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Identification of autosomal recessive nonsyndromic hearing impairment genes through the study of consanguineous and non-consanguineous families: past, present, and future

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HUMAN GENETICS 2022年第3-4期141卷 413-430页

作者： Acharya, Anushree schrauwen, isabelle 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 Columbia Univ Med Ctr Taub Inst Alzheimers Dis & Aging Brain New York NY 10027 USA

Hearing impairment (HI) is one of the most common sensory disabilities with exceptionally high genetic heterogeneity. Of genetic HI cases, 30% are syndromic and 70% are nonsyndromic. For nonsyndromic (NS) HI, 77% of the cases are due to autosomal recessive (AR) inheritance. ARNSHI is usually congenital/prelingual, severe-to-profound, affects all frequencies and is not progressive. Thus far, 73 ARNSHI genes have been identified. Populations with high rates of consanguinity have been crucial in the identification of ARNSHI genes, and 92% (67/73) of these genes were identified in consanguineous families. Recent changes in genomic technologies and analyses have allowed a shift towards ARNSHI gene discovery in outbred populations. The latter is crucial towards understanding the genetic architecture of ARNSHI in diverse and understudied populations. We present an overview of the 73 ARNSHI genes, the methods used to identify them, including next-generation sequencing which revolutionized the field, and new technologies that show great promise in advancing ARNSHI discoveries.

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A De Novo HECW2 Variant in a Patient with Acetazolamide-Responsive Episodic Ataxia

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CEREBELLUM 2023年第5期22卷 1029-1033页

作者： Silva, Leticia Maria Tedesco Sharma, Sonali schrauwen, isabelle Margolesky, Jason Detyniecki, Kamil Univ Miami Neurol Dept Epilepsy Div 1120 NW 14th St13th Floor Miami FL 33136 USA Columbia Univ Med Ctr Ctr Stat Genet New York NY USA Columbia Univ Gertrude H Sergievsky Ctr Med Ctr New York NY 10027 USA Columbia Univ Dept Neurol Med Ctr New York NY USA Univ Miami Neurol Dept Movements Disorders Div Miami FL USA

To the best of our knowledge, this is the first case to address episodic ataxia (EA) as a possible phenotypic feature of HECW2-related disorder. This single case study describes a 26-year-old female born at term with mild intellectual disability, neonatal hypotonia, and a history of febrile seizures who presented with paroxysmal events since the age of 2. These episodes include frequent falls due to imbalance, dilated pupils, vertigo, diaphoresis, nausea, vomiting, and nystagmus. Brain imaging was normal. A prolonged electroencephalogram (EEG) revealed interictal epileptiform discharges but failed to capture her clinical events. For several years, she was treated for presumed focal seizures with preserved awareness and trialed on adequate dosing of several antiepileptic medications without improvement. After 25 years, given the more prolonged nature of her episodes and the mild interictal cerebellar signs, empiric treatment with acetazolamide was initiated for a presumed diagnosis of EA. Acetazolamide treatment led to a dramatic reduction in event frequency and severity. The initial EA genetic panel was negative. Clinical exome sequence analysis revealed a novel pathogenic de novo missense variant in the HECW2 gene [c.3829 T > C;(***1277His)], located in the HECT domain. HECW2 variants are associated with neurodevelopmental delay, hypotonia, and epilepsy. This study expands the genetic and clinical spectrum of HECW2-related disorder and adds EA to the phenotypic spectrum in affected individuals.

关键词： Episodic ataxia Epilepsy HECW2 Adult

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A pathogenic COL7A1 variant highlights semi-dominant inheritance in dystrophic epidermolysis bullosa

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BMC MEDICAL GENOMICS 2025年第1期18卷 1-7页

作者： Sattar, Saira Bharadwaj, Thashi Kalsoom, Umm-e- Acharya, Anushree Khan, Saadullah Leal, Suzanne M. schrauwen, isabelle Hazara Univ Dept Biochem Mansehra Kpk Pakistan Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Dept NeurolMed Ctr New York NY 10032 USA Kohat Univ Sci & Technol Dept Biotechnol & Genet Engn Kohat Pakistan Columbia Univ Taub Inst Med Ctr New York NY USA Univ Arizona Coll Med Dept Translat Neurosci 475 N 5th St Phoenix AZ 85004 USA

