Colin M E Halverson, Tom A Doyle, Samantha Vershaw
Background: Patients with uncommon genetic conditions often face limited in-person resources for social and informational support. Hypermobile Ehlers-Danlos syndrome (hEDS) is a rare or underdiagnosed hereditary disorder of the connective tissue, and like those with similar diseases, patients with hEDS have begun to turn to social media in search of care and community. The aims of our study were to understand the usage habits and perceptions of utility of social media use for patients with hEDS in order to formulate suggestions for how clinicians may best engage these and similar patient populations about this topic.
Methods: We conducted both a quantitative survey and qualitative interviews with patients who had received a robust clinical diagnosis of hEDS.
Results: Twenty-four individuals completed the initial survey, and a subset of 21 of those participants completed an interview. Through thematic analysis, we identified four primary themes related to their experience with social media: (1) befriending others with their disease, (2) seeking and vetting information, (3) the risks and downsides of social media use, and (4) the desire for clinicians to discuss this topic with them.
Conclusion: We conclude by proposing five suggestions that emerge empirically from our data. These proposals will help clinicians engage their patients regarding social media use in order to promote its potential benefits and circumvent its potential harms as they pursue support for their hereditary condition.
{"title":"Social media use by patients with hypermobile Ehlers-Danlos syndrome.","authors":"Colin M E Halverson, Tom A Doyle, Samantha Vershaw","doi":"10.1002/mgg3.2467","DOIUrl":"10.1002/mgg3.2467","url":null,"abstract":"<p><strong>Background: </strong>Patients with uncommon genetic conditions often face limited in-person resources for social and informational support. Hypermobile Ehlers-Danlos syndrome (hEDS) is a rare or underdiagnosed hereditary disorder of the connective tissue, and like those with similar diseases, patients with hEDS have begun to turn to social media in search of care and community. The aims of our study were to understand the usage habits and perceptions of utility of social media use for patients with hEDS in order to formulate suggestions for how clinicians may best engage these and similar patient populations about this topic.</p><p><strong>Methods: </strong>We conducted both a quantitative survey and qualitative interviews with patients who had received a robust clinical diagnosis of hEDS.</p><p><strong>Results: </strong>Twenty-four individuals completed the initial survey, and a subset of 21 of those participants completed an interview. Through thematic analysis, we identified four primary themes related to their experience with social media: (1) befriending others with their disease, (2) seeking and vetting information, (3) the risks and downsides of social media use, and (4) the desire for clinicians to discuss this topic with them.</p><p><strong>Conclusion: </strong>We conclude by proposing five suggestions that emerge empirically from our data. These proposals will help clinicians engage their patients regarding social media use in order to promote its potential benefits and circumvent its potential harms as they pursue support for their hereditary condition.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11165341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141301118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jing Wang, Huijun Yu, Xiaoying Zhang, Xiuyun Zhou, Ya Tan, Zhi Li, Ying Gu, Li Lin
Background: The protein kinase domain containing cytoplasmic (PKDCC) gene (OMIM#618821) is associated with bone development. Biallelic variants in the PKDCC gene can cause rhizomelic limb shortening with dysmorphic features.
Case report: A fetus was found to be rhizomelic limb shortening at 16 weeks of gestation and amniocentesis was performed at 19 weeks of gestation. Genomic DNA extracted from the amniotic fluid was subjected to chromosomal microarray analysis (CMA), and Trio-total whole-exome sequencing (Trio-WES). Sanger sequencing was used to verify the candidate pathogenic variants. CMA was normal, while Trio-WES identified two compound heterozygous variants in the PKDCC gene, namely c.417_c.423delCGGCGCG insTCATGGGCTCAGTACAC(p.G140fs*35) and c.345G>A (p.W115*,379). Then the fetus was aborted and the development of its bone cells were compared with that of a normal fetus of similar gestational age by histopathological examination. Clinical findings of the fetus were shortening humerus and femur, synophrys, much hair on the side face, simian line on the right palm, etc. Histopathological examination showed that the affected fetus had increased proliferative chondrocytes, widened proliferative bands, and delayed bone mineralization.
Conclusions: We reported a prenatal case of rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene, which emphasized the important role of Trio-WES for diagnosis of skeletal dysplasia in fetuses.
