Clinical Genetics最新文献_第8页

Novel BRAT1 Deep Intronic Variant Affects Splicing Regulatory Elements Causing Cerebellar Hypoplasia Syndrome: Genotypic and Phenotypic Expansion. 新型 BRAT1 深度非线性变异影响剪接调控元件，导致小脑发育不全综合征：基因型和表型扩展。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-11-25 DOI: 10.1111/cge.14653

Tomer Poleg, Regina Proskorovski-Ohayon, Vadim Dolgin, Noam Hadar, Amit Safran, Nadav Agam, Matan M Jean, Ofek Freund, Libe Gradstein, Ilan Shelef, Yair Sadaka, Ohad S Birk

{"title":"Novel BRAT1 Deep Intronic Variant Affects Splicing Regulatory Elements Causing Cerebellar Hypoplasia Syndrome: Genotypic and Phenotypic Expansion.","authors":"Tomer Poleg, Regina Proskorovski-Ohayon, Vadim Dolgin, Noam Hadar, Amit Safran, Nadav Agam, Matan M Jean, Ofek Freund, Libe Gradstein, Ilan Shelef, Yair Sadaka, Ohad S Birk","doi":"10.1111/cge.14653","DOIUrl":"https://doi.org/10.1111/cge.14653","url":null,"abstract":"Biallelic mutations in BRAT1 result in lethal neonatal rigidity and multifocal seizure syndrome and a milder neurodevelopmental disorder of cerebellar atrophy with or without seizures (NEDCAS, MIM 618056). Combining linkage analysis and whole-genome sequencing (WGS), we identified a novel deep intronic BRAT1 variant, NC_000007.14 (NM_152743.4):c.128-1585 T > G, in 3 siblings of a consanguineous Bedouin family exhibiting NEDCAS. In silico analyses followed by molecular studies demonstrated this variant's impact on splice regulatory elements, forming a cryptic exon, resulting in a deleterious frameshift and aberrant transcript. Previously reported pathogenic BRAT1 splice-site mutations were adjacent to exons, affecting canonical consensus splice sites, and identifiable by whole-exome sequencing. The deep intronic BRAT1 disease-causing variant is thus unique and underscores the potential of intronic splice regulatory elements in BRAT1 disease pathogenesis, demonstrating the utility of WGS in identifying noncoding variants in unresolved cases. The affected individuals (deep into their twenties) are among the longest-surviving patients described to date-delineating the NEDCAS phenotype at these ages. Although sharing homozygosity of the same variant, they show varying penetrance of nystagmus and extreme variability in the extent of ataxia and age of onset of developmental delay. Notably, we summarize all documented BRAT1 splice variants reported to date and their phenotypic associations.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mobile Element Insertion in the APOB Exon 3 Coding Sequence: A New Challenge in Hypobetalipoproteinemia Diagnosis. APOB 第 3 外显子编码序列中的移动元素插入：低脂蛋白血症诊断的新挑战

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-11-25 DOI: 10.1111/cge.14655

Laurie Surles, Alexandre Janin, Corentin Molitor, Nicolas Chatron, Myriam Moret, Séverine Nony, Sabrina Dumont, Oriane Marmontel, Thomas Simonet, Agnès Sassolas, Philippe Moulin, Mathilde Di Filippo

{"title":"Mobile Element Insertion in the APOB Exon 3 Coding Sequence: A New Challenge in Hypobetalipoproteinemia Diagnosis.","authors":"Laurie Surles, Alexandre Janin, Corentin Molitor, Nicolas Chatron, Myriam Moret, Séverine Nony, Sabrina Dumont, Oriane Marmontel, Thomas Simonet, Agnès Sassolas, Philippe Moulin, Mathilde Di Filippo","doi":"10.1111/cge.14655","DOIUrl":"https://doi.org/10.1111/cge.14655","url":null,"abstract":"Mobile elements (ME) can transpose by copy-and-paste mechanisms. A heterozygous insertion in APOB exon 3 coding sequence was suspected in a patient with hypobetalipoproteinemia (HBL), by gel electrophoresis of the PCR products. An insertion of a 85 bp fragment flanked by a polyA stretch and a target replication site duplication was identified as a ME insertion (MEI) from the AluYa5 subfamily, NM_000384.3(APOB):c.135_136ins(160). Then, the DNA was reanalyzed using our NGS custom panel. Routine analysis did not reveal any causative variant, but manual inspection of the alignments and MELT enabled us to detect this MEI from NGS data. A functional study revealed that this MEI introduces a stop codon p.(Phe46Alafs*2) and additionally leads to p.(Lys41Serfs*2) due to an exon skipping. This is the first report of a MEI into APOB, as a cause of HBL. Furthermore, our study highlights the value of including MEI-callers in routine pipelines to improve primary dyslipidemia diagnosis.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rare Causes and Differential Diagnosis in Patients With Silver-Russell Syndrome. 银-拉塞尔综合征患者的罕见病因和鉴别诊断。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-11-25 DOI: 10.1111/cge.14659