Dystrophic epidermolysis bullosa is a rare subtype of inherited epidermolysis bullosa, caused by variants in the collagen type VII alpha 1 chain (COL7A1) gene (MIM120120). Both autosomal dominant and recessive inheritance has been reported with variable phenotype. We investigated a Pakistani family with dystrophic epidermolysis bullosa via exome sequencing and identified a pathogenic nonsense variant in COL7A1 NM_000094 c.1573 C > T:p.(Arg525*). The inheritance pattern observed was consistent with a semi-dominant model, where heterozygous parents exhibited a mild phenotype, and homozygous children were more severely affected. For dystrophic epidermolysis bullosa, loss-of-function variants are typically associated with the autosomal recessive form, while missense variants are linked to the autosomal dominant form. A review of the literature suggests a semi-dominance pattern for some missense variants, particularly glycine substitutions, but this concept had not been formally recognized. This study highlights the importance of considering semi-dominant inheritance models for dystrophic epidermolysis bullosa and other Mendelian diseases with an autosomal recessive mode of inheritance, as it can significantly impact diagnosis and genetic counseling.

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THBS1 is a new autosomal recessive non-syndromic hearing impairment gene

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BMC MEDICAL GENOMICS 2024年第1期17卷 1-7页

作者： Bharadwaj, Thashi Acharya, Anushree Khan, Fati Ullah Khan, Saadullah Ullah, Irfan schrauwen, isabelle Ahmad, Wasim Leal, Suzanne M. Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Med CtrDept Neurol New York NY 10027 USA Quaid I Azam Univ Fac Biol Sci Dept Biochem Islamabad Pakistan Kohat Univ Sci & Technol KUST Dept Biotechnol & Genet Engn Kohat Pakistan Shaheed Benazir Bhutto Univ Dept Chem Sheringal Pakistan Univ Arizona Coll Med Phoenix Dept Translat Neurosci Phoenix AZ USA Columbia Univ Taub Inst Alzheimers Dis & Aging Brain Med Ctr New York NY 10027 USA

BackgroundPrelingual hearing impairment (HI) is genetically highly heterogenous. Early diagnosis and intervention are essential for psychosocial development. In this study we investigated a consanguineous family from Pakistan with autosomal recessive (AR) non-syndromic sensorineural HI (NSHI).MethodsA DNA sample from an HI member of a consanguineous Pakistani family segregating ARNSHL underwent exome sequencing. Using Sanger sequencing select variants were validated and tested for segregation using DNA samples from additional family members. We further investigated RNA expression data for the candidate gene in mouse and human inner ear and human inner ear organoids using data obtained from the gene Expression Analysis *** identified thrombospondin 1 (THBS1) as a new NSHI gene. A homozygous frameshift variant [c.1470del: p.(Ile491Serfs*45)] was observed in the three hearing-impaired and in the heterozygous state in three unaffected family members. Unlike for most ARNSHI, hearing-impaired individuals had audiograms with a sloping pattern, showing more pronounced HI in the mid and high frequencies (ranging from moderate to profound) compared to the low frequencies. RNA expression data indicates THBS1 is expressed during human inner ear development. Additionally, THBS1 is expressed in the cochlear epithelium and supporting cells of the mouse inner ear during embryonic and postnatal stages. Previously, THBS1 was demonstrated to affect hearing in knockout mice by influencing the formation and function of afferent synapses in the inner *** findings highlight THBS1 as a potential novel candidate gene for human HI characterized by a sloping high-frequency audio profile. This discovery enhances our understanding of the genetic etiology of HI and will aid in advancing molecular diagnosis.

