scholarly journals NyuWa Genome Resource: Deep Whole Genome Sequencing Based Chinese Population Variation Profile and Reference Panel

2020 ◽  
Author(s):  
Peng Zhang ◽  
Huaxia Luo ◽  
Yanyan Li ◽  
You Wang ◽  
Jiajia Wang ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Chinese Population ◽  
Population Variation ◽  
Reference Panel ◽  
Specific Reference ◽  
Whole Genome ◽  
Loss Of Function ◽  
Southern Chinese ◽  
Novel Variants

AbstractThe lack of Chinese population specific haplotype reference panel and whole genome sequencing resources has greatly hindered the genetics studies in the world’s largest population. Here we presented the NyuWa genome resource of 71.1M SNPs and 8.2M indels based on deep (26.2X) sequencing of 2,999 Chinese individuals, and constructed NyuWa reference panel of 5,804 haplotypes and 19.3M variants, which is the first publicly available Chinese population specific reference panel with thousands of samples. There were 25.0M novel variants in NyuWa genome resource, and 3.2M specific variants in NyuWa reference panel. Compared with other panels, NyuWa reference panel reduces the Han Chinese imputation error rate by the range of 30% to 51%. Population structure and imputation simulation tests supported the applicability of one integrated reference panel for both northern and southern Chinese. In addition, a total of 22,504 loss-of-function variants in coding and noncoding genes were identified, including 11,493 novel variants. These results highlight the value of NyuWa genome resource to facilitate genetics research in Chinese and Asian populations.

scholarly journals NyuWa Genome resource: A deep whole-genome sequencing-based variation profile and reference panel for the Chinese population

Cell Reports ◽  
2021 ◽  
Vol 37 (7) ◽  
pp. 110017
Author(s):  
Peng Zhang ◽  
Huaxia Luo ◽  
Yanyan Li ◽  
You Wang ◽  
Jiajia Wang ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Chinese Population ◽  
Reference Panel ◽  
Whole Genome

scholarly journals Identification of a novel heterozygous SPTB mutation by whole genome sequencing in a Chinese patient with hereditary spherocytosis and atrial septal defect: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zhanhui Du ◽  
Gang Luo ◽  
Kuiliang Wang ◽  
Zhen Bing ◽  
Silin Pan
Keyword(s):  
Atrial Septal Defect ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Chinese Population ◽  
Septal Defect ◽  
Hereditary Spherocytosis ◽  
Valuable Insight ◽  
Whole Genome ◽  
Biochemical Tests ◽  
Chinese Girl

Abstract Background Hereditary spherocytosis (HS) is a common inherited red blood cell membrane disorder characterized by an abnormal increase of spherocytes in peripheral blood. SPTB gene mutation is one of the most common causes of HS; however, few cases of HS resulting from SPTB mutation in the Chinese population have been reported so far. Case presentation A 3-year-old Chinese girl presented to Qingdao Women and Children’s Hospital, Qingdao University, with atrial septal defect (ASD). Meanwhile, she was clinically diagnosed with HS. Whole genome sequencing (WGS) was performed for the proband and her parents for genetic molecular analysis. A novel SPTB mutation (c.1756delG) was detected by WGS and confirmed by Sanger sequencing in the proband. This mutation results in a frameshift with a premature termination codon in exon 12, leading to a nonsense mutation (p.Ala586Profs*7). Her parents had no similar symptoms, and blood routine and serum biochemical tests showed no significant abnormalities. The patient’s mother did not know of any relatives with HS-like symptoms. Percutaneous transcatheter closure was successfully performed for treating the ASD. Conclusion In this study, we identified a novel SPTB frameshift mutation in a Chinese girl with HS. This finding would expand the spectrum of SPTB mutations, provide a valuable insight into the genotyping of HS in the Chinese population, and contribute to the clinical management and genetic counseling in HS.

scholarly journals Whole genome sequencing data of multiple individuals of Pakistani descent