{"title":"Prenatal diagnosis of a skeletal disorder characterized by rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene: Case report and literature review.","authors":"Jing Wang, Huijun Yu, Xiaoying Zhang, Xiuyun Zhou, Ya Tan, Zhi Li, Ying Gu, Li Lin","doi":"10.1002/mgg3.2477","DOIUrl":"10.1002/mgg3.2477","url":null,"abstract":"<p><strong>Background: </strong>The protein kinase domain containing cytoplasmic (PKDCC) gene (OMIM#618821) is associated with bone development. Biallelic variants in the PKDCC gene can cause rhizomelic limb shortening with dysmorphic features.</p><p><strong>Case report: </strong>A fetus was found to be rhizomelic limb shortening at 16 weeks of gestation and amniocentesis was performed at 19 weeks of gestation. Genomic DNA extracted from the amniotic fluid was subjected to chromosomal microarray analysis (CMA), and Trio-total whole-exome sequencing (Trio-WES). Sanger sequencing was used to verify the candidate pathogenic variants. CMA was normal, while Trio-WES identified two compound heterozygous variants in the PKDCC gene, namely c.417_c.423delCGGCGCG insTCATGGGCTCAGTACAC(p.G140fs*35) and c.345G>A (p.W115*,379). Then the fetus was aborted and the development of its bone cells were compared with that of a normal fetus of similar gestational age by histopathological examination. Clinical findings of the fetus were shortening humerus and femur, synophrys, much hair on the side face, simian line on the right palm, etc. Histopathological examination showed that the affected fetus had increased proliferative chondrocytes, widened proliferative bands, and delayed bone mineralization.</p><p><strong>Conclusions: </strong>We reported a prenatal case of rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene, which emphasized the important role of Trio-WES for diagnosis of skeletal dysplasia in fetuses.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11165336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141301117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Irene Capelli, Roberta Di Costanzo, Valeria Aiello, Sarah Lerario, Paola De Giovanni, Marcello Montevecchi, Davide Cerretani, Vincenzo Donadio, Gaetano La Manna, Renzo Mignani
Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by variants in GLA gene leading to deficient α-galactosidase A enzyme activity. This deficiency leads to the accumulation of glycosphingolipids, particularly globotriaosylceramide (Gb3), in various tissues and organs, which can result in life-threatening complications. The clinical presentation of the disease can vary from the "classic" phenotype with pediatric onset and multi-organ involvement to the "later-onset" phenotype, which presents with predominantly cardiac symptoms. In recent years, advances in screening studies have led to the identification of an increasing number of variants of unknown significance that have not yet been described, and whose pathogenic role remains undetermined.
Methods: In this clinical report, we describe the case of an asymptomatic adult female who was found to have a new variant of unknown significance, p.Met70Val. Given the unknown pathogenic role of this variant, a thorough analysis of the potential organ involvement was conducted. The clinical data were analyzed retrospectively.
Results: The analysis revealed that there were no signs of significant organ involvement, and the benignity of the variant was confirmed.
Conclusion: This case underscores the importance of a comprehensive evaluation of new variants of unknown significance to establish their pathogenicity accurately.
背景:法布里病(FD)是一种罕见的 X 连锁溶酶体储积症,由 GLA 基因变异导致α-半乳糖苷酶 A 酶活性缺乏引起。这种缺陷会导致糖磷脂(尤其是球糖基甘油三酯(Gb3))在各种组织和器官中蓄积,从而引发危及生命的并发症。该病的临床表现多种多样,既有儿科发病、多器官受累的 "典型 "表型,也有主要表现为心脏症状的 "晚发 "表型。近年来,随着筛查研究的进展,发现了越来越多意义不明的变异,这些变异尚未被描述,其致病作用也仍未确定:在这份临床报告中,我们描述了一个无症状的成年女性病例,她被发现患有一种新的意义不明的变异体 p.Met70Val。鉴于该变异体的致病作用未知,我们对其可能涉及的器官进行了全面分析。对临床数据进行了回顾性分析:结果:分析结果显示,没有明显的器官受累迹象,证实了该变异体的良性:本病例强调了对意义不明的新变异体进行全面评估以准确确定其致病性的重要性。
{"title":"No evidence of Fabry disease in a patient with the new p.Met70Val GLA gene variant.","authors":"Irene Capelli, Roberta Di Costanzo, Valeria Aiello, Sarah Lerario, Paola De Giovanni, Marcello Montevecchi, Davide Cerretani, Vincenzo Donadio, Gaetano La Manna, Renzo Mignani","doi":"10.1002/mgg3.2390","DOIUrl":"10.1002/mgg3.2390","url":null,"abstract":"<p><strong>Background: </strong>Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by variants in GLA gene leading to deficient α-galactosidase A enzyme activity. This deficiency leads to the accumulation of glycosphingolipids, particularly globotriaosylceramide (Gb3), in various tissues and organs, which can result in life-threatening complications. The clinical presentation of the disease can vary from the \"classic\" phenotype with pediatric onset and multi-organ involvement to the \"later-onset\" phenotype, which presents with predominantly cardiac symptoms. In recent years, advances in screening studies have led to the identification of an increasing number of variants of unknown significance that have not yet been described, and whose pathogenic role remains undetermined.