scholarly journals Novel variants of ABCA4 in Han Chinese families with Stargardt disease

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Fang-Yuan Hu ◽  
Feng-Juan Gao ◽  
Jian-kang Li ◽  
Ping Xu ◽  
Dan-Dan Wang ◽  
...  
Keyword(s):  
In Silico ◽  
Early Adulthood ◽  
Han Chinese ◽  
Macular Dystrophy ◽  
Stargardt Disease ◽  
Causative Gene ◽  
Chinese Families ◽  
Pathogenic Variants ◽  
Potential Pathogenicity ◽  
Coding Variants

Abstract Background Stargardt disease (STGD1) is a common recessive hereditary macular dystrophy in early adulthood or childhood, with an estimated prevalence of 1:8000 to 1:10,000. ABCA4 is the causative gene for STGD1. The current study aims at identifying the novel disease-related ABCA4 variants in Han Chinese families with STGD1 using next-generation sequencing (NGS). Methods In the present study, 12 unrelated Han Chinese families (19 males and 17 females) with STGD1 were tested by panel-based NGS. In order to capture the coding exons and the untranslated regions (UTRs) plus 30 bp of intronic flanking sequences of 792 genes, which were closely associated with usual ophthalmic genetic disease, we designed a customized panel, namely, Target_Eye_792_V2 chip. STGD1 patients were clinically diagnosed by experienced ophthalmologists. All the detected variants were filtered and analyzed through the public databases and in silico programs to assess potential pathogenicity. Results Twenty-one ABCA4 mutant variants were detected in 12 unrelated Han Chinese families with STGD1, containing 14 missense, three splicing, two frameshift, one small deletion, and one nonsense variants. Base on the American College of Medical Genetics (ACMG) guidelines, 8 likely pathogenic and 13 pathogenic variants were determined. The functional consequences of these mutant variants were predicted through in silico programs. Of the 21 mutant variants in ABCA4, two novel coding variants c.3017G > A and c.5167 T > C and one novel null variant c.3051-1G > A were detected in three unrelated probands. Conclusions By panel-based NGS, 21 ABCA4 variants were confirmed in 12 unrelated Han Chinese families. Among them, 3 novel mutant variants were found, which further expanded the ABCA4 mutation spectrum in STGD1 patients.

scholarly journals Sequence characterization of RET in 117 Chinese Hirschsprung disease families identifies a large burden of de novo and parental mosaic mutations

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Qian Jiang ◽  
Yang Wang ◽  
Qi Li ◽  
Zhen Zhang ◽  
Ping Xiao ◽  
...  
Keyword(s):  
De Novo ◽  
Hirschsprung Disease ◽  
Causative Gene ◽  
High Coverage ◽  
Chinese Families ◽  
Sequence Characterization ◽  
Pathogenic Variants ◽  
Enteric Ganglia ◽  
Digital Polymerase Chain Reaction ◽  
Coding Variants

Abstract Background Hirschsprung disease (HSCR) is an inherited congenital disorder characterized by the absence of enteric ganglia in the distal part of the gut. RET is the major causative gene and contains > 80% of all known disease-causing mutations. Results To determine the incidence of RET pathogenic variants, be they Mendelian inherited, mosaic in parents or true de novo variants (DNVs) in 117 Chinese families, we used high-coverage NGS and droplet digital polymerase chain reaction (ddPCR) to identify 15 (12.8%) unique RET coding variants (7 are novel); one was inherited from a heterozygous unaffected mother, 11 were DNVs (73.3%), and 3 full heterozygotes were inherited from parental mosaicism (2 paternal, 1 maternal): two clinically unaffected parents were identified by NGS and confirmed by ddPCR, with mutant allele frequency (13–27%) that was the highest in hair, lowest in urine and similar in blood and saliva. An extremely low-level paternal mosaicism (0.03%) was detected by ddPCR in blood. Six positive-controls were examined to compare the mosaicism detection limit and sensitivity of NGS, amplicon-based deep sequencing and ddPCR. Conclusion Our findings expand the clinical and molecular spectrum of RET variants in HSCR and reveal a high frequency of RET DNVs in the Chinese population.

scholarly journals Targeted Next-Generation Sequencing Identifies ABCA4 Mutations in Chinese Families with Childhood-Onset and Adult-Onset Stargardt Disease

2021 ◽  
Author(s):  
Ling-hui Qu ◽  
Xin Jin ◽  
Chao Zeng ◽  
Nian-gou Zhou ◽  
Yan-hong Liu ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Variants ◽  
Chinese Patients ◽  
Macular Dystrophy ◽  
Adult Onset ◽  
Next Generation ◽  
Childhood Onset ◽  
Stargardt Disease ◽  
Chinese Families ◽  
Generation Sequencing

Background: Stargardt disease (STGD) is the most common form of juvenile macular dystrophy associated with progressive central vision loss, and is agenetically and clinically heterogeneous disease. Molecular diagnosis is of great significance in aiding the clinical diagnosis, helping to determine the phenotypic severity and visual prognosis. In this study, we determined the clinical and genetic features of seven childhood-onset and three adult-onset Chinese STGD families. We performed capture next generation sequencing (NGS) of the probands and searched for potentially disease-causing genetic variants in previously identified retinal or macular dystrophy genes.  Methods: In all, 10unrelated Chinese families were enrolled. Panel based NGS was performed to identify potentially disease-causing genetic variants in previously identified retinal or macular dystrophy genes, including the five known STGD genes (ABCA4, PROM1, PRPH2, VMD2 and ELOVL4). Variant analysis, Sanger validation, and segregation tests were utilized to validate the disease-causing mutations inthese families. Results: Using systematic data analysis with an established bioinformatics pipeline and segregation analysis, 17 pathogenic mutations in ABCA4 were identified in the ten STGD families. Four of these mutations were novel: c.371delG, c.681T > G, c.5509C > T and EX37del. Childhood-onset STGD was associated with severe visual loss, generalized retinal dysfunction and was due to more severe variants in ABCA4 than those found in adult-onset disease. Conclusions: We expand the existing spectrum of STGD and reveal the genotype-phenotype relationships of the ABCA4 mutations in Chinese patients. Childhood-onset STGD lies at the severe end of the spectrum of ABCA4-associated retinal phenotypes.

scholarly journals Identification of novel pathogenic ABCA4 variants in a Han Chinese family with Stargardt disease

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Qin Xiang ◽  
Yanna Cao ◽  
Hongbo Xu ◽  
Yi Guo ◽  
Zhijian Yang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Retinal Pigment ◽  
Han Chinese ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Stargardt Disease ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Stargardt disease (STGD1, OMIM 248200) is a common hereditary juvenile or early adult onset macular degeneration. It ultimately leads to progressive central vision loss. Here, we sought to identify gene mutations associated with STGD1 in a three-generation Han Chinese pedigree by whole exome sequencing and Sanger sequencing. Two novel potentially pathogenic variants in a compound heterozygous state, c.3607G>T (p.(Gly1203Trp)) and c.6722T>C (p.(Leu2241Pro)), in the ATP binding cassette subfamily A member 4 gene (ABCA4) were identified as contributing to the family’s STGD1 phenotype. These variants may impact the ABCA4 protein structure and reduce the retinal-activated ATPase activity, leading to abnormal