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A monoallelic variant in EYA1 is associated with Branchio-Otic syndrome in a Malian family

MOLECULAR GENETICS & GENOMIC MEDICINE 2022年第7期10卷 e1995页

作者： Yalcouye, Abdoulaye Traore, Oumou Diarra, Salimata schrauwen, isabelle Esoh, Kevin Kadlubowska, Magda Kamila Bharadwaj, Thashi Adadey, Samuel Mawuli Keita, Mohamed Guinto, Cheick O. Leal, Suzanne M. Landoure, Guida Wonkam, Ambroise Univ Cape Town Fac Hlth Sci Dept Med Div Human Genet Cape Town South Africa USTTB Fac Med & Odondostomatol Bamako Mali NINDS Neurogenet Branch Bldg 36Rm 4D04 Bethesda MD 20892 USA Columbia Univ Gertrude H Sergievsky Ctr Med Ctr Ctr Stat Genet New York NY 10027 USA Columbia Univ Med Ctr Dept Neurol New York NY USA Ctr Hosp Univ Gabriel Toure Serv ORL Bamako Mali Ctr Hosp Univ Point G Serv Neurol Bamako Mali Columbia Univ Med Ctr Taub Inst Alzheimers Dis & Aging Brain New York NY USA Johns Hopkins Univ McKusick Nathans Inst Baltimore MD 21218 USA Johns Hopkins Univ Dept Genet Med Baltimore MD 21218 USA

Background: Branchio-otic syndrome (BO) is one of the most common types of syndromic hearing impairment (HI) with an incidence of 1/40,000 globally. It is an autosomal dominant disorder typically characterized by the coexistence of branchial cysts or fistulae, malformations of the external, middle, and inner ears with preauricular pits or tags and a variable degree of HI. Most cases of BO have been reported in populations of European ancestry. To date, only few cases have been reported in people from African descent. Methods: After a careful clinical examination, a pure tone audiometry was performed. DNA was extracted from peripheral blood and whole exome, and Sanger sequencing were performed for genetic analysis. Results: light individuals from a large non-consanguineous Malian family, with autosomal dominant inheritance were enrolled. The ages at diagnosis ranged from 8 to 54 years. A high phenotypic variability was noted among the affected individuals. Four patients presented with a post-lingual and mixed type of HI, one individual had conductive HI while three had normal healing but presented other BO features namely branchial fistulae and preauricular sinus. Serum creatinine level and renal ultrasonography were normal in three affected individuals who performed them. Genetic testing identified a monoallelic pathogenic variant in EYA1 (c.1286A> G;***429Gly) segregating with BO syndrome in the family. Conclusion: This is the first genetically confirmed case of BO syndrome caused by EYA1 variant in the sub-Saharan African population. expanding the genetic spectrum of the condition.

关键词： Africa Branchio-otic syndrome EYA1 Mali syndromic hearing impairment

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Identification of microduplications at Xp21.2 and Xq13.1 in neurodevelopmental disorders

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MOLECULAR GENETICS & GENOMIC MEDICINE 2021年第12期9卷 e1703页

作者： Kokkonen, Hannaleena Siren, Auli Maatta, Tuomo Kamila Kadlubowska, Magda Acharya, Anushree Nouel-Saied, Liz M. Leal, Suzanne M. Jarvela, Irma schrauwen, isabelle Oulu Univ Hosp Northern Finland Lab Ctr NordLab Oulu Finland Oulu Univ Hosp Med Res Ctr Oulu Finland Univ Oulu Oulu Finland Kanta Hame Cent Hosp Hameenlinna Finland Joint Author Kainuu Disabil Serv Kajaani Finland Columbia Univ Med Ctr Ctr Stat Genet Sergievsky CtrDept Neurol New York NY USA Columbia Univ Med Ctr Taub Inst Alzheimers Dis & Aging Brain New York NY USA Univ Helsinki Dept Med Genet Helsinki Finland