</p><p><strong>Methods: </strong>In this clinical report, we describe the case of an asymptomatic adult female who was found to have a new variant of unknown significance, p.Met70Val. Given the unknown pathogenic role of this variant, a thorough analysis of the potential organ involvement was conducted. The clinical data were analyzed retrospectively.</p><p><strong>Results: </strong>The analysis revealed that there were no signs of significant organ involvement, and the benignity of the variant was confirmed.</p><p><strong>Conclusion: </strong>This case underscores the importance of a comprehensive evaluation of new variants of unknown significance to establish their pathogenicity accurately.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11185943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lilia Kraoua, Assaad Louati, Sarra Ben Ahmed, Nesrine Abida, Monia Khemiri, Khaled Menif, Ridha Mrad, Stéphane Zaffran, Hager Jaouadi
Background: Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle, systolic dysfunction, and normal or reduced thickness of the left ventricular wall. It is a leading cause of heart failure and cardiac death at a young age. Cases with neonatal onset DCM were correlated with severe clinical presentation and poor prognosis. A monogenic molecular etiology accounts for nearly half of cases.
Family description: Here, we report a family with three deceased offspring at the age of 1 year old. The autopsy of the first deceased infant revealed a DCM. The second infant presented a DCM phenotype with a severely reduced Left Ventricular Ejection Fraction (LVEF) of 10%. Similarly, the third infant showed a severe DCM phenotype with LVEF of 30% as well, in addition to eccentric mitral insufficiency.
Results: Exome sequencing was performed for the trio (the second deceased infant and her parents). Data analysis following the autosomal dominant and recessive patterns of inheritance was carried out along with a mitochondrial pathways-based analysis. We identified a homozygous frameshift variant in the TNNI3 gene (c.204delG; p.(Arg69AlafsTer8)). This variant has been recently reported in the ClinVar database in association with cardiac phenotypes as pathogenic or likely pathogenic and classified as pathogenic according to ACMG.
Conclusion: Genetic counseling was provided for the family and a prenatal diagnosis of choronic villus was proposed in the absence of pre-implantation genetic diagnosis possibilities. Our study expands the case series of early-onset DCM patients with a protein-truncating variant in the TNNI3 gene by reporting three affected infant siblings.
{"title":"Homozygous TNNI3 frameshift variant in a consanguineous family with lethal infantile dilated cardiomyopathy.","authors":"Lilia Kraoua, Assaad Louati, Sarra Ben Ahmed, Nesrine Abida, Monia Khemiri, Khaled Menif, Ridha Mrad, Stéphane Zaffran, Hager Jaouadi","doi":"10.1002/mgg3.2486","DOIUrl":"10.1002/mgg3.2486","url":null,"abstract":"<p><strong>Background: </strong>Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle, systolic dysfunction, and normal or reduced thickness of the left ventricular wall. It is a leading cause of heart failure and cardiac death at a young age. Cases with neonatal onset DCM were correlated with severe clinical presentation and poor prognosis. A monogenic molecular etiology accounts for nearly half of cases.</p><p><strong>Family description: </strong>Here, we report a family with three deceased offspring at the age of 1 year old. The autopsy of the first deceased infant revealed a DCM. The second infant presented a DCM phenotype with a severely reduced Left Ventricular Ejection Fraction (LVEF) of 10%. Similarly, the third infant showed a severe DCM phenotype with LVEF of 30% as well, in addition to eccentric mitral insufficiency.</p><p><strong>Results: </strong>Exome sequencing was performed for the trio (the second deceased infant and her parents). Data analysis following the autosomal dominant and recessive patterns of inheritance was carried out along with a mitochondrial pathways-based analysis. We identified a homozygous frameshift variant in the TNNI3 gene (c.204delG; p.(Arg69AlafsTer8)). This variant has been recently reported in the ClinVar database in association with cardiac phenotypes as pathogenic or likely pathogenic and classified as pathogenic according to ACMG.</p><p><strong>Conclusion: </strong>Genetic counseling was provided for the family and a prenatal diagnosis of choronic villus was proposed in the absence of pre-implantation genetic diagnosis possibilities. Our study expands the case series of early-onset DCM patients with a protein-truncating variant in the TNNI3 gene by reporting three affected infant siblings.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11196996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Irene Mademont-Soler, Susanna Esteba-Castillo, Aida Jiménez-Xifra, Berta Alemany, Núria Ribas-Vidal, Maria Cutillas, Mònica Coll, Mel Lina Pinsach, Sara Pagans, Mireia Alcalde, Marina Viñas-Jornet, Mercedes Montero-Vale, Marta de Castro-Miró, Jairo Rodríguez, Lluís Armengol, Xavier Queralt, María Obón
Background: Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11 gene (MIM *610844).
