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Iman G. Mahmoud Mohamed A. Elmonem Maha S. Zaki Areef Ramadan Nihal M. Al-Menabawy Aya El-Gamal Lobna Mansour Mahmoud Y. Issa Mohamed S. Abdel-Hamid Sawsan Abdel-Hady Iman Khalifa Ahmed Ibrahim Alexander Solyom Arndt Rolfs Laila Selim 《Clinical genetics》2020,98(6):598-605
Acid ceramidase deficiency is an orphan lysosomal disorder caused by ASAH1 pathogenic variants and presenting with either Farber disease or spinal muscle atrophy with progressive myoclonic epilepsy (SMA-PME). Phenotypic and genotypic features are rarely explored beyond the scope of case reports. Furthermore, the new biomarker C26-Ceramide requires validation in a clinical setting. We evaluated the clinical, biomarker and genetic spectrum of 15 Egyptian children from 14 unrelated families with biallelic pathogenic variants in ASAH1 (12 Farber and 3 SMA-PME). Recruited children were nine females/six males ranging in age at diagnosis from 13 to 118 months. We detected ASAH1 pathogenic variants in all 30 alleles including three novel variants (c.1126A>G (p.Thr376Ala), c.1205G>A (p.Arg402Gln), exon-5-deletion). Both total C26-Ceramide and its trans- isomer showed 100% sensitivity for the detection of ASAH1-related disorders in tested patients. A 10-year-old girl with the novel variant c.1205G>A (p.Arg402Gln) presented with a new peculiar phenotype of PME without muscle atrophy. We expanded the phenotypic spectrum of ASAH1-related disorders and validated the biomarker C26-Ceramide for supporting diagnosis in symptomatic patients. 相似文献
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Diana Gallego Ftima Leal Alejandra Gmez Margarita Castro Rosa Navarrete Obdulia Sanchez‐Lijarcio Isidro Vitoria María Bueno‐Delgado Amaya Belanger‐Quintana Ana Morais Consuelo Pedrn‐Giner Inmaculada García Jaume Campistol Rafael Artuch Carlos Alcaide Veronica Cornejo David Gil Raquel Yahyaoui Lourdes R. Desviat Magdalena Ugarte Aurora Martínez Beln Prez 《Human mutation》2020,41(7):1329-1338
Biallelic variants of the gene DNAJC12, which encodes a cochaperone, were recently described in patients with hyperphenylalaninemia (HPA). This paper reports the retrospective genetic analysis of a cohort of unsolved cases of HPA. Biallelic variants of DNAJC12 were identified in 20 patients (generally neurologically asymptomatic) previously diagnosed with phenylalanine hydroxylase (PAH) deficiency (phenylketonuria [PKU]). Further, mutations of DNAJC12 were identified in four carriers of a pathogenic variant of PAH. The genetic spectrum of DNAJC12 in the present patients included four new variants, two intronic changes c.298‐2A>C and c.502+1G>C, presumably affecting the splicing process, and two exonic changes c.309G>T (p.Trp103Cys) and c.524G>A (p.Trp175Ter), classified as variants of unknown clinical significance (VUS). The variant p.Trp175Ter was detected in 83% of the mutant alleles, with 14 cases homozygous, and was present in 0.3% of a Spanish control population. Functional analysis indicated a significant reduction in PAH and its activity, reduced tyrosine hydroxylase stability, but no effect on tryptophan hydroxylase 2 stability, classifying the two VUS as pathogenic variants. Additionally, the effect of the overexpression of DNAJC12 on some destabilizing PAH mutations was examined and a mutation‐specific effect on stabilization was detected suggesting that the proteostasis network could be a genetic modifier of PAH deficiency and a potential target for developing mutation‐specific treatments for PKU. 相似文献
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Qingming Wang Ye Han Xinlong Zhou ShuangXi Cheng Xin Wang Xiaoli Chen Haiming Yuan 《Clinical genetics》2023,104(2):259-265