Background: Microduplications are a rare cause of disease in X-linked neurodevelopmental disorders but likely have been under reported due challenges in detection and interpretation. Methods: We performed exome sequencing and subsequent microarray analysis in two families with a neurodevelopmental disorder. Results: Here, we report on two families each with unique inherited microduplications at Xp21.2 and Xq13.1, respectively. In the first family, a 562.8-kb duplication at Xq13.1 covering DLG3, TEX11, SLC7A3, GDPD2, and part KIF4A was identified in a boy whose phenotype was characterized by delayed speech development, mild intellectual disability (ID), mild dysmorphic facial features, a heart defect, and neuropsychiatric symptoms. By interrogating all reported Xq13.1 duplications in individuals affected with a neurodevelopmental disorder, we provide evidence that this genomic region and particularly DLG3 might be sensitive to an increased dosage. In the second family with four affected males, we found a noncontinuous 223- and 204-kb duplication at Xp21.2, of which the first duplication covers exon 6 of IL1RAPL1. The phenotype of the male patients was characterized by delayed speech development, mild to moderate ID, strabismus, and neurobehavioral symptoms. The carrier daughter and her mother had learning difficulties. IL1RAPL1 shows nonrecurrent causal structural variation and is located at a common fragile site (FRAXC), prone to re-arrangement. Conclusion: In conclusion, we show that comprehensive clinical and genetic examination of microduplications on the X-chromosome can be helpful in undiagnosed cases of neurodevelopmental disease.

关键词： exome sequencing intellectual disability microduplication neurodevelopmental disorders X-chromosome

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Variants of LRP2, encoding a multifunctional cell-surface endocytic receptor, associated with hearing loss and retinal dystrophy

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CLINICAL GENETICS 2023年第6期103卷 699-703页

作者： Faridi, Rabia Yousaf, Rizwan Gu, Shoujun Inagaki, Sayaka Turriff, Amy E. Pelstring, Keith Guan, Bin Naik, Amelia Griffith, Andrew J. Adadey, Samuel Mawuli Aboagye, Elvis Twumasi Awandare, Gordon A. Morell, Robert J. Tsilou, Ekaterini Noyes, Amanda G. Sulmonte, Laura A. G. Wonkam, Ambroise schrauwen, isabelle Leal, Suzanne M. Azaiez, Hela Brewer, Carmen C. Riazuddin, Sheikh Hufnagel, Robert B. Hoa, Michael Zein, Wadih M. de Dios, J. Karl Friedman, Thomas B. Natl Inst Deafness & Other Commun Disorders NIDCD NIH Lab Mol Genet Bethesda MD USA NIDCD Auditory Dev & Restorat Program NIH Bethesda MD USA NEI Ophthalm Genet & Visual Funct Branch NIH Bethesda MD USA Dayton Childrens Hosp Div Med Genet Dayton OH USA NIDCD Otolaryngol Branch NIH Bethesda MD USA Univ Ghana West African Ctr Cell Biol Infect Pathogens WACCBI Accra Ghana Univ Cape Town Fac Hlth Sci Dept Med Div Human Genet Cape Town South Africa NIDCD Genom & Computat Biol Core NIH Bethesda MD USA GeneDx Inc Gaithersburg MD USA PerkinElmer Genom Sch Med McKusick Nathans Inst Baltimore MD USA Johns Hopkins Univ Sch Med Dept Genet Med Hlth Sci Ctr Baltimore MD USA Columbia Univ Med Ctr Gertrude H Sergievsky Ctr Ctr Stat Genet New York NY USA Columbia Univ Dept Neurol Med Ctr New York NY USA Columbia Univ Taub Inst Alzheimers Dis & Aging Brain Med Ctr New York NY USA Univ Iowa Carver Coll Med Dept Otolaryngol Mol Otolaryngol & Renal Res Labs Iowa IA USA Jinnah Hosp Complex Allama Iqbal Med Res Ctr Lahore Pakistan LMG NIDCD NIH 35A-1F141 Bethesda MD 20892 USA