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Shahid Y. Khan ◽  
Muhammad Ali ◽  
Mei-Chong W. Lee ◽  
Zhiwei Ma ◽  
Pooja Biswas ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Sequence Data ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
Asian Populations ◽  
Ethnic Populations ◽  
Novel Variants ◽  
Intergenic Regions

Abstract Here we report whole genome sequencing of four individuals (H3, H4, H5, and H6) from a family of Pakistani descent. Whole genome sequencing yielded 1084.92, 894.73, 1068.62, and 1005.77 million mapped reads corresponding to 162.73, 134.21, 160.29, and 150.86 Gb sequence data and 52.49x, 43.29x, 51.70x, and 48.66x average coverage for H3, H4, H5, and H6, respectively. We identified 3,529,659, 3,478,495, 3,407,895, and 3,426,862 variants in the genomes of H3, H4, H5, and H6, respectively, including 1,668,024 variants common in the four genomes. Further, we identified 42,422, 39,824, 28,599, and 35,206 novel variants in the genomes of H3, H4, H5, and H6, respectively. A major fraction of the variants identified in the four genomes reside within the intergenic regions of the genome. Single nucleotide polymorphism (SNP) genotype based comparative analysis with ethnic populations of 1000 Genomes database linked the ancestry of all four genomes with the South Asian populations, which was further supported by mitochondria based haplogroup analysis. In conclusion, we report whole genome sequencing of four individuals of Pakistani descent.

scholarly journals Mitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy

2018 ◽  
Vol 55 (9) ◽  
pp. 599-606 ◽  
Author(s):  
Yeshaya Langer ◽  
Adi Aran ◽  
Suleyman Gulsuner ◽  
Bassam Abu Libdeh ◽  
Paul Renbaum ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Whole Genome Sequencing ◽  
Spinocerebellar Ataxia ◽  
Genome Sequencing ◽  
Novel Mutation ◽  
Cerebellar Atrophy ◽  
Whole Genome ◽  
Loss Of Function ◽  
Childhood Onset ◽  
Whole Exome

ObjectiveTo identify the genetic basis of a childhood-onset syndrome of variable severity characterised by progressive spinocerebellar ataxia, mental retardation, psychotic episodes and cerebellar atrophy.MethodsIdentification of the underlying mutations by whole exome and whole genome sequencing. Consequences were examined in patients’ cells and in yeast.ResultsTwo brothers from a consanguineous Palestinian family presented with progressive spinocerebellar ataxia, mental retardation and psychotic episodes. Serial brain imaging showed severe progressive cerebellar atrophy. Whole exome sequencing revealed a novel mutation: pitrilysin metallopeptidase 1 (PITRM1) c.2795C>T, p.T931M, homozygous in the affected children and resulting in 95% reduction in PITRM1 protein. Whole genome sequencing revealed a chromosome X structural rearrangement that also segregated with the disease. Independently, two siblings from a second Palestinian family presented with similar, somewhat milder symptoms and the same PITRM1 mutation on a shared haplotype. PITRM1T931M carrier frequency was 0.027 (3/110) in the village of the first family evaluated, and 0/300 among Palestinians from other locales. PITRM1 is a mitochondrial matrix enzyme that degrades 10–65 amino acid oligopeptides, including the mitochondrial fraction of amyloid-beta peptide. Analysis of peptide cleavage activity by the PITRM1T931M protein revealed a significant decrease in the degradation capacity specifically of peptides ≥40 amino acids.ConclusionPITRM1T931M results in childhood-onset recessive cerebellar pathology. Severity of PITRM1-related disease may be affected by the degree of impairment in cleavage of mitochondrial long peptides. Disruption and deletion of X linked regulatory segments may also contribute to severity.

