scholarly journals Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Hao-Ling Cheng ◽  
Ya-Ru Shao ◽  
Yi Dong ◽  
Hai-Lin Dong ◽  
Lu Yang ◽  
...  
Keyword(s):  
Clinical Features ◽  
Autosomal Recessive ◽  
High Efficiency ◽  
De Novo ◽  
Uniparental Disomy ◽  
Genetic Diagnosis ◽  
Chinese Patients ◽  
Molecular Diagnostic ◽  
Autosomal Recessive Cerebellar Ataxia ◽  
First Time

Abstract Background Although many causative genes have been uncovered in recent years, genetic diagnosis is still missing for approximately 50% of autosomal recessive cerebellar ataxia (ARCA) patients. Few studies have been performed to determine the genetic spectrum and clinical profile of ARCA patients in the Chinese population. Methods Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing (WES) and copy number variation (CNV) calling with ExomeDepth. Likely causal CNV predictions were validated by CNVseq. Results Thirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients, providing a 46.3% positive molecular diagnostic rate. Ten different genes were involved, of which four most common genes were SACS, SYNE1, ADCK3 and SETX, which accounted for 76.0% (19/25) of the positive cases. The de novo microdeletion in SACS was reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide. Clinical features of the patients carrying SACS, SYNE1 and ADCK3 mutations were summarized. Conclusions Our results expand the genetic spectrum and clinical profiles of ARCA patients, demonstrate the high efficiency and reliability of WES combined with CNV analysis in the diagnosis of suspected ARCA, and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis.

scholarly journals Genetic Spectrum and Clinical Features in a Cohort of Chinese Patients with Autosomal Recessive Cerebellar Ataxias

2021 ◽  
Author(s):  
Hao-Ling Cheng ◽  
Ya-Ru Shao ◽  
Yi Dong ◽  
Hai-Lin Dong ◽  
Lu Yang ◽  
...  
Keyword(s):  
Clinical Features ◽  
Autosomal Recessive ◽  
High Efficiency ◽  
De Novo ◽  
Uniparental Disomy ◽  
Genetic Diagnosis ◽  
Chinese Patients ◽  
Molecular Diagnostic ◽  
Autosomal Recessive Cerebellar Ataxia ◽  
Clinical Profiles

Abstract Background: Although many causative genes have been uncovered in recent years, genetic diagnosis is still missing for approximately 50% of autosomal recessive cerebellar ataxia (ARCA) patients. Few studies have been performed to determine the genetic spectrum and clinical profiles of ARCA patients in the Chinese population.Methods: Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing (WES) and copy number variation (CNV) calling with Exome Depth. Likely causal CNV predictions were validated by CNVseq. Results: Thirty-eight mutations including 29 novel ones were identified in 25 out of 54 patients, providing a 46.3% positive molecular diagnostic rate. Ten different genes were involved, and the four most common genes were SACS, SYNE1, ADCK3 and SETX, which accounted for 76.0% (19/25) of the positive cases. The de novo microdeletion in SACS was firstly reported in China and the uniparental disomy of ADCK3 was reported for the first time worldwide. Furthermore, the clinical features of the patients carrying SACS, SYNE1and ADCK3 mutations were summarized. Conclusions: Our results expand the genetic spectrum and clinical profiles of ARCA patients, demonstrate the high efficiency and reliability of WES combined CNV analysis in diagnosing suspected ARCA, and emphasize the importance of complete bioinformatics analysis of WES data in making an accurate diagnosis.