Methods: The proband is a 36-year-old female referred for genetic evaluation due to cognitive dysfunction, gait impairment, and corpus callosum atrophy (brain MRI was normal at 25-years-old). Diagnostic approaches included CGH array, next-generation sequencing, and whole transcriptome sequencing.
Results: CGH array revealed a 180 kb deletion located upstream of SPG11. Sequencing of SPG11 uncovered two rare single nucleotide variants: the novel variant c.3143C>T in exon 17 (in cis with the deletion), and the previously reported pathogenic variant c.6409C>T in exon 34 (in trans). Whole transcriptome sequencing revealed that the variant c.3143C>T caused exon 17 skipping.
Conclusion: We report a novel sequence variant in the SPG11 gene resulting in exon 17 skipping, which, along with a nonsense variant, causes Spastic Paraplegia 11 in our proband. In addition, a deletion upstream of SPG11 was identified in the patient, whose implication in the phenotype remains uncertain. Nonetheless, the deletion apparently affects cis-regulatory elements of the gene, suggesting a potential new pathogenic mechanism underlying the disease in a subset of undiagnosed patients. Our findings further support the hypothesis that the origin of thin corpus callosum in patients with SPG11 is of progressive nature.
{"title":"Unexpected complexity in the molecular diagnosis of spastic paraplegia 11.","authors":"Irene Mademont-Soler, Susanna Esteba-Castillo, Aida Jiménez-Xifra, Berta Alemany, Núria Ribas-Vidal, Maria Cutillas, Mònica Coll, Mel Lina Pinsach, Sara Pagans, Mireia Alcalde, Marina Viñas-Jornet, Mercedes Montero-Vale, Marta de Castro-Miró, Jairo Rodríguez, Lluís Armengol, Xavier Queralt, María Obón","doi":"10.1002/mgg3.2475","DOIUrl":"https://doi.org/10.1002/mgg3.2475","url":null,"abstract":"<p><strong>Background: </strong>Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11 gene (MIM *610844).</p><p><strong>Methods: </strong>The proband is a 36-year-old female referred for genetic evaluation due to cognitive dysfunction, gait impairment, and corpus callosum atrophy (brain MRI was normal at 25-years-old). Diagnostic approaches included CGH array, next-generation sequencing, and whole transcriptome sequencing.</p><p><strong>Results: </strong>CGH array revealed a 180 kb deletion located upstream of SPG11. Sequencing of SPG11 uncovered two rare single nucleotide variants: the novel variant c.3143C>T in exon 17 (in cis with the deletion), and the previously reported pathogenic variant c.6409C>T in exon 34 (in trans). Whole transcriptome sequencing revealed that the variant c.3143C>T caused exon 17 skipping.</p><p><strong>Conclusion: </strong>We report a novel sequence variant in the SPG11 gene resulting in exon 17 skipping, which, along with a nonsense variant, causes Spastic Paraplegia 11 in our proband. In addition, a deletion upstream of SPG11 was identified in the patient, whose implication in the phenotype remains uncertain. Nonetheless, the deletion apparently affects cis-regulatory elements of the gene, suggesting a potential new pathogenic mechanism underlying the disease in a subset of undiagnosed patients. Our findings further support the hypothesis that the origin of thin corpus callosum in patients with SPG11 is of progressive nature.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cecilie F Rustad, Paul Hoff Backe, Chunsheng Jin, Else Merckoll, Kristian Tveten, Marissa Lucy Maciej-Hulme, Niclas Karlsson, Trine Prescott, Elise Sandås Sand, Berit Woldseth, Katja Benedikte Prestø Elgstøen, Øystein L Holla
Background: Serine residues in the protein backbone of heavily glycosylated proteoglycans are bound to glycosaminoglycans through a tetrasaccharide linker. UXS1 encodes UDP-glucuronate decarboxylase 1, which catalyzes synthesis of UDP-xylose, the donor of the first building block in the linker. Defects in other enzymes involved in formation of the tetrasaccharide linker cause so-called linkeropathies, characterized by short stature, radio-ulnar synostosis, decreased bone density, congenital contractures, dislocations, and more.