Hereditary deafness and retinal dystrophy are each genetically heterogenous and clinically variable. Three small unrelated families segregating the combination of deafness and retinal dystrophy were studied by exome sequencing (ES). The proband of Family 1 was found to be compound heterozygous for NM_004525.3: LRP2: c.5005A > G, p.(Asn1669Asp) and c.149C > G, p.(Thr50Ser). In Family 2, two sisters were found to be compound heterozygous for LRP2 variants, p.(Tyr3933Cys) and an experimentally confirmed c.7715 + 3A > T consensus splice-altering variant. In Family 3, the proband is compound heterozygous for a consensus donor splice site variant LRP2: c.8452_8452 + 1del and p.(Cys3150Tyr). In mouse cochlea, Lrp2 is expressed abundantly in the stria vascularis marginal cells demonstrated by smFISH, single-cell and single-nucleus RNAseq, suggesting that a deficiency of LRP2 may compromise the endocochlear potential, which is required for hearing. LRP2 variants have been associated with Donnai-Barrow syndrome and other multisystem pleiotropic phenotypes different from the phenotypes of the four cases reported herein. Our data expand the phenotypic spectrum associated with pathogenic variants in LRP2 warranting their consideration in individuals with a combination of hereditary hearing loss and retinal dystrophy.

关键词： deafness Donnai-Barrow syndrome LRP2 megalin retinal dystrophy RNAseq stria vascularis

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Utilizing RNA and outlier analysis to identify an intronic splice-altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia

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HUMAN MUTATION 2020年第2期41卷 412-419页

作者： McCullough, Carmel G. Szelinger, Szabolcs Belnap, Newell Ramsey, Keri schrauwen, isabelle Claasen, Ana M. Burke, Leah W. Siniard, Ashley L. Huentelman, Matthew J. Narayanan, Vinodh Craig, David W. Univ Southern Calif Dept Translat Genom 1450 Biggy StRoom 2517K Los Angeles CA 90033 USA Translat Genom Res Inst Neurogen Div Ctr Rare Childhood Disorders Phoenix AZ USA Univ Vermont Larner Coll Med Dept Pediat Burlington VT USA

We report a likely pathogenic splice-altering AP4S1 intronic variant in two sisters with progressive spastic paraplegia, global developmental delay, shy character, and foot deformities. Sequencing was completed on whole-blood messenger RNA (mRNA) and analyzed for gene expression outliers after exome sequencing analysis failed to identify a causative variant. AP4S1 was identified as an outlier and contained a rare homozygous variant located three bases upstream of exon 5 (NC_000014.8(NM_007077.4):c.295-3C>A). Confirmed by additional RNA-seq, reverse-transcription polymerase chain reaction, and Sanger sequencing, this variant corresponded with exon 5, including skipping, altered isoform usage, and loss of expression from the canonical isoform 2 (NM_001128126.3). Previously, loss-of-function variants within AP4S1 were associated with a quadriplegic cerebral palsy-6 phenotype, AP-4 Deficiency Syndrome. In this study, the inclusion of mRNA-seq allowed for the identification of a previously missed splice-altering variant, and thereby expands the mutational spectrum of AP-4 Deficiency Syndrome to include impacts to some tissue-dependent isoforms.

关键词： AP-4 deficiency syndrome intronic variant spastic paraplegia type 52 splicing

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Long-read whole-genome sequencing for the genetic diagnosis of dystrophinopathies

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ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY 2020年第10期7卷 2041-2046页

作者： Xie, Zhiying Sun, Chengyue Zhang, Siwen Liu, Yilin Yu, Meng Zheng, Yiming Meng, Lingchao Acharya, Anushree Cornejo-Sanchez, Diana M. Wang, Gao Zhang, Wei schrauwen, isabelle Leal, Suzanne M. Wang, Zhaoxia Yuan, Yun Peking Univ Hosp 1 Dept Neurol 8 Xishiku St Beijing 100034 Peoples R China GrandOm Biosci Beijing Peoples R China Columbia Univ Med Ctr Taub Inst Alzheimers Dis & Aging Brain Ctr Stat GenetSergievsky Ctr New York NY 10027 USA Columbia Univ Med Ctr Dept Neurol New York NY 10027 USA