Biallelic pathogenic variants in RNASEH2C cause Aicardi-Goutières syndrome 3 (AGS3, MIM #610329), a rare early-onset encephalopathy characterized by intermittent unexplained fever, chilblains, irritability, progressive microcephaly, dystonia, spasticity, severe psychomotor retardation and abnormal brain imaging. Currently, approximately 50 individuals with AGS3 and 19 variants in RNASEH2C have been revealed. Here, we reported the novel clinical manifestations and genotypic information of three unrelated Chinese patients with AGS3 caused by pathogenic variants in RNASEH2C. In addition to three novel missense variants (c.101G>A, p.Cys34Tyr; c.401T>A, p.Leu134Gln and c.434G>T, p.Arg145Leu), one missense variant (c.194G>A, p.Gly65Asp) reoccurred in all patients but was completely absent in South Asian and other ethnicities. Our study expanded the variant spectrum of RNASEH2C and identified RNASEH2C c.194G>A as a Chinese-specific founder mutation. The novel phenotypes, including mouth ulcers, hip dysplasia, retarded dentition and hypogonadism, observed in our patients greatly enriched the clinical characteristics of AGS3. 相似文献
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Frank X. Donovan Avani Solanki Minako Mori Niranjan Chavan Merin George Selvaa Kumar C Yusuke Okuno Hideki Muramastsu Kenichi Yoshida Akira Shimamoto Akifumi Takaori‐Kondo Hiromasa Yabe Seishi Ogawa Seiji Kojima Miharu Yabe Ramanagouda Ramanagoudr‐Bhojappa Agata Smogorzewska Sheila Mohan Aruna Rajendran Arleen D. Auerbach Minoru Takata Settara C. Chandrasekharappa Babu Rao Vundinti 《Human mutation》2020,41(1):122-128
Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, predisposition to cancer, and congenital abnormalities. FA is caused by pathogenic variants in any of 22 genes involved in the DNA repair pathway responsible for removing interstrand crosslinks. FANCL, an E3 ubiquitin ligase, is an integral component of the pathway, but patients affected by disease‐causing FANCL variants are rare, with only nine cases reported worldwide. We report here a FANCL founder variant, anticipated to be synonymous, c.1092G>A;p.K364=, but demonstrated to induce aberrant splicing, c.1021_1092del;p.W341_K364del, that accounts for the onset of FA in 13 cases from South Asia, 12 from India and one from Pakistan. We comprehensively illustrate the pathogenic nature of the variant, provide evidence for a founder effect, and propose including this variant in genetic screening of suspected FA patients in India and Pakistan, as well as those with ancestry from these regions of South Asia. 相似文献
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《Genetics in medicine》2019,21(7):1629-1638
PurposeThe diagnostic rate for Mendelian diseases by exome sequencing (ES) is typically 20–40%. The low rate is partly because ES misses deep-intronic or synonymous variants leading to aberrant splicing. In this study, we aimed to apply RNA sequencing (RNA-seq) to efficiently detect the aberrant splicings and their related variants.MethodsAberrant splicing in biopsied muscles from six nemaline myopathy (NM) cases unresolved by ES were analyzed with RNA-seq. Variants related to detected aberrant splicing events were analyzed with Sanger sequencing. Detected variants were screened in NM patients unresolved by ES.ResultsWe identified a novel deep-intronic NEB pathogenic variant, c.1569+339A>G in one case, and another novel synonymous NEB pathogenic variant, c.24684G>C (p.Ser8228Ser) in three cases. The c.24684G>C variant was observed to be the most frequent among all NEB pathogenic variants in normal Japanese populations with a frequency of 1 in 178 (20 alleles in 3552 individuals), but was previously unrecognized. Expanded screening of the variant identified it in a further four previously unsolved nemaline myopathy cases.ConclusionThese results indicated that RNA-seq may be able to solve a large proportion of previously undiagnosed muscle diseases. 相似文献
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O. Korvatska A. Estes J. Munson G. Dawson L.M. Bekris R. Kohen C.‐E. Yu G.D. Schellenberg W.H. Raskind 《American journal of medical genetics. Part B, Neuropsychiatric genetics》2011,156(3):303-311
Linkage to 7q has been the most robust genetic finding in familial autism. A previous scan of multiplex families with autism spectrum disorders found a linkage signal of genome‐wide significance at D7S530 on 7q32. We searched a candidate imprinted region at this location for genetic variants in families with positive linkage scores. Using exon resequencing, we identified three rare potentially pathogenic variants in the TSGA14 gene, which encodes a centrosomal protein. Two variants were missense mutations (c.664C>G; p.P206A and c.766T>G; p.C240G) that changed conserved residues in the same protein domain; the third variant (c.192+5G>A) altered splicing, which resulted in a protein with an internal deletion of 16 residues and a G33D substitution. These rare TSGA14 variants are enriched in the affected subjects (6/348 patients versus 2/670 controls, Fisher's exact two tailed P = 0.022). This is the first report of a possible link of a gene with a centrosomal function with familial autism. © 2011 Wiley‐Liss, Inc. 相似文献