Methods: Whole exome sequencing was performed in a father and son who presented with a mild skeletal dysplasia, as well as the father's unaffected parents. Wild-type and mutant UXS1 were recombinantly expressed in Escherichia coli and purified. Enzyme activity was evaluated by LC-MS/MS. In vivo effects were studied using HeparinRed assay and metabolomics.
Results: The son had short long bones, normal epiphysis, and subtle metaphyseal changes especially in his legs. The likely pathogenic heterozygous variant NM_001253875.1(UXS1):c.557T>A p.(Ile186Asn) detected in the son was de novo in the father. Purified Ile186Asn-UXS1, in contrast to the wild-type, was not able to convert UDP-glucuronic acid to UDP-xylose. Plasma glycosaminoglycan levels were decreased in both son and father.
Conclusion: This is the first report linking UXS1 to short-limbed short stature in humans.
{"title":"A monoallelic UXS1 variant associated with short-limbed short stature.","authors":"Cecilie F Rustad, Paul Hoff Backe, Chunsheng Jin, Else Merckoll, Kristian Tveten, Marissa Lucy Maciej-Hulme, Niclas Karlsson, Trine Prescott, Elise Sandås Sand, Berit Woldseth, Katja Benedikte Prestø Elgstøen, Øystein L Holla","doi":"10.1002/mgg3.2472","DOIUrl":"10.1002/mgg3.2472","url":null,"abstract":"<p><strong>Background: </strong>Serine residues in the protein backbone of heavily glycosylated proteoglycans are bound to glycosaminoglycans through a tetrasaccharide linker. UXS1 encodes UDP-glucuronate decarboxylase 1, which catalyzes synthesis of UDP-xylose, the donor of the first building block in the linker. Defects in other enzymes involved in formation of the tetrasaccharide linker cause so-called linkeropathies, characterized by short stature, radio-ulnar synostosis, decreased bone density, congenital contractures, dislocations, and more.</p><p><strong>Methods: </strong>Whole exome sequencing was performed in a father and son who presented with a mild skeletal dysplasia, as well as the father's unaffected parents. Wild-type and mutant UXS1 were recombinantly expressed in Escherichia coli and purified. Enzyme activity was evaluated by LC-MS/MS. In vivo effects were studied using HeparinRed assay and metabolomics.</p><p><strong>Results: </strong>The son had short long bones, normal epiphysis, and subtle metaphyseal changes especially in his legs. The likely pathogenic heterozygous variant NM_001253875.1(UXS1):c.557T>A p.(Ile186Asn) detected in the son was de novo in the father. Purified Ile186Asn-UXS1, in contrast to the wild-type, was not able to convert UDP-glucuronic acid to UDP-xylose. Plasma glycosaminoglycan levels were decreased in both son and father.</p><p><strong>Conclusion: </strong>This is the first report linking UXS1 to short-limbed short stature in humans.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11165340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141301085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Spinocerebellar ataxia 29 (SCA29) is a rare genetic disorder characterized by early-onset ataxia, gross motor delay, and infantile hypotonia, and is primarily associated with variants in the ITPR1 gene. Cases of SCA29 in Asia are rarely reported, limiting our understanding of this disease.
Methods: A female Korean infant, demonstrating clinical features of SCA29, underwent evaluation and rehabilitation at our outpatient clinic from the age of 3 months to the current age of 4 years. Trio-based genome sequencing tests were performed on the patient and her biological parents.
Results: The infant initially presented with macrocephaly, hypotonia, and nystagmus, with nonspecific findings on initial neuroimaging. Subsequent follow-up revealed gross motor delay, early onset ataxia, strabismus, and cognitive impairment. Further neuroimaging revealed atrophy of the cerebellum and vermis, and genetic analysis revealed a de novo pathogenic heterozygous c.800C>T, p.Thr267Met missense mutation in the ITPR1 gene (NM_001378452.1).
Conclusion: This is the first reported case of SCA29 in a Korean patient, expanding the genetic and phenotypic spectrum of ITPR1-related ataxias. Our case highlights the importance of recognizing early-onset ataxic symptoms, central hypotonia, and gross motor delays with poor ocular fixation, cognitive deficits, and isolated cerebellar atrophy as crucial clinical indicators of SCA29.