The precise genetic diagnosis of dystrophinopathies can be challenging, largely due to rare deep intronic variants and more complex structural variants (SVs). We report on the genetic characterization of a dystrophinopathy patient. He remained without a genetic diagnosis after routine genetic testing, dystrophin protein and mRNA analysis, and short- and long-read wholeDMDgene sequencing. We finally identified a novel complex SV inDMDvia long-read whole-genome sequencing. The variant consists of a large-scale (similar to 1Mb) inversion/deletion-insertion rearrangement mediated by LINE-1s. Our study shows that long-read whole-genome sequencing can serve as a clinical diagnostic tool for genetically unsolved dystrophinopathies.

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ADAMTS1, MPDZ, MVD, and SEZ6: candidate genes for autosomal recessive nonsyndromic hearing impairment

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EUROPEAN JOURNAL OF HUMAN GENETICS 2022年第1期30卷 22-33页

作者： Bharadwaj, Thashi schrauwen, isabelle Rehman, Sakina Liaqat, Khurram Acharya, Anushree Giese, Arnaud P. J. Nouel-Saied, Liz M. Nasir, Abdul Everard, Jenna L. Pollock, Lana M. Zhu, Shaoyuan Bamshad, Michael J. Nickerson, Deborah A. Ali, Raja Hussain Ullah, Asmat Wali, Abdul Ali, Ghazanfar Santos-Cortez, Regie Lyn P. Ahmed, Zubair M. McDermott Jr, Brian M. Ansar, Muhammad Riazuddin, Saima Ahmad, Wasim Leal, Suzanne M. Columbia Univ Gertrude H Sergievsky Ctr Med Ctr Ctr Stat Genet New York NY 10027 USA Columbia Univ Med Ctr Dept Neurol New York NY 10027 USA Univ Maryland Dept Otorhinolaryngol Head & Neck Surg Baltimore MD 21201 USA Ajou Univ Dept Mol Sci & Technol Synthet Prot Engn Lab SPEL Suwon South Korea Case Western Reserve Univ Dept Otolaryngol Head & Neck Surg Cleveland OH 44106 USA Univ Washington Dept Genome Sci Seattle WA 98195 USA Univ Washington Dept Pediat Seattle WA 98195 USA Boston Childrens Hosp Dept Hematol Oncol Boston MA USA Univ Copenhagen Fac Hlth & Med Sci Novo Nordisk Fdn Ctr Basic Metab Res Copenhagen Denmark BUITEMS Fac Life Sci & Informat Dept Biotechnol & Informat Quetta Pakistan Univ Azad Jammu & Kashmir Dept Biotechnol Muzaffarabad Pakistan Univ Colorado Sch Med Dept Otolaryngol Head & Neck Surg Anschutz Med Campus Aurora CO USA Quaid I Azam Univ Fac Biol Sci Dept Biochem Islamabad Pakistan Columbia Univ Med Ctr Taub Inst Alzheimers Dis & Aging Brain New York NY USA