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

2021 ◽  
Author(s):  
Irma Järvelä ◽  
Tuomo Määttä ◽  
Anushree Acharya ◽  
Juha Leppälä ◽  
Shalini N. Jhangiani ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
De Novo ◽  
Uniparental Disomy ◽  
Molecular Testing ◽  
Potential Candidate ◽  
Founder Population ◽  
Id Genes

AbstractThe 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.

scholarly journals Metagenomic analysis of gut microbiota in Parkinson's disease patients from Central China

2020 ◽  
Author(s):  
Fan Zhang ◽  
Qiang Zhao ◽  
Xing Fang ◽  
Meiling Xu ◽  
Jie Tang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gut Microbiota ◽  
Clinical Features ◽  
De Novo ◽  
Central China ◽  
Chinese Patients ◽  
Fecal Microbiome ◽  
Potential Biomarker ◽  
Functional Pathways

Abstract Background: Parkinson's disease (PD) is one of the most common neurodegenerative diseases, pathologic and epidemiologic studies suggest that gut microbiota may play important roles in the occurrence and progression of Parkinson's disease. However, the alterations in fecal microbiome in PD patients from Central China has not been investigated. Therefore, in this case-control study, we characterised the gut microbial community of 46 PD patients and compared it to those of healthy spouses by using metagenomic shotgun sequencing. Correlation between altered microbiota and clinical features were examined, functional pathways of gut microbiota were estimated, and potential biomarker were explored for further understaning of gut microbiota in PD. Results: Microbial communities in the feces of PD patients were notably different from those of healthy spouses at species level. Gut microbiota of patients was characterized by depletion of Prevotella_copri and Bacteroides_fragilis, while the Bacteroides_stercoris and Escherichia_coli were markedly elevated. Correlation analysis found that most identified species were negatively correlated with disease clinical features. In particular, Prevotella_copri was negatively correlated with age and UPDRS Ⅲ score. Random forest model indicated that 6 species including Prevotella_copri had good predictive value for disease. Functional analyses of the metagenomes revealed differences in microbiota metabolism. Pathways associated with superpathway of thiamin diphosphate biosynthesis, 4-aminobutanoate degradation, glucose-1-phosphate degradation and methylphosphonate degradation were significant increase in patients, while pathways associated with aromatic amino acid biosynthesis, chorismate biosynthesis, thiamin formation and pyrimidine deoxyribonucleosides salvage were significantly decrease. Functional pathways of Prevotella_copri were mainly concentrated in UMP biosynthesis, S-adenosyl-L-methionine cycle and guanosine ribonucleotides de novo biosynthesis. Conclusion: Our findings confirmed changes of gut microbiota in Chinese patients with PD. Altered microbiota had correlation with the clinical characteristics of disease, which may used as potential biomarkers. Different functional pathways of gut microbiota in PD patients will help to improve our understanding of the mechanism in disease, and targeting on gut microbiota may be one of the new therapeutic choices of PD in the future.

scholarly journals Molecular Confirmation of G1138A Mutation in FGFR gene in Achondroplasia

2018 ◽  
Vol 56 (211) ◽  
pp. 683-686
Author(s):  
Shyam Bahadur Khanal ◽  
Mitesh Shrestha ◽  
Hemanta Kumari Chaudhary ◽  
Smita Shrestha ◽  
Rohit Kumar Pokharel
Keyword(s):  
Point Mutation ◽  
Clinical Features ◽  
Transmembrane Domain ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Growth Factor Receptor ◽  
Negative Control ◽  
De Novo Mutation ◽  
Heterozygous Mutation

Introduction: Achondroplasia (ACH) is the most common form of skeletal dysplasia of genetic origin in humans which is characterized by disproportionate rhizomelic dwarfism. Heterozygous mutation in the transmembrane domain of the FGFR3 gene (4p16.3) occurs as a de novo mutation in most of the cases.  Methods: DNA was isolated from seven samples, out of which, five had clinical features of Achondroplasia while one was dwarf but did not show symptoms of the disorder and one as negative control. PCR was performed for the region incorporating the hotspot region viz. 1138th nucleotide. PCR amplicon of size 164 bp was obtained from all the samples, and was sequenced. Results: Sequence analysis showed the presence of mutation (G to A transition) in all of the five samples. The five samples that showed the clinical features of Achondroplasia had mutation in the region being analyzed while the single patient who had no clinical manifestations of the disorder despite being dwarf had no such mutation. Among the five patients studied, one patient had a family history of Achondroplasia as observed through pedigree analysis while the remaining four cases were sporadic in nature.  Conclusions: This study further supports that the G1138A mutation is the one of the most common point mutation among Achondroplasia cases. Genetic diagnosis can be useful to identify the disease prenatally and differentiate other life threatening dwarfism for the safety of both mother and fetus.  Keywords: achondroplasia; dwarfism; fibroblast growth factor receptor 3 (FGFR3); point Mutation.