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Zhidai Liu Chaowen Yu Qingge Li Ren Cai Yiping Qu Weipeng Wang Jie Wang Jinwen Feng Wenbin Zhu Mingcai Ou Weitong Huang Deguo Tang Wei Guo Fangjie Liu Yanhua Chen Lifang Fu Yanxia Zhou Wenqiong Lv Hang Zhang Juan Zhang Ming Wang Jing Yang Kexing Wan Jingkun Miao Zhaojian Yuan Hao Liu Xiaoyan He Wenjie Li Wengao Chen Lixin Ye Yajun Chen Shuodan Huang Haiping Liu Hongxiang Ding Xinhui Gan Shuyuan Wang Rong Qiang Minhong Gong Ping Teng Hua Wang Muping Zhou Hongwei Wei Xiangju Liu Kai Tang Yahong Ma Hongliang Wu Xiaoli Shu Yizhen Chen Danyan Zhuang Hui Li Zhi Liu Xiulian Liu Yao Chen Lidan Zhu Xiaoyan Zhu Caihong Mo Hua Tang Feng Yin Zhibing Shao Penghui Zhang Bin Peng Qing Lu Zhiguo Wang Lin Zou 《Human mutation》2020,41(1):212-221
Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is one of the most common X‐linked enzymopathies caused by G6PD gene variant. We aimed to provide the characteristics of G6PD deficiency and G6PD gene variant distribution in a large Chinese newborn screening population. We investigated the prevalence of G6PD in China from 2013 to 2017. Then, we examined G6PD activity and G6PD gene in representative Chinese birth cohort to explore the distribution of G6PD gene variant in 2016. We then performed multicolor melting curve analysis to classify G6PD gene variants in 10,357 neonates with activity‐confirmed G6PD deficiency, and DNA Sanger sequencing for G6PD coding exons if hot site variants were not found. The screened population, organizations, and provinces of G6PD deficiency were increased from 2013 to 2017 in China. The top five frequency of G6PD gene variants were c.1376G>T, c.1388G>A, c.95A>G, c.1024C>T, and c.871G>A and varied in different provinces, with regional and ethnic features, and four pathogenic variant sites (c.152C>T, c.290A>T, c.697G>C, and c.1285A>G) were first reported. G6PD deficiency mainly occurs in South China, and the frequency of G6PD gene variant varies in different regions and ethnicities. 相似文献
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Josefina Chinton Victoria Huckstadt Mafalda Mucciolo Francesca Lepri Antonio Novelli María Gabriela Obregon 《American journal of medical genetics. Part A》2020,182(2):409-414
Noonan syndrome (NS, OMIM 163950) is a common autosomal dominant RASopathy caused mainly by gain‐of‐function germline pathogenic variants in genes involved in the RAS/MAPK signaling pathway. LZTR1 gene has been associated with both dominant and recessive NS. Here, we present seven patients with NS and variants in the LZTR1 gene from seven unrelated families, 14 individuals in total. The detection rAte of LZTR1 variants in our NS cohort was 4% similar to RAF1 and KRAS genes, indicating that variants in this gene might be frequent among our population. Three different variants were detected, c.742G>A (p.Gly248Arg), c.360C>A (p.His120Gln), and c.2245T>C (p.Tyr749His). The pathogenic variant c.742G>A (p.Gly248Arg) was found in five/seven patients. In our cohort 50% of patients presented heart defects and neurodevelopment delay or learning disabilities, short stature was present in 21% of them and one patient had acute lymphoblastic leukemia. This study broadens the spectrum of variants in the LZTR1 gene and provides increased knowledge of the clinical phenotypes observed in Argentinean NS patients. 相似文献
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E. Weh L.M. Reis R.C. Tyler D. Bick W.J. Rhead S. Wallace T.L. McGregor S.K. Dills M.‐C. Chao J.C. Murray E.V. Semina 《Clinical genetics》2014,86(2):142-148