Hearing impairment (HI) is a common disorder of sensorineural function with a highly heterogeneous genetic background. Although substantial progress has been made in the understanding of the genetic etiology of hereditary HI, many genes implicated in HI remain undiscovered. Via exome and Sanger sequencing of DNA samples obtained from consanguineous Pakistani families that segregate profound prelingual sensorineural HI, we identified rare homozygous missense variants in four genes (ADAMTS1, MPDZ, MVD, and SEZ6) that are likely the underlying cause of HI. Linkage analysis provided statistical evidence that these variants are associated with autosomal recessive nonsyndromic HI. In silico analysis of the mutant proteins encoded by these genes predicted structural, conformational or interaction changes. RNAseq data analysis revealed expression of these genes in the sensory epithelium of the mouse inner ear during embryonic, postnatal, and adult stages. Immunohistochemistry of the mouse cochlear tissue, further confirmed the expression of ADAMTS1, SEZ6, and MPDZ in the neurosensory hair cells of the organ of Corti, while MVD expression was more prominent in the spiral ganglion cells. Overall, supported by in silico mutant protein analysis, animal models, linkage analysis, and spatiotemporal expression profiling in the mouse inner ear, we propose four new candidate genes for HI and expand our understanding of the etiology of HI.

关键词： Genetics Genetics research Biomedicine general Human Genetics Bioinformatics Gene Expression Cytogenetics

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Disparities in discovery of pathogenic variants for autosomal recessive non-syndromic hearing impairment by ancestry

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EUROPEAN JOURNAL OF HUMAN GENETICS 2019年第9期27卷 1456-1465页

作者： Chakchouk, Imen Zhang, Di Zhang, Zhihui Francioli, Laurent C. Santos-Cortez, Regie Lyn P. schrauwen, isabelle Leal, Suzanne M. Baylor Coll Med Dept Mol & Human Genet Ctr Stat Genet Houston TX 77030 USA Massachusetts Gen Hosp Analyt & Translat Genet Unit Boston MA 02114 USA Broad Inst MIT & Harvard Med & Populat Genet Cambridge MA USA Univ Colorado Sch Med Dept Otolaryngol Aurora CO USA Columbia Univ Med Ctr Gertrude H Sergievsky Ctr Ctr Stat GenetDept Neurol New York NY 10032 USA

Hearing impairment (HI) is characterized by extensive genetic heterogeneity. To determine the population-specific contribution of known autosomal recessive nonsyndromic (ARNS)HI genes and variants to HI etiology;pathogenic and likely pathogenic (PLP) ARNSHI variants were selected from ClinVar and the Deafness Variation Database and their frequencies were obtained from gnomAD for seven populations. ARNSHI prevalence due to PLP variants varies greatly by population ranging from 96.9 affected per 100,000 individuals for Ashkenazi Jews to 5.2 affected per 100,000 individuals for Africans/African Americans. For Europeans, Finns have the lowest prevalence due to ARNSHI PLP variants with 9.5 affected per 100,000 individuals. For East Asians, Latinos, non-Finish Europeans, and South Asians, ARNSHI prevalence due to PLP variants ranges from 17.1 to 33.7 affected per 100,000 individuals. ARNSHI variants that were previously reported in a single ancestry or family were observed in additional populations, e.g., USH1C p.(Q723*) reported in a Chinese family was the most prevalent pathogenic variant observed in gnomAD for African/African Americans. Variability between populations is due to how extensively ARNSHI has been studied, ARNSHI prevalence and ancestry specific ARNSHI variant architecture which is impacted by population history. Our study demonstrates that additional gene and variant discovery studies are necessary for all populations and particularly for individuals of African ancestry.

关键词： Genetics Mutation

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Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency

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AMERICAN JOURNAL OF HUMAN GENETICS 2025年第4期112卷 952-962页