{"title":"Discovery of a de novo ITPR1 missense mutation in a patient with early-onset cerebellar ataxia: A rare case report of spinocerebellar ataxia 29.","authors":"Jae In Lee, Ja Young Choi, Shin-Seung Yang","doi":"10.1002/mgg3.2466","DOIUrl":"10.1002/mgg3.2466","url":null,"abstract":"<p><strong>Background: </strong>Spinocerebellar ataxia 29 (SCA29) is a rare genetic disorder characterized by early-onset ataxia, gross motor delay, and infantile hypotonia, and is primarily associated with variants in the ITPR1 gene. Cases of SCA29 in Asia are rarely reported, limiting our understanding of this disease.</p><p><strong>Methods: </strong>A female Korean infant, demonstrating clinical features of SCA29, underwent evaluation and rehabilitation at our outpatient clinic from the age of 3 months to the current age of 4 years. Trio-based genome sequencing tests were performed on the patient and her biological parents.</p><p><strong>Results: </strong>The infant initially presented with macrocephaly, hypotonia, and nystagmus, with nonspecific findings on initial neuroimaging. Subsequent follow-up revealed gross motor delay, early onset ataxia, strabismus, and cognitive impairment. Further neuroimaging revealed atrophy of the cerebellum and vermis, and genetic analysis revealed a de novo pathogenic heterozygous c.800C>T, p.Thr267Met missense mutation in the ITPR1 gene (NM_001378452.1).</p><p><strong>Conclusion: </strong>This is the first reported case of SCA29 in a Korean patient, expanding the genetic and phenotypic spectrum of ITPR1-related ataxias. Our case highlights the importance of recognizing early-onset ataxic symptoms, central hypotonia, and gross motor delays with poor ocular fixation, cognitive deficits, and isolated cerebellar atrophy as crucial clinical indicators of SCA29.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11165338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141301086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Subacute myelo-optico-neuropathy (SMON) is a neurological disorder associated with the administration of clioquinol, particularly at very high doses. Although clioquinol has been used worldwide, there was an outbreak of SMON in the 1950s-1970s in which the majority of cases were in Japan, prompting speculation that the unique genetic background of the Japanese population may have contributed to the development of SMON. Recently, a possible association between loss-of-function polymorphisms in NQO1 and the development of SMON has been reported. In this study, we analyzed the relationship between NQO1 polymorphisms and SMON in Japan.
Methods: We analyzed 125 Japanese patients with SMON. NQO1 loss-of-function polymorphisms (rs1800566, rs10517, rs689452, and rs689456) were evaluated. The allele frequency distribution of each polymorphism was compared between the patients and the healthy Japanese individuals (Human Genomic Variation Database and Integrative Japanese Genome Variation Database), as well as our in-house healthy controls.
Results: The frequencies of the loss-of-function NQO1 alleles in patients with SMON and the normal control group did not differ significantly.
Conclusion: We conclude that known NQO1 polymorphisms are not associated with the development of SMON.
{"title":"Loss-of-function polymorphisms in NQO1 are not associated with the development of subacute myelo-optico-neuropathy.","authors":"Hideki Matsumoto, Hideo Sasai, Norio Kawamoto, Masato Katsuyama, Makoto Minamiyama, Satoshi Kuru, Toshiyuki Fukao, Hidenori Ohnishi","doi":"10.1002/mgg3.2470","DOIUrl":"10.1002/mgg3.2470","url":null,"abstract":"<p><strong>Background: </strong>Subacute myelo-optico-neuropathy (SMON) is a neurological disorder associated with the administration of clioquinol, particularly at very high doses. Although clioquinol has been used worldwide, there was an outbreak of SMON in the 1950s-1970s in which the majority of cases were in Japan, prompting speculation that the unique genetic background of the Japanese population may have contributed to the development of SMON. Recently, a possible association between loss-of-function polymorphisms in NQO1 and the development of SMON has been reported. In this study, we analyzed the relationship between NQO1 polymorphisms and SMON in Japan.</p><p><strong>Methods: </strong>We analyzed 125 Japanese patients with SMON. NQO1 loss-of-function polymorphisms (rs1800566, rs10517, rs689452, and rs689456) were evaluated. The allele frequency distribution of each polymorphism was compared between the patients and the healthy Japanese individuals (Human Genomic Variation Database and Integrative Japanese Genome Variation Database), as well as our in-house healthy controls.</p><p><strong>Results: </strong>The frequencies of the loss-of-function NQO1 alleles in patients with SMON and the normal control group did not differ significantly.</p><p><strong>Conclusion: </strong>We conclude that known NQO1 polymorphisms are not associated with the development of SMON.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11165339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141301087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Hearing loss (HL) is the most frequent sensory deficit in humans, with strong genetic heterogeneity. The genetic diagnosis of HL is very important to aid treatment decisions and to provide prognostic information and genetic counselling for the patient's family.