scholarly journals Prenatal Genetic Diagnosis in Three Fetuses With Left Heart Hypoplasia (LHH) From Three Unrelated Families

2021 ◽  
Vol 8 ◽  
Author(s):  
Sukun Luo ◽  
Luyi Chen ◽  
Weizhong Wei ◽  
Li Tan ◽  
Meng Zhang ◽  
...  
Keyword(s):  
De Novo ◽  
Heart Defects ◽  
Genetic Diagnosis ◽  
Severe Form ◽  
Left Heart ◽  
Whole Exome ◽  
Number Variation ◽  
Cardiovascular Defects ◽  
First Time ◽  
Generation Sequencing

Background: Congenital heart defects (CHDs) are the most common birth defects, and left heart hypoplasia (LHH) is a severe form of CHD and responsible for more than 20% cardiac deaths during the first week of life, however, its genetic causes remain largely elusive.Methods: Three families with fetal LHH were recruited. Genomic DNA from amniotic fluid or peripheral blood, and trio whole exome sequencing (trio-WES) and copy number variation sequencing (CNV-seq) were performed.Results: All the three couples had no family history, and mid-gestation ultrasound revealed LHH and other variable cardiovascular defects in the fetuses. Trio-WES revealed de novo pathogenic variations in KMT2D (p.Gly3465Aspfs*37) (NM_003482) and WDFY3 (p.Ser117Xfs*) (NM_014991), and CNV-seq identified a deletion of 150 kb encompassing NOTCH1. KMT2D and NOTCH1 previously have been reported to be associated with CHDs, however, WDFY3 is reported for the first time to be possibly related to CHD in human.Conclusion: Our study suggested that genetic component is an important risk factor for the development of LHH, and next generation sequencing is a powerful tool for genetic diagnosis in fetuses with CHDs and genetic counseling, however, more studies and data are need to establish the correlation of fetal phenotypes and genotypes.

scholarly journals Maternal Isodisomy of Chromosome 3 Combined with a De Novo Mutation in the ABHD5 Gene Causes Autosomal Recessive Chanarin-Dorfman Syndrome

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1164
Author(s):  
Julia Kopp ◽  
Cristina Has ◽  
Alrun Hotz ◽  
Sarah C. Grünert ◽  
Judith Fischer
Keyword(s):  
Autosomal Recessive ◽  
De Novo ◽  
Uniparental Disomy ◽  
Rare Event ◽  
De Novo Mutation ◽  
Chromosome 3 ◽  
Lipid Storage Disease ◽  
First Case ◽  
Neutral Lipid Storage Disease ◽  
Biallelic Mutations

Autosomal recessive Chanarin-Dorfman syndrome (CDS, MIM #275630) is defined as a neutral lipid storage disease with ichthyosis (NLSDI) due to an accumulation of lipid droplets in a variety of different tissues including liver and muscle cells, leucocytes, fibroblasts and nerve cells It is caused by biallelic mutations in the abhydrolase domain containing 5 gene (ABHD5, MIM *604780) which is localized on the short arm of chromosome 3. Here we report an 18 month-old girl in whom we have identified the homozygous ABHD5 mutation c.700C > T, p.(Arg234*). Since none of the parents carried this point mutation, parentage was confirmed by microsatellite marker analysis. Suspected uniparental disomy (UPD) was confirmed by microsatellite genotyping over the entire chromosome 3 and indicated a maternal origin. UPD is an extremely rare event that is not necessarily pathogenic, but may cause disease if the affected chromosome contains genes that are imprinted. Here we report the first case of Chanarin-Dorfman syndrome due to a de novo ABHD5 mutation in the maternal germ cell, combined with a maternal uniparental isodisomy of chromosome 3. This case demonstrates that genetic analysis of the patient and both parents is crucial to provide correct genetic counseling.