作者： Thomas, Huw B. Demain, Leigh A. M. Cabrera-Orefice, Alfredo schrauwen, isabelle Shamseldin, Hanan E. Rea, Alessandro Bharadwaj, Thashi Smith, Thomas B. Olahova, Monika Thompson, Kyle He, Langping Kaur, Namanpreet Shukla, Anju Abukhalid, Musaad Ansar, Muhammad Rehman, Sakina Riazuddin, Saima Abdulwahab, Firdous Smith, Janine M. Stark, Zornitza Mancilar, Hanifenur Tumer, Sait Esen, Fatma N. Uctepe, Eyyup Topcu, Vehap Yesilyurt, Ahmet Afzal, Erum Salari, Mehri Carroll, Christopher Zifarelli, Giovanni Bauer, Peter Kor, Deniz Bulut, Fatma D. Houlden, Henry Maroofian, Reza Carrera, Samantha Yue, Wyatt W. Munro, Kevin J. Alkuraya, Fowzan S. Jamieson, Peter Ahmed, Zubair M. Leal, Suzanne M. Taylor, Robert W. Wittig, Ilka O'Keefe, Raymond T. Newman, William G. Univ Manchester Sch Biol Sci Div Evolut Infect & Genom Manchester M13 9PL England Manchester Univ NHS Fdn Trust St Marys Hosp Manchester Ctr Genom Med Manchester M13 9WL Lancs England Goethe Univ Inst Cardiovasc Physiol Med Fac Ctr Funct Prote D-60596 Frankfurt Germany Justus Liebig Univ Inst Biochem Med Fac D-35392 Giessen Germany Univ Arizona Coll Med Phoenix Dept Translat Neurosci Phoenix AZ USA King Faisal Specialist Hosp & Res Ctr Ctr Genom Med Dept Translat Genom Riyadh Saudi Arabia Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Med CtrDept Neurol New York NY 10032 USA Northumbria Univ Fac Hlth & Life Sci Dept Appl Sci Newcastle Upon Tyne England Newcastle Univ Fac Med Sci Mitochondrial Res Grp Clin & Translat Res Inst Newcastle Upon Tyne NE2 4HH England Newcastle Upon Tyne Hosp NHS Fdn Trust NHS Highly Specialised Serv Rare Mitochondrial Dis Newcastle Upon Tyne NE1 4LP England Manipal Acad Higher Educ Kasturba Med Coll Manipal Dept Med Genet Manipal Karnataka India King Faisal Specialist Hosp & Res Ctr Dept Neurosci Riyadh Saudi Arabia Quaid I Azam Univ Dept Biochem Fac Biol Sci Islamabad 45320 Pakistan Univ Maryland Dept Otorhinolaryngol Head & Neck Surg Sch Med Baltimore MD USA Univ Punjab Ctr Excellence Mol Biol Lahore Pakistan Univ Sydney Fac Med & Hlth Specialty Genom Med Sydney NSW 2000 Australia Sydney Childrens Hosp Network Dept Clin Genet Western Sydney Genet Program Westmead NSW 2145 Australia Murdoch Childrens Res Inst Victorian Clin Genet Serv Flemington Rd Melbourne Vic Australia Univ Melbourne Melbourne Vic Australia Acibadem Labgen Genet Diag Ctr Istanbul Turkiye Childrens Hosp & Inst Child Hlth Dept Dev Pediat Multan Pakistan Shahid Beheshti Univ Med Sci Dept Neurol Tehran Iran St Georges Univ London Mol & Clin Sci Res Inst Genet Sect London England CENTOGENE GmbH Strande 7 D-18055 Rostock Germany Cukurova Univ Med Fac Dept Pediat Metab & Nutr Adana Turkiye UCL Inst Neurol Dept Neur

Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits. There was no evidence of altered mitoribosomal assembly. The reductions in levels of oxidative phosphorylation (OXPHOS) enzyme complexes I and IV are consistent with a form of COXPD associated with bi-allelic MRPL49 variants, expanding the understanding of how disruption of the mitochondrial ribosomal large subunit results in multisystem phenotypes.

关键词： r Sensorineural hearing loss Primary ovarian insufficiency Clinical presentations

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Transcriptional profiling of multiple system atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

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ACTA NEUROPATHOLOGICA COMMUNICATIONS 2020年第1期8卷 1页