Barbara Leitao Braga, Renata da Cunha Scalco, Thais Kataoka Homma, Bruna Lucheze Freire, Laurana De Polli Cellin, Ana Pinheiro Machado Canton, Antônio Marcondes Lerario, Mariana Ferreira de Assis Funari, Vinicius de Souza, Debora Romeo Bertola, Alexsandra Christianne Malaquias, Berenice Bilharinho Mendonca, Alexander Augusto de Lima Jorge

{"title":"Rare Causes and Differential Diagnosis in Patients With Silver-Russell Syndrome.","authors":"Barbara Leitao Braga, Renata da Cunha Scalco, Thais Kataoka Homma, Bruna Lucheze Freire, Laurana De Polli Cellin, Ana Pinheiro Machado Canton, Antônio Marcondes Lerario, Mariana Ferreira de Assis Funari, Vinicius de Souza, Debora Romeo Bertola, Alexsandra Christianne Malaquias, Berenice Bilharinho Mendonca, Alexander Augusto de Lima Jorge","doi":"10.1111/cge.14659","DOIUrl":"https://doi.org/10.1111/cge.14659","url":null,"abstract":"Silver-Russell syndrome (SRS) is an imprinting disorder mainly characterized by pre- and postnatal growth restriction. Most SRS cases are due to 11p15.5 loss of methylation (11p15.5 LOM) or maternal uniparental disomy of chromosome 7 [UPD(7)mat], but several patients remain molecularly undiagnosed. This study describes the molecular investigation of children with a clinical diagnosis or suspicion of SRS at a tertiary center specialized in growth disorders. Thirty-nine patients were evaluated with multiplex ligation-dependent probe amplification, chromosomal microarray and/or massively parallel sequencing. The most common result was 11p15.5 LOM (n = 17; 43.5%), followed by UPD(7)mat (n = 2; 5.1%). Additionally, we found maternal duplications of the imprinting centers in 11p15.5 (n = 2; 5.1%), and genetic defects in SRS-causing genes (IGF2 and HMGA2) (n = 3; 7.7%; two mutations and one deletion). Alternative molecular diagnoses included UPD(14)mat (n = 1; 2,6%), UPD(20)mat (n = 1;2,6%), copy number variants (n = 2; 5.1%), and mutations in genes associated with other growth disorders (n = 4; 10.3%), leading to diagnoses of Temple syndrome, Mulchandani-Bhoj-Conlin syndrome, IGF-1 resistance (IGF1R), Bloom syndrome (BLM), Gabriele-De Vries syndrome (YY1), Intellectual developmental disorder autosomal dominant 50 with behavioral abnormalities (NAA15), and Intellectual developmental disorder 64 (ZNF292). These findings underscore the importance of establishing the molecular diagnosis of SRS and its differential diagnoses to guide appropriate management and genetic counseling.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Skeletal Phenotype in Mulibrey Nanism, A Monogenic Skeletal Dysplasia With Fibrous Dysplasia. Mulibrey Nanism（一种伴有纤维性发育不良的单基因骨骼发育不良）的骨骼表型。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-11-18 DOI: 10.1111/cge.14647

Susann Karlberg, Sanna Toiviainen-Salo, Marita Lipsanen-Nyman, Outi Mäkitie

{"title":"Skeletal Phenotype in Mulibrey Nanism, A Monogenic Skeletal Dysplasia With Fibrous Dysplasia.","authors":"Susann Karlberg, Sanna Toiviainen-Salo, Marita Lipsanen-Nyman, Outi Mäkitie","doi":"10.1111/cge.14647","DOIUrl":"10.1111/cge.14647","url":null,"abstract":"Mulibrey nanism (MUL) is a monogenic growth disorder caused by mutations in TRIM37, with pre-and postnatal growth failure, typical craniofacial features, perimyocardial heart disease, infertility and predisposition to tumors. Clinically, patients are gracile with relative macrocephaly, thin extremities, and narrow shoulders, but the full spectrum of skeletal features remains unknown. We conducted a cross-sectional study in order to further clarify the skeletal phenotype. We assessed radiographs of the long bones and spine in 33 MUL patients, aged 4.5-48 years (14 females and 19 males, median age 16.7 years) for skeletal features. Hospital records were reviewed for clinical characteristics and fractures. Results confirmed significant skeletal abnormalities related to MUL. Skeletal changes were present in all patients; long bones were slender and bowed with broad metaphyses and narrow diaphysis, the cortices were thick, and medullary cavities were narrow. The vertebral bodies were tall. Fibrous dysplasia was found in 19/33 patients (58%); changes were monostotic in 58% and polyostotic in 42%. Altogether 17/33 patients (52%) had a history of fractures. This study confirms that in addition to short stature, patients with MUL have a specific skeletal dysplasia. Our findings suggest an important role for TRIM37 in cellular functions governing skeletal modelling and remodelling.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BRCC3-Associated Syndromic Moyamoya Angiopathy Diagnosed Through Clinical RNA Sequencing. 通过临床 RNA 测序确诊的 BRCC3 相关综合征莫亚莫亚血管病变。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-11-17 DOI: 10.1111/cge.14650