关键词： Autosomal recessive non-syndromic hearing impairment Consanguinity Exome sequencing Inner ear Thrombospondin THBS1

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Mendelian non-syndromic and syndromic hearing loss genes contribute to presbycusis

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EUROPEAN JOURNAL OF HUMAN GENETICS 2025年 1-10页

作者： Cornejo-Sanchez, Diana M. Bharadwaj, Thashi Dong, Rui Wang, Gao T. schrauwen, isabelle Dewan, Andrew T. Leal, Suzanne M. Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Med Ctr New York NY 10032 USA Columbia Univ Dept Neurol Med Ctr New York NY 10032 USA Yale Sch Publ Hlth Dept Chron Dis Epidemiol New Haven CT USA Yale Sch Publ Hlth Ctr Perinatal Pediat & Environm Epidemiol New Haven CT USA Columbia Univ Taub Inst Alzheimers Dis & Aging Brain Med Ctr New York NY 10032 USA Univ Arizona Dept Translat Neurosci Coll Med Phoenix Phoenix AZ USA

Age-related (AR) hearing loss (HL) is the most prevalent sensorineural disorder in older adults. Here we demonstrate that rare-variants in well-established Mendelian HL genes play an important role in ARHL etiology. In all we identified 32 Mendelian HL genes which are associated with ARHL. We performed single and rare-variant aggregate association analyses using exome data obtained from white-Europeans with self-reported hearing phenotypes from the UK Biobank. Our analysis revealed previously unreported associations between ARHL and rare-variants in Mendelian non-syndromic and syndromic HL genes, including MYO15A, and WFS1. Additionally, rare-variant aggregate association analyses identified associations with Mendelian HL genes i.e., ACTG1, GRHL2, KCNQ4, MYO7A, PLS1, TMPRSS3, and TNRC6B. Four novel ARHL genes were also detected: FBXO2 and PALM3, implicated in HL in mice, TWF1, associated with HL in Dalmatian dogs, and TXNDC17. In-silico analyses provided further evidence of inner ear expression of these genes in both murine and human models, supporting their relevance to ARHL. Analysis of variants with minor allele frequency >0.005 revealed additional ARHL associations with known e.g., ILDR1 and novel i.e., ABHD12, COA8, KANSL1, SERAC1, and UBE3B Mendelian non-syndromic and syndromic HL genes as well as ARHL associations with genes that have not been previously reported to be involved in HL e.g., VCL. Rare-variants in Mendelian HL genes typically exhibited higher effect sizes for ARHL compared to those in other associated genes. In conclusion, this study highlights the critical role Mendelian non-syndromic and syndromic HL genes play in the etiology of ARHL.

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A splice site variant in TCTN3 underlies an atypical form of orofaciodigital syndrome IV

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ANNALS OF HUMAN GENETICS 2022年第6期86卷 291-296页

作者： Hussain, Shabir Nawaz, Shoaib Khan, Hammal Acharya, Anushree schrauwen, isabelle Ahmad, Wasim Leal, Suzanne M. Quaid I Azam Univ Fac Biol Sci Dept Biochem Islamabad Pakistan Quaid I Azam Univ Fac Biol Sci Dept Biotechnol Islamabad Pakistan COMSATS Univ Dept Biosci Islamabad Pakistan Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Med Ctr New York NY 10032 USA Columbia Univ Dept Neurol Med Ctr New York NY 10032 USA Columbia Univ Taub Inst Alzheimers Dis & Aging Brain Med Ctr New York NY 10032 USA

Orofaciodigital syndrome (OFD) is clinically heterogeneous and is characterized by abnormalities in the oral cavity, facial features, digits, and central nervous system. At least 18 subtypes of the condition have been described in the literature. OFD is caused by variants in several genes with overlapping phenotypes. We studied a consanguineous Pakistani family with two affected siblings with an atypical form of OFD type 4 (OFD4). In addition to the typical features of OFD4 that include limb defects and growth retardation, the siblings displayed rare features of scaphocephaly and seizures. Exome sequencing analysis revealed a novel homozygous splice site variant c.257-1G>A in TCTN3 that segregated with disease. This homozygous splice site variant in TCTN3 is most likely the underlying cause of the atypical form of OFD4 observed in this family. Our results contribute to the phenotypic spectrum of TCTN3 associated ciliopathies and will facilitate better clinical diagnosis.

