results indicate the importance of comprehensive genetic testing and improved variant classification.
{"title":"Genetic findings in people with schwannomas who do not meet clinical diagnostic criteria for <i>NF2</i>-related schwannomatosis.","authors":"Miriam J Smith, Cristina Perez-Becerril, Mwee van der Meer, George J Burghel, Sarah J Waller, Megan Carney, Sancha Bunstone, Katherine Fryer, Naomi L Bowers, Claire L Hartley, Philip T Smith, Scott A Rutherford, Simon R Freeman, Simon K W Lloyd, Omar N Pathmanaban, Andrew Thomas King, Dorothy Halliday, Chris Duff, D Gareth Evans","doi":"10.1136/jmg-2024-110217","DOIUrl":"10.1136/jmg-2024-110217","url":null,"abstract":"<p><strong>Background: </strong>Most schwannomas are isolated tumours occurring in otherwise healthy people. However, bilateral vestibular schwannomas (BVS) or multiple non-vestibular schwannomas indicate an underlying genetic predisposition. This is most commonly <i>NF2</i>-related schwannomatosis (SWN), but when BVS are absent, this can also indicate <i>SMARCB1</i>-related or <i>LZTR1</i>-related SWN.</p><p><strong>Methods: </strong>We assessed the variant detection rates for the three major SWN genes (<i>NF2</i>, <i>LZTR1</i> and <i>SMARCB1</i>) in 154 people, from 150 families, who had at least one non-vestibular schwannoma, but who did not meet clinical criteria for <i>NF2</i>-related SWN at the time of genetic testing.</p><p><strong>Results: </strong>We found that 17 (11%) people from 13 families had a germline <i>SMARCB1</i> variant and 19 (12%) unrelated individuals had a germline <i>LZTR1</i> variant. 19 people had an <i>NF2</i> variant, but 18 of these were mosaic and 17 were only detected when 2 tumours were available for testing. The overall detection rate was 25% using blood alone, but increased to 36% when tumour analysis was included. Another 12 people had a germline variant of uncertain significance (VUS).</p><p><strong>Conclusions: </strong>There were similar proportions of <i>LZTR1</i>, <i>SMARCB1</i> or mosaic <i>NF2</i>. However, since an <i>NF2</i> variant was detected in tumours from 103 people, it is likely that further cases of mosaicism would be detected if more people had additional tumours available for analysis. In addition, if further evidence becomes available to show that the VUSs are pathogenic, this would significantly increase the proportion of people with a genetic diagnosis. Our results indicate the importance of comprehensive genetic testing and improved variant classification.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1011-1015"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108225","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}
Duchenne muscular dystrophy (DMD) is a commonly encountered genetic ailment marked by loss-of-function mutations in the Dystrophin gene, ultimately resulting in progressive debilitation of skeletal muscle. The investigation into the pathogenesis of DMD has increasingly converged on the role of histone modifications within the broader context of epigenetic regulation. These modifications, including histone acetylation, methylation and phosphorylation, are catalysed by specific enzymes and play a critical role in gene expression. This article provides an overview of the histone modifications occurring in DMD and analyses the research progress and potential of different types of histone modifications in DMD due to changes in cellular signalling for muscle regeneration, to provide new insights into diagnostic and therapeutic options for DMD.
{"title":"Histone modifications in Duchenne muscular dystrophy: pathogenesis insights and therapeutic implications.","authors":"Yanning Wei, Yuanyuan Jiang, Yufei Lu, Qiping Hu","doi":"10.1136/jmg-2024-110045","DOIUrl":"10.1136/jmg-2024-110045","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is a commonly encountered genetic ailment marked by loss-of-function mutations in the <i>Dystrophin</i> gene, ultimately resulting in progressive debilitation of skeletal muscle. The investigation into the pathogenesis of DMD has increasingly converged on the role of histone modifications within the broader context of epigenetic regulation. These modifications, including histone acetylation, methylation and phosphorylation, are catalysed by specific enzymes and play a critical role in gene expression. This article provides an overview of the histone modifications occurring in DMD and analyses the research progress and potential of different types of histone modifications in DMD due to changes in cellular signalling for muscle regeneration, to provide new insights into diagnostic and therapeutic options for DMD.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1003-1010"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348351","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}