scholarly journals Spondylo-ocular Syndrome Due to a Novel Variant in XYLT2 in an Omani Patient

2020 ◽  
Author(s):  
Musallam Al-Araimi ◽  
Nishath Hamza ◽  
Aliya Al-Hosni ◽  
Ashwaq Al Maimani
Keyword(s):  
Case Report ◽  
Middle East ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Autosomal Recessive Disorder ◽  
Marriage Rate ◽  
Rare Autosomal Recessive Disorder ◽  
Middle East Countries ◽  
Novel Variant ◽  
First Time

AbstractSpondylo-ocular syndrome (SOS) is a rare autosomal recessive disorder and affects primarily ocular and spinal tissues. This case report presents an Omani child with a novel homozygous variant, c.2070 G > A (p.Trp690Ter) in XYLT2 associated with SOS for the first time. Oman and other Middle East countries have a high consanguine marriage rate. Our case report will increase knowledge of SOS syndrome to be able to provide genetic diagnosis and counseling for other family members and families as well as prenatal diagnostics for the future pregnancies.

scholarly journals Gitelman syndrome caused by a novel hemiallelic missense mutation in SLC12A3 revealed by 16q12.2q21 microdeletion

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Yuki Abe ◽  
Toshiyuki Yamamoto ◽  
Yukie Izumita ◽  
Shinya Tsukano
Keyword(s):  
Missense Mutation ◽  
Clinical Features ◽  
Autosomal Recessive ◽  
De Novo ◽  
Missense Variant ◽  
Gitelman Syndrome ◽  
Recessive Trait ◽  
Autosomal Recessive Trait ◽  
Biallelic Mutations

AbstractGitelman syndrome (GS) is caused by biallelic mutations in SLC12A3 as an autosomal recessive trait. A patient with a de novo 16q12.2q21 microdeletion showed clinical features of GS. SLC12A3 included in the deletion was analyzed, and a rare missense variant (c.1222A>C [p.N406H]) was identified as hemizygous. Consequently, GS was caused by the revealed SLC12A3 variant owing to chromosomal microdeletion.

scholarly journals High Genetic Heterogeneity in Chinese Patients With Waardenburg Syndrome Revealed by Next-Generation Sequencing

2021 ◽  
Vol 12 ◽  
Author(s):  
Sen Zhang ◽  
Hongen Xu ◽  
Yongan Tian ◽  
Danhua Liu ◽  
Xinyue Hou ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Sanger Sequencing ◽  
De Novo ◽  
Sensorineural Hearing ◽  
Chinese Patients ◽  
Waardenburg Syndrome ◽  
Genetic Causes ◽  
Whole Exome ◽  
First Time

ObjectiveThis study aimed to explore the genetic causes of probands who were diagnosed with Waardenburg syndrome (WS) or congenital sensorineural hearing loss.MethodsA detailed physical and audiological examinations were carried out to make an accurate diagnosis of 14 patients from seven unrelated families. We performed whole-exome sequencing in probands to detect the potential genetic causes and further validated them by Sanger sequencing in the probands and their family members.ResultsThe genetic causes for all 14 patients with WS or congenital sensorineural hearing loss were identified. A total of seven heterozygous variants including c.1459C > T, c.123del, and c.959-409_1173+3402del of PAX3 gene (NM_181459.4), c.198_262del and c.529_556del of SOX10 gene (NM_006941.4), and c.731G > A and c.970dup of MITF gene (NM_000248.3) were found for the first time. Of these mutations, we had confirmed two (c.1459C > T and c.970dup) are de novo by Sanger sequencing of variants in the probands and their parents.ConclusionWe revealed a total of seven novel mutations in PAX3, SOX10, and MITF, which underlie the pathogenesis of WS. The clinical and genetic characterization of these families with WS elucidated high heterogeneity in Chinese patients with WS. This study expands the database of PAX3, SOX10, and MITF mutations and improves our understanding of the causes of WS.

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