Peters plus syndrome (PPS) is a rare autosomal‐recessive disorder characterized by Peters anomaly of the eye, short stature, brachydactyly, dysmorphic facial features, developmental delay, and variable other systemic abnormalities. In this report, we describe screening of 64 patients affected with PPS, isolated Peters anomaly and PPS‐like phenotypes. Mutations in the coding region of B3GALTL were identified in nine patients; six had a documented phenotype of classic PPS and the remaining three had a clinical diagnosis of PPS with incomplete clinical documentation. A total of nine different pathogenic alleles were identified. Five alleles are novel including one frameshift, c.168dupA, p.(Gly57Argfs*11), one nonsense, c.1234C>T, p.(Arg412*), two missense, c.1045G>A, p.(Asp349Asn) and c.1181G>A, p.(Gly394Glu), and one splicing, c.347+5G>T, mutations. Consistent with previous reports, the c.660+1G>A mutation was the most common mutation identified, seen in eight of the nine patients and accounting for 55% of pathogenic alleles in this study and 69% of all reported pathogenic alleles; while two patients were homozygous for this mutation, the majority had a second rare pathogenic allele. We also report the absence of B3GALTL mutations in 55 cases of PPS‐like phenotypes or isolated Peters anomaly, further establishing the strong association of B3GALTL mutations with classic PPS only. 相似文献
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Guy Helman Asako Takanohashi Tracy L. Hagemann Ming D. Perng Marzena Walkiewicz Sarah Woidill Sunetra Sase Zachary Cross Yangzhu Du Ling Zhao Amy Waldman Bret C. Haake Ali Fatemi Michael Brenner Omar Sherbini Albee Messing Adeline Vanderver Cas Simons 《Human mutation》2020,41(6):1131-1137
Alexander disease results from gain‐of‐function mutations in the gene encoding glial fibrillary acidic protein (GFAP). At least eight GFAP isoforms have been described, however, the predominant alpha isoform accounts for ~90% of GFAP protein. We describe exonic variants identified in three unrelated families with Type II Alexander disease that alter the splicing of GFAP pre‐messenger RNA (mRNA) and result in the upregulation of a previously uncharacterized GFAP lambda isoform (NM_001363846.1). Affected members of Family 1 and Family 2 shared the same missense variant, NM_001363846.1:c.1289G>A;p.(Arg430His) while in Family 3 we identified a synonymous variant in the adjacent nucleotide, NM_001363846.1:c.1290C>A;p.(Arg430Arg). Using RNA and protein analysis of brain autopsy samples, and a mini‐gene splicing reporter assay, we demonstrate both variants result in the upregulation of the lambda isoform. Our approach demonstrates the importance of characterizing the effect of GFAP variants on mRNA splicing to inform future pathophysiologic and therapeutic study for Alexander disease. 相似文献
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Schaida Schirwani Emily Woods David A. Koolen Charlotte W. Ockeloen Sally Ann Lynch Karl Kavanagh John M. Graham Jr Katheryn Grand Tyler Mark Pierson Jeffrey M. Chung Meena Balasubramanian 《American journal of medical genetics. Part A》2023,191(1):29-36
De novo truncating and splicing pathogenic variants in the Additional Sex Combs-Like 3 (ASXL3) gene are known to cause neurodevelopmental delay, intellectual disability, behavioral difficulties, hypotonia, feeding problems and characteristic facial features. We previously reported 45 patients with ASXL3-related disorder including three individuals with a familial variant. Here we report the detailed clinical and molecular characteristics of these three families with inherited ASXL3-related disorder. First, a father and son with c.2791_2792del p.Gln931fs pathogenic variant. The second, a mother, daughter and son with c.4534C > T, p.Gln1512Ter pathogenic variant. The third, a mother and her daughter with c.4441dup, p.Leu1481fs maternally inherited pathogenic variant. This report demonstrates intrafamilial phenotypic heterogeneity and confirms heritability of ASXL3-related disorder. 相似文献
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Logan C. Walker Phillip J. Whiley Fergus J. Couch Daniel J. Farrugia Sue Healey Diana M. Eccles Feng Lin Samantha A. Butler Sheila A. Goff Bryony A. Thompson Sunil R. Lakhani Leonard M. Da Silva Sean V. Tavtigian David E. Goldgar Melissa A. Brown Amanda B. Spurdle 《Human mutation》2010,31(6):E1484-E1505
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Natalya Karp Donald Lee Salma Shickh Mary E. Jenkins 《European journal of medical genetics》2019,62(4):235-238