Myrrhe Venema, Fatimah Albuainain, Rachel Schot, Bob Roozenbeek, Frank Sleutels, Tjakko van Ham, Tahsin Stefan Barakat

{"title":"BRCC3-Associated Syndromic Moyamoya Angiopathy Diagnosed Through Clinical RNA Sequencing.","authors":"Myrrhe Venema, Fatimah Albuainain, Rachel Schot, Bob Roozenbeek, Frank Sleutels, Tjakko van Ham, Tahsin Stefan Barakat","doi":"10.1111/cge.14650","DOIUrl":"https://doi.org/10.1111/cge.14650","url":null,"abstract":"Moyamoya angiopathy is a cerebral vasculopathy causing progressive stenosis of the internal carotid arteries and the compensatory development of collateral blood vessels, leading to brain ischemia and an increased risk of cerebral haemorrhage. Although multiple non-genetic causes have been associated with moyamoya syndrome, it can also be associated with rare genetic syndromes. Moyamoya Disease 4, characterised by a short stature, hypergonadotropic hypogonadism and facial dysmorphism (MYMY4, OMIM #300845), also referred to as BRCC3-associated moyamoya syndrome, has so far been described in 11 individuals. Here, we describe a 23-year-old male presenting with moyamoya syndrome, global developmental delay and intellectual disability, epilepsy, short stature and dysmorphic features, who after > 17 years of uninformative diagnostics was diagnosed with BRCC3-associated moyamoya syndrome after clinical RNA-seq. Transcriptome analysis showed reduced expression of the likely disease-causing gene BRCC3 in patient-derived fibroblasts, which was subsequently found to be caused by a ~ 26 kb Xq28 deletion. We furthermore review all reported cases of BRCC3-associated moyamoya syndrome, further delineating this clinical entity.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic, Clinical, and Biochemical Characterization of a Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome. 大量巴勒斯坦范柯尼-比克尔综合征患者的遗传、临床和生化特征。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-11-16 DOI: 10.1111/cge.14648

Tamer Hodrob, Alaaeddin Abusalameh, Ibrahim Ismail, Imad Dweikat, Sarah Abu Rmeilah, Mutaz Sultan, Bassam Abu Libdeh, Abd-Al-Salam Abu Libdeh, Shaher Shweiki, Nadirah Damseh

{"title":"Genetic, Clinical, and Biochemical Characterization of a Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome.","authors":"Tamer Hodrob, Alaaeddin Abusalameh, Ibrahim Ismail, Imad Dweikat, Sarah Abu Rmeilah, Mutaz Sultan, Bassam Abu Libdeh, Abd-Al-Salam Abu Libdeh, Shaher Shweiki, Nadirah Damseh","doi":"10.1111/cge.14648","DOIUrl":"https://doi.org/10.1111/cge.14648","url":null,"abstract":"This study aims to investigate the clinical, biochemical, and genetic characteristics of Fanconi-Bickel syndrome (FBS) in a cohort of 20 individuals from Palestine and to identify novel pathogenic variants. A retrospective analysis was conducted on medical records from Al-Makassed Hospital's pediatric department spanning 2015 to 2023. Individuals diagnosed with FBS via molecular genetic testing were included in the study. Among the 20 genetically confirmed FBS patients, hepatomegaly was prevalent in 95%, whereas 70% exhibited both developmental delay and hypophosphatemic rickets, and 68.4% experienced growth retardation. Hypertriglyceridemia (HTG) was universal. Elevated liver enzymes and alkaline phosphatase were common, along with hypophosphatemia (95%) and urinary abnormalities. Genetic analysis revealed five distinct SLC2A2 pathogenic variants, including three previously unreported variants: p.Gln23Arg (c.68A > G), p.Thr353Arg (c.1058_1059delinsGG), and an exon 7 deletion. This study presents the largest single-center cohort of FBS patients, expanding our understanding of the disorder's phenotypic and genotypic spectrum. Despite FBS generally carrying a favorable prognosis, timely diagnosis remains crucial to prevent severe complications.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Excess of Carriers in Rare Disorders Suggests a Nonpathogenic Effect for Most Variants of Uncertain Significance. 罕见疾病中的过多携带者表明大多数意义不明的变异体具有非致病性效应。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-11-05 DOI: 10.1111/cge.14642