scholarly journals Whole-genome sequencing reveals KRTAP1-1 as a novel genetic variant associated with antidepressant treatment outcomes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jong-Ho Park ◽  
Shinn-Won Lim ◽  
Woojae Myung ◽  
Inho Park ◽  
Hyeok-Jae Jang ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Treatment Outcomes ◽  
Genetic Markers ◽  
Genome Sequencing ◽  
Genetic Variants ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Remission Rate ◽  
Antidepressant Treatment ◽  
Whole Genome ◽  
Loss Of Function

AbstractAchieving remission following initial antidepressant therapy in patients with major depressive disorder (MDD) is an important clinical result. Making predictions based on genetic markers holds promise for improving the remission rate. However, genetic variants found in previous genetic studies do not provide robust evidence to aid pharmacogenetic decision-making in clinical settings. Thus, the objective of this study was to perform whole-genome sequencing (WGS) using genomic DNA to identify genetic variants associated with the treatment outcomes of selective serotonin reuptake inhibitors (SSRIs). We performed WGS on 100 patients with MDD who were treated with escitalopram (discovery set: 36 remitted and 64 non-remitted). The findings were applied to an additional 553 patients with MDD who were treated with SSRIs (replication set: 185 remitted and 368 non-remitted). A novel loss-of-function variant (rs3213755) in keratin-associated protein 1–1 (KRTAP1-1) was identified in this study. This rs3213755 variant was significantly associated with remission following antidepressant treatment (p = 0.0184, OR 3.09, 95% confidence interval [CI] 1.22–7.80 in the discovery set; p = 0.00269, OR 1.75, 95% CI 1.22–2.53 in the replication set). Moreover, the expression level of KRTAP1-1 in surgically resected human temporal lobe samples was significantly associated with the rs3213755 genotype. WGS studies on a larger sample size in various ethnic groups are needed to investigate genetic markers useful in the pharmacogenetic prediction of remission following antidepressant treatment.

scholarly journals Whole-genome Sequencing Reveals De-novo Mutations Associated with Nonsyndromic Cleft Lip/Palate

2021 ◽  
Author(s):  
Waheed Awotoye ◽  
Peter A. Mossey ◽  
Jacqueline B. Hetmanski ◽  
Lord Jephthah Joojo Gowans ◽  
Mekonen A. Eshete ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cleft Lip ◽  
De Novo ◽  
Association Studies ◽  
Whole Genome ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Pathogenic Variants ◽  
Cleft Lip Palate

Abstract The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact DNMs that contribute to the risk of nsCL/P, we conducted whole genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs that contribute to the risk of nsCL/P. These include novel loss-of-function DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Experimental evidence showed that ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, MINK1, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TTN genes contribute to facial development and mutations in these genes could contribute to CL/P. Association studies have identified TULP4 as a potential cleft candidate gene, while ARHGAP10 interacts with CTNNB1 to control WNT signaling. DLX6, EPHB2, SEMA3C and SEMA4D harbor novel damaging DNMs that may affect their role in neural crest migration and palatal development. This discovery of pathogenic DNMs also confirms the power of WGS analysis of trios in the discovery of potential pathogenic variants.

scholarly journals Whole genome sequencing of apparently mutation-negative MEN1 patients

2020 ◽  
Vol 182 (1) ◽  
pp. 35-45 ◽  
Author(s):  
Samuel Backman ◽  
Duska Bajic ◽  
Joakim Crona ◽  
Per Hellman ◽  
Britt Skogseid ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Missense Variant ◽  
Endocrine Tumors ◽  
Whole Genome ◽  
Loss Of Function ◽  
Chromosome 1Q ◽  
Pathogenic Variants ◽  
Sporadic Disease ◽  
Tumor Dna

Objective Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1 gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1 mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1. Design Fourteen patients with a clinical diagnosis (n = 13) or suspicion (n = 1) of MEN1 who had negative genetic screening of the MEN1 gene were included. Methods Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model. Results Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson’s two-hit model. Conclusion These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent disease-causing mutations suggests that a fraction of MEN1 mutation-negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.

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