Alexander disease (AD) is a rare form of leukodystrophy caused by pathogenic variants in the GFAP gene. In young children the condition is fatal, while adults have variable neurological symptoms and prognosis. On magnetic resonance imaging, a pattern of atrophy of the medulla oblongata and cervical spinal cord with a ‘tadpole’ appearance is highly suggestive of adult-onset Alexander disease (AOAD). GFAP gene sequencing is used to confirm the diagnosis. Pre-mRNA of this gene undergoes alternative splicing resulting in formation of at least 8 different protein isoforms. Most patients with AD described to date have a pathogenic variant in the coding sequence of the main and the most abundant gene isoform, the GFAPα. Recently, two half-siblings with neurological symptoms and radiological signs of AOAD were reported and were not found to have any pathogenic variants in the GFAPα gene while further genetic testing by next generation sequencing revealed a c.1289G>A (p.Arg430His) variant in the alternative exon 7A of the GFAPε isoform.Here we present a case of another patient with symptoms and brain MRI pattern suggestive of AOAD. Similarly to the previously described patients, this patient did not have any pathogenic variants in the main gene isoform and had the same c.1289G>A (p.Arg430His) variant in the GFAPε. This report contributes to evidence of pathogenicity of the c.1289G>A (p.Arg430His) variant in the GFAPε. 相似文献
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FGFR1 Analyses in Four Patients with Hypogonadotropic Hypogonadism with Split‐Hand/Foot Malformation: Implications for the Promoter Region 下载免费PDF全文
Kohnosuke Ohtaka Yasuko Fujisawa Fumio Takada Yukihiro Hasegawa Tatsuya Miyoshi Tomonobu Hasegawa Hideaki Miyoshi Hiraku Kameda Misuzu Kurokawa‐Seo Maki Fukami Tsutomu Ogata 《Human mutation》2017,38(5):503-506
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Liangpu Xu Xinrui Wang Jia Li Lingji Chen Haiwei Wang Shiyi Xu Yanhong Zhang Wei Li Pengcheng Yao Meihua Tan Si Zhou Meihuan Chen Yali Pan Xuemei Chen Xiaolan Chen Yunliang Liu Na Lin Hailong Huang Hua Cao 《Clinical genetics》2023,103(4):413-423
The fimbrin protein family contains a variety of proteins, among which Plastin1 (PLS1) is an important member. According to recent studies, variations in the coding region of the PLS1 gene are associated with the development of deafness. However, the molecular mechanism of deafness caused by PLS1 gene variants remains unknown. Whole-exome sequencing was performed on hearing-impaired family members and hearing family members to identify pathogenic variants, followed by Sanger sequencing. A minigene assay was conducted to investigate the effect of the variant on PLS1 mRNA splicing. The pathogenicity of the variant was further investigated in zebrafish. RNA-sequencing (RNA-seq) was performed to analyze the dysregulation of downstream signaling pathways caused by knockdown of PLS1 expression. We identified a novel variant, PLS1 c.981+1G>A, in a large Chinese family with hearing loss and showed that the variant is responsible for the occurrence of hearing loss by inducing exon 8 skipping. The variant caused abnormal inner ear phenotypes, characterized by decreases in the mean otolith distance, anterior otolith diameter, posterior otolith diameter, cochlear diameter, and swimming speed and distance in zebrafish. Furthermore, silencing PLS1 expression significantly upregulated the expression of genes in the PI3K-Akt signaling pathway, including Col6a3, Spp1, Itgb3 and hepatocyte growth factor (Hgf). PLS1 c.981+1G>A is a novel pathogenic variant causing hearing loss by inducing exon 8 skipping. Upregulation of the expression of genes in the PI3K-Akt signaling pathway plays an important role in the pathogenesis caused by variants in the PLS1 gene. 相似文献
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Experimental Assessment of Splicing Variants Using Expression Minigenes and Comparison with In Silico Predictions 下载免费PDF全文
Neeraj Sharma Patrick R. Sosnay Anabela S. Ramalho Christopher Douville Arianna Franca Laura B. Gottschalk Jeenah Park Melissa Lee Briana Vecchio‐Pagan Karen S. Raraigh Margarida D. Amaral Rachel Karchin Garry R. Cutting 《Human mutation》2014,35(10):1249-1259