关键词： orofaciodigital syndrome scaphocephaly seizures TCTN3

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Nonsense variant in a consanguineous family expands the phenotype of KPTN gene-related syndrome to include hearing impairment

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CLINICAL GENETICS 2023年第4期104卷 499-501页

作者： Liaqat, Khurram Bharadwaj, Thashi Shah, Khadim Nasir, Abdul Acharya, Anushree Khan, Saadullah Ullah, Irfan schrauwen, isabelle Ahmad, Wasim Leal, Suzanne M. Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Dept NeurolMed Ctr New York NY 10027 USA COMSATS Univ Islamabad Dept Biotechnol Islamabad Khyber Pakhtunk Pakistan Zhengzhou Univ Dept Anesthesiol Affiliated Hosp 2 Zhengzhou Peoples R China Kohat Univ Sci & Technol Dept Biotechnol & Genet Engn Kohat Khyber Pakhtunk Pakistan Shaheed Benazir Bhutto Univ Dept Chem Sheringal Pakistan Quaid I Azam Univ Fac Biol Sci Dept Biochem Islamabad Pakistan Columbia Univ Inst Alzheimers Dis & Aging Brain Med Ctr New York NY USA

A short report with two affected siblings from consanguineous family born with intellectual disability, motor disability, language deficit, and hearing impairment and found to carry biallelic nonsense variant in KPTN ...

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A loss of function variant in AGPAT3 underlies intellectual disability and retinitis pigmentosa (IDRP) syndrome

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EUROPEAN JOURNAL OF HUMAN GENETICS 2023年第12期31卷 1447-1454页

作者： Malik, Madiha Amin Saqib, Muhammad Arif Nadeem Mientjes, Edwin Acharya, Anushree Alam, Muhammad Rizwan Wallaard, Ilse schrauwen, isabelle Bamshad, Michael J. Santos-Cortez, Regie Lyn P. Elgersma, Ype Leal, Suzanne M. Ansar, Muhammad Quaid I Azam Univ Fac Biol Sci Dept Biochem Islamabad 45320 Pakistan Erasmus Univ Med Ctr Dept Neurosci Rotterdam Netherlands Natl Skills Univ Dept Med Lab Technol Islamabad 44000 Pakistan Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Med Ctr New York NY 10027 USA Columbia Univ Dept Neurol Med Ctr New York NY 10027 USA Univ Washington Dept Genome Sci William H Foege Hall3720 15th Ave NE Seattle WA 98195 USA Univ Washington Dept Pediat Seattle WA USA Univ Colorado Anschutz Med Campus CU AMC Sch Med Dept Otolaryngol Head & Neck Surg 12700 E 19th Ave Aurora CO 80045 USA Columbia Univ Med Ctr Taub Inst Res Alzheimers Dis & Aging Brain New York NY 10027 USA

Intellectual disability (ID) and retinal dystrophy (RD) are the frequently found features of multiple syndromes involving additional systemic manifestations. Here, we studied a family with four members presenting severe ID and retinitis pigmentosa (RP). Using genome wide genotyping and exome sequencing, we identified a nonsense variant c.747 C > A (***249Ter) in exon 7 of AGPAT3 which co-segregates with the disease phenotype. Western blot analysis of overexpressed WT and mutant AGPAT3 in HEK293T cells showed the absence of AGPAT3, suggesting instability of the truncated protein. Knockdown of Agpat3 in the embryonic mouse brain caused marked deficits in neuronal migration, strongly suggesting that reduced expression of AGPAT3 affects neuronal function. Altogether, our data indicates that AGPAT3 activity is essential for neuronal functioning and loss of its activity probably causes intellectual disability and retinitis pigmentosa (IDRP) syndrome.

关键词： Mutation Neurodevelopmental disorders

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A novel variant in CYFIP2 in a girl with severe disabilities and bilateral perisylvian polymicrogyria

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AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2024年第4期194卷 e63478-e63478页