Methods: We detected and analysed 362 Chinese non-syndromic HL patients by screening of variants in 15 hot spot mutations. Subsequently, 40 patients underwent further whole-exome sequencing (WES) to determine genetic aetiology. The candidate variants were verified using Sanger sequencing. Twenty-three carrier couples with pathogenic variants or likely pathogenic variants chose to proceed with prenatal diagnosis using Sanger sequencing.
Results: Among the 362 HL patients, 102 were assigned a molecular diagnosis with 52 different variants in 22 deafness genes. A total of 41 (11.33%) cases with the biallelic GJB2 (OMIM # 220290) gene mutations were detected, and 21 (5.80%) had biallelic SLC26A4 (OMIM # 605646) mutations. Mitochondrial gene (OMIM # 561000) mutations were detected in seven (1.93%) patients. Twenty of the variants in 15 deafness genes were novel. SOX10 (OMIM # 602229), MYO15A (OMIM # 602666) and WFS1 (OMIM # 606201) were each detected in two patients. Meanwhile, OSBPL2 (OMIM # 606731), RRM2B (OMIM # 604712), OTOG (OMIM # 604487), STRC (OMIM # 606440), PCDH15 (OMIM # 605514), LOXHD1 (OMIM # 613072), CDH23 (OMIM # 605516), TMC1 (OMIM # 606706), CHD7 (OMIM # 608892), DIAPH3 (OMIM # 614567), TBC1D24 (OMIM # 613577), TIMM8A (OMIM # 300356), PTPRQ (OMIM # 603317), SALL1 (OMIM # 602218), and GSDME (OMIM # 608798) were each detected in one patient. In addition, as regards one couple with a heterozygous variant of CDH23 and PCDH15, respectively, prenatal diagnosis results suggest that the foetus had double heterozygous (DH) variants of CDH23 and PCDH15, which has a high risk to cause ID/F type Usher syndrome.
Conclusion: Our study expanded the spectrum of deafness gene variation, which will contribute to the genetic diagnosis, prenatal diagnosis and the procreation guidance of deaf couple. In addition, the deafness caused by two genes should be paid attention to in the prenatal diagnosis of families with both deaf patients.
{"title":"Mutation spectrum of hearing loss patients in Northwest China: Identification of 20 novel variants.","authors":"Panpan Ma, Bingbo Zhou, Qichao Kang, Xue Chen, Xinyuan Tian, Ling Hui, Shengju Hao, Huiyan Wu, Chuan Zhang","doi":"10.1002/mgg3.2434","DOIUrl":"10.1002/mgg3.2434","url":null,"abstract":"<p><strong>Background: </strong>Hearing loss (HL) is the most frequent sensory deficit in humans, with strong genetic heterogeneity. The genetic diagnosis of HL is very important to aid treatment decisions and to provide prognostic information and genetic counselling for the patient's family.</p><p><strong>Methods: </strong>We detected and analysed 362 Chinese non-syndromic HL patients by screening of variants in 15 hot spot mutations. Subsequently, 40 patients underwent further whole-exome sequencing (WES) to determine genetic aetiology. The candidate variants were verified using Sanger sequencing. Twenty-three carrier couples with pathogenic variants or likely pathogenic variants chose to proceed with prenatal diagnosis using Sanger sequencing.</p><p><strong>Results: </strong>Among the 362 HL patients, 102 were assigned a molecular diagnosis with 52 different variants in 22 deafness genes. A total of 41 (11.33%) cases with the biallelic GJB2 (OMIM # 220290) gene mutations were detected, and 21 (5.80%) had biallelic SLC26A4 (OMIM # 605646) mutations. Mitochondrial gene (OMIM # 561000) mutations were detected in seven (1.93%) patients. Twenty of the variants in 15 deafness genes were novel. SOX10 (OMIM # 602229), MYO15A (OMIM # 602666) and WFS1 (OMIM # 606201) were each detected in two patients. Meanwhile, OSBPL2 (OMIM # 606731), RRM2B (OMIM # 604712), OTOG (OMIM # 604487), STRC (OMIM # 606440), PCDH15 (OMIM # 605514), LOXHD1 (OMIM # 613072), CDH23 (OMIM # 605516), TMC1 (OMIM # 606706), CHD7 (OMIM # 608892), DIAPH3 (OMIM # 614567), TBC1D24 (OMIM # 613577), TIMM8A (OMIM # 300356), PTPRQ (OMIM # 603317), SALL1 (OMIM # 602218), and GSDME (OMIM # 608798) were each detected in one patient. In addition, as regards one couple with a heterozygous variant of CDH23 and PCDH15, respectively, prenatal diagnosis results suggest that the foetus had double heterozygous (DH) variants of CDH23 and PCDH15, which has a high risk to cause ID/F type Usher syndrome.</p><p><strong>Conclusion: </strong>Our study expanded the spectrum of deafness gene variation, which will contribute to the genetic diagnosis, prenatal diagnosis and the procreation guidance of deaf couple. In addition, the deafness caused by two genes should be paid attention to in the prenatal diagnosis of families with both deaf patients.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11165335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141301088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thy Ngoc Nguyen, Giang Son Tran, Hai Duc Hoang, Long Giang Nguyen
Background: Polydactyly, particularly of the index finger, remains an intriguing anomaly for which no specific gene or locus has been definitively linked to this phenotype. In this study, we conducted an investigation of a three-generation family displaying index finger polydactyly.