Stefano Medaglia, Jaume Reig-Palou, Ariadna Bellés, Nerea Moreno-Ruiz, Jairo Rodríguez, Xavier Armengol, Juan Ignacio Aróstegui, Lluís Armengol, Juan José Guillén, Hafid Laayouni, Ferran Casals

{"title":"The Excess of Carriers in Rare Disorders Suggests a Nonpathogenic Effect for Most Variants of Uncertain Significance.","authors":"Stefano Medaglia, Jaume Reig-Palou, Ariadna Bellés, Nerea Moreno-Ruiz, Jairo Rodríguez, Xavier Armengol, Juan Ignacio Aróstegui, Lluís Armengol, Juan José Guillén, Hafid Laayouni, Ferran Casals","doi":"10.1111/cge.14642","DOIUrl":"https://doi.org/10.1111/cge.14642","url":null,"abstract":"Functional annotation and interpretation of genetic variants are a critical step in genetic diagnosis, as it may lead to personalized therapeutic options and genetic counseling. While the number of confirmed pathogenic genetic variants in an individual is relatively low, the number of variants of uncertain significance (VOUS) can be considerably higher, increasing the number of potential carriers of genetic disorders. Thus, reducing uncertainty and assessing the real effect of VOUS are crucial for clinical and medical genetics. In this study, we evaluated the efficacy of genetic screening technologies in accurately predicting pathogenic variants and their corresponding disease prevalence in a cohort of over 6000 healthy individuals involved in assisted reproduction programs. Using data from 305 genes associated with recessive disorders, we determined the frequency of carriers of pathogenic variants and VOUS in our dataset and compared the predicted prevalence based on this information with reported population prevalence data. The higher predicted prevalence in some disorders when considering VOUS suggests a mostly benign effect.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PERCC1-Related Congenital Enteropathy 与 PERCC1 相关的先天性肠病

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-29 DOI: 10.1111/cge.14638

Lena S. Kerle, Pia Karlsland Åkeson, Thomas Müller, Andreas R. Janecke

引用次数: 0

Recognisable Neuroradiological Findings in Five Neurogenetic Disorders 五种神经遗传性疾病中可识别的神经放射学发现。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-27 DOI: 10.1111/cge.14637

Jessica Rosenblum, Marije Meuwissen, Anna C. Jansen, Renske Oegema, Nihaal Reddy, Kshitij Mankad, Sniya Sudhakar

{"title":"Recognisable Neuroradiological Findings in Five Neurogenetic Disorders","authors":"Jessica Rosenblum, Marije Meuwissen, Anna C. Jansen, Renske Oegema, Nihaal Reddy, Kshitij Mankad, Sniya Sudhakar","doi":"10.1111/cge.14637","DOIUrl":"10.1111/cge.14637","url":null,"abstract":"<div>\u0000 \u0000 The rate of discovery and increased understanding of genetic causes for neurodevelopmental disorders has peaked over the past decade. It is well recognised that some genes show marked variability in neuroradiological phenotypes, and inversely, some radiological phenotypes are associated with several different genetic conditions. However, some readily recognisable brain magnetic resonance imaging (MRI) patterns, especially in the context of corresponding associated clinical findings, should prompt consideration of a pathogenic variant in a specific gene or gene pathway. As these conditions can often prove challenging to diagnose, a clinical suspicion of a specific disorder may be invaluable to guide and interpret genetic testing. This review focuses on five neurogenetic syndromes with recognisable brain findings that radiologists, paediatric neurologists, geneticists, and other specialists involved in neurodevelopmental disorders should be able to recognise in order to pinpoint the gene or gene groups involved and delve into their molecular mechanisms. The comprehensively reviewed conditions include DDX3X-related neurodevelopmental disorder, Van Maldergem syndrome, NMDAR-related disorders, EML1-associated disorder and ARFGEF2-related periventricular nodular heterotopia with microcephaly.\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 1","pages":"13-22"},"PeriodicalIF":2.9,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of Two Novel Missense Variants in BNC1 in Han Chinese Patients With Non-syndromic Premature Ovarian Insufficiency 在非综合征性卵巢早衰的中国汉族患者中发现 BNC1 的两个新型错义变异基因

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-27 DOI: 10.1111/cge.14639

Yuncheng Pan, Jitong Mo, Shuting Ren, Yifei Zhang, Feng Zhang, Xiaojin Zhang, Yanhua Wu

引用次数: 0