作者： Salokivi, Tommi Parkkola, Riitta Rajendran, Yasmin Bharadwaj, Thashi Acharya, Anushree Leal, Suzanne M. Jarvela, Irma Arvio, Maria schrauwen, isabelle Wellbeing Serv Cty Southwest Finland Dept Disabil Serv Paimio Finland Univ Turku Dept Radiol Turku Finland Turku Univ Hosp Turku Finland Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Med Ctr New York NY USA Columbia Univ Dept Neurol Med Ctr New York NY USA Columbia Univ Med Ctr Taub Inst New York NY USA Univ Helsinki Dept Med Genet Helsinki Finland Paijat Hame Joint Municipal Author Dept Neurol Lahti Finland Turku Univ Gen Practice Turku Finland Turku Univ Cent Hosp Turku Finland Wellbeing Serv Cty Southwest Finland Dept Disabil Serv Naskarlanraitti 3 Paimio 21520 Finland Columbia Univ Ctr Stat Genet Gertrude H Sergievsky Ctr Dept Neurol 630 W 168th St New York NY 10032 USA

Bilateral perisylvian polymicrogyria (BPP) is a structural malformation of the cerebral cortex that can be caused by several genetic abnormalities. The most common clinical manifestations of BPP include intellectual disability and epilepsy. Cytoplasmic FMRP-interacting protein 2 (CYFIP2) is a protein that interacts with the fragile X mental retardation protein (FMRP). CYFIP2 variants can cause various brain structural abnormalities with the most common clinical manifestations of intellectual disability, epileptic encephalopathy and dysmorphic features. We present a girl with multiple disabilities and BPP caused by a heterozygous, novel, likely pathogenic variant (c.1651G>C: p.(Val551Leu) in the CYFIP2 gene. Our case report broadens the spectrum of genetic diversity associated with BPP by incorporating CYFIP2.

关键词： CYFIP2 intellectual disability polymicrogyria

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Syntaxin 4 is essential for hearing in human and zebrafish

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HUMAN MOLECULAR GENETICS 2023年第7期32卷 1184-1192页

作者： schrauwen, isabelle Ghaffar, Amama Bharadwaj, Thashi Shah, Khadim Rehman, Sakina Acharya, Anushree Liaqat, Khurram Lin, Nicole S. Everard, Jenna L. Khan, Anwar Ahmed, Zubair M. Ahmad, Wasim Riazuddin, Saima Leal, Suzanne M. Columbia Univ Med Ctr Ctr Stat Genet Sergievsky Ctr New York NY USA Columbia Univ Med Ctr Dept Neurol New York NY USA Univ Maryland Sch Med Dept Otorhinolaryngol Head & Neck Surg Baltimore MD USA COMSATS Univ Islamabad Dept Biotechnol Abbottabad Campus Islamabad Khyber Pakhtunk Pakistan Hazara Univ Mansehra Dept Biochem Mansehra Khyber Pakhtunk Pakistan Quaid I Azam Univ Islamabad Fac Biol Sci Dept Biochem Islamabad Pakistan Columbia Univ Taub Inst Alzheimers Dis & Aging Brain Med Ctr New York NY USA Columbia Univ Med Ctr Dept Neurol New York NY USA Columbia Univ Taub Inst Alzheimers Dis & Aging Brain Ctr Stat Genet Sergievsky Ctr 630 168th St New York NY 10032 USA Columbia Univ Dept Neurol 630 168th St New York NY 10032 USA

Congenital hearing impairment (HI) is a genetically highly heterogeneous disorder in which prompt recognition and intervention are crucial to optimize outcomes. In this study, we used exome sequencing to investigate a large consanguineous Pakistani family with eight affected individuals showing bilateral severe-to-profound HI. This identified a homozygous splice region variant in STX4 (c.232 + 6T>C), which causes exon skipping and a frameshift, that segregated with HI (two-point logarithm of odds (LOD) score = 5.9). STX4, a member of the syntaxin family, is a component of the SNARE machinery involved in several vesicle transport and recycling pathways. In silico analysis showed that murine orthologue Stx4a is highly and widespread expressed in the developing and adult inner ear. Immunofluorescent imaging revealed localization of STX4A in the cell body, cell membrane and stereocilia of inner and outer hair cells. Furthermore, a morpholino-based knockdown of stx4 in zebrafish showed an abnormal startle response, morphological and developmental defects, and a disrupted mechanotransduction function in neuromast hair cells measured via FM1-43 uptake. Our findings indicate that STX4 dysfunction leads to HI in humans and zebrafish and supports the evolutionary conserved role of STX4 in inner ear development and hair cell functioning.

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