Methods: Exome sequencing was conducted on the patient, with a filtration to identify potential causal variation. Validation of the obtained variant was conducted by Sanger sequencing, encompassing all family members.
Results: Exome analysis uncovered a novel heterozygous missense variant (c.1482A>T; p.Gln494His) at the zinc finger DNA-binding domain of the GLI3 protein within the proband and all affected family members. Remarkably, the variant was absent in unaffected individuals within the pedigree, underscoring its association with the polydactyly phenotype. Computational analyses revealed that GLI3 p.Gln494His impacts a residue that is highly conserved across species.
Conclusion: The GLI3 zinc finger DNA-binding region is an essential part of the Sonic hedgehog signaling pathway, orchestrating crucial aspects of embryonic development through the regulation of target gene expression. This novel finding not only contributes valuable insights into the molecular pathways governing polydactyly during embryonic development but also has the potential to enhance diagnostic and screening capabilities for this condition in clinical settings.
背景:多指畸形,尤其是食指多指畸形,仍然是一种令人困惑的异常现象,目前还没有特定的基因或基因位点与这种表型有明确的联系。在本研究中,我们对一个食指多指症三代家族进行了调查:方法:对患者进行外显子组测序,筛选出潜在的因果变异。结果:外显子组分析发现了一个新的杂合变异:结果:外显子组分析发现了一个新型杂合子错义变异(c.1482A>T; p.Gln494His),该变异位于该患者和所有受影响家庭成员体内的 GLI3 蛋白锌指 DNA 结合域。值得注意的是,该变异在血统中未受影响的个体中并不存在,这突显了它与多指畸形表型的关联。计算分析表明,GLI3 p.Gln494His影响了一个在不同物种中高度保守的残基:结论:GLI3 锌指 DNA 结合区是音速刺猬信号通路的重要组成部分,通过调控靶基因表达协调胚胎发育的关键环节。这项新发现不仅有助于深入了解胚胎发育过程中多指畸形的分子通路,还有可能提高临床诊断和筛查多指畸形的能力。
{"title":"A novel missense variant located within the zinc finger domain of the GLI3 gene was identified in a Vietnamese pedigree with index finger polydactyly.","authors":"Thy Ngoc Nguyen, Giang Son Tran, Hai Duc Hoang, Long Giang Nguyen","doi":"10.1002/mgg3.2468","DOIUrl":"10.1002/mgg3.2468","url":null,"abstract":"<p><strong>Background: </strong>Polydactyly, particularly of the index finger, remains an intriguing anomaly for which no specific gene or locus has been definitively linked to this phenotype. In this study, we conducted an investigation of a three-generation family displaying index finger polydactyly.</p><p><strong>Methods: </strong>Exome sequencing was conducted on the patient, with a filtration to identify potential causal variation. Validation of the obtained variant was conducted by Sanger sequencing, encompassing all family members.</p><p><strong>Results: </strong>Exome analysis uncovered a novel heterozygous missense variant (c.1482A>T; p.Gln494His) at the zinc finger DNA-binding domain of the GLI3 protein within the proband and all affected family members. Remarkably, the variant was absent in unaffected individuals within the pedigree, underscoring its association with the polydactyly phenotype. Computational analyses revealed that GLI3 p.Gln494His impacts a residue that is highly conserved across species.</p><p><strong>Conclusion: </strong>The GLI3 zinc finger DNA-binding region is an essential part of the Sonic hedgehog signaling pathway, orchestrating crucial aspects of embryonic development through the regulation of target gene expression. This novel finding not only contributes valuable insights into the molecular pathways governing polydactyly during embryonic development but also has the potential to enhance diagnostic and screening capabilities for this condition in clinical settings.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11167515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}