作者： Piras, Ignazio S. Bleul, Christiane schrauwen, isabelle Talboom, Joshua Llaci, Lorida De Both, Matthew D. Naymik, Marcus A. Halliday, Glenda Bettencourt, Conceicao Holton, Janice L. Serrano, Geidy E. Sue, Lucia, I Beach, Thomas G. Stefanova, Nadia Huentelman, Matthew J. Translat Genom Res Inst Neurogen Div Phoenix AZ 85004 USA Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Dept NeurolMed Ctr 630 W 168th St New York NY 10032 USA Washington Univ Div Biol & Biomed Sci Mol Genet & Genom Program St Louis MO 63110 USA Univ Sydney Brain & Mind Ctr Sydney NSW Australia Univ Sydney Fac Med & Hlth Sch Med Sci Sydney NSW Australia Univ Sydney Neurosci Res Australia Sydney NSW Australia UCL Queen Sq Inst Neurol Queen Sq Brain Bank Neurol Disorders London England UCL Queen Sq Inst Neurol Dept Clin & Movement Neurosci London England Banner Sun Hlth Res Inst Civin Lab Neuropathol Sun City AZ 85351 USA Med Univ Innsbruck Dept Neurol Div Neurobiol Innsbruck Austria

Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n=66) and healthy controls (HC;n=66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical *** detected the highest number of DEGs in the MSA-C group (n=747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for beta -amyloid related functional classes, including the known Alzheimer's disease (AD) genes, APP and *** is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregul

关键词： Multiple system atrophy RNA sequencing Oligodendrocytes Neurodegeneration

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Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland

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HUMAN GENETICS 2021年第7期140卷 1011-1029页

作者： Jarvela, Irma Maatta, Tuomo Acharya, Anushree Leppala, Juha Jhangiani, Shalini N. Arvio, Maria Siren, Auli Kankuri-Tammilehto, Minna Kokkonen, Hannaleena Palomaki, Maarit Varilo, Teppo Fang, Mary Hadley, Trevor D. Jolly, Angad Linnankivi, Tarja Paetau, Ritva Saarela, Anni Kalviainen, Reetta Olme, Jan Nouel-Saied, Liz M. Cornejo-Sanchez, Diana M. Llaci, Lorida Lupski, James R. Posey, Jennifer E. Leal, Suzanne M. schrauwen, isabelle Univ Helsinki Dept Med Genet POB 720 Helsinki 00251 Finland Joint Author Kainuu Disabil Serv Kajaani Finland Columbia Univ Med Ctr Ctr Stat Genet Sergievsky CtrTaub Inst Alzheimers Dis & Aging B New York NY USA Columbia Univ Med Ctr Dept Neurol New York NY USA Eskoo Ctr Disabil Empowerment Seinajoki Finland Baylor Coll Med Human Genome Sequencing Ctr Houston TX 77030 USA KTO Special Welf Dist Varsinais Suomi Paimio Finland Paijat Hame Joint Municipal Author Lahti Finland Univ Oulu PEDEGO Oulu Finland Turku Univ Hosp Dept Clin Genet Turku Finland Kanta Hame Cent Hosp Hameenlinna Finland Univ Turku Dept Clin Genet Turku Finland Oulu Univ Hosp Northern Finland Lab Ctr NordLab Oulu Finland Oulu Univ Hosp Med Res Ctr Oulu Finland Univ Oulu Oulu Finland Helsinki Univ Hosp Dept Radiol Helsinki Finland Baylor Coll Med Houston TX 77030 USA Baylor Coll Med Dept Mol & Human Genet Houston TX 77030 USA Univ Helsinki Dept Child Neurol Helsinki Finland Helsinki Univ Hosp Helsinki Finland Univ Eastern Finland Inst Clin Med Sch Med Fac Hlth Sci Kuopio Finland Kuopio Univ Hosp Kuopio Epilepsy Ctr Neuroctr Kuopio Finland Vaasa Cent Hosp Dept Child Neurol Vaasa Finland Washington Univ Div Biol & Biomed Sci St Louis MO 63110 USA Baylor Coll Med Dept Pediat Houston TX 77030 USA Texas Childrens Hosp Houston TX 77030 USA

The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant;11% X-linked) and 25% were inherited (14% autosomal recessive;7% X-linked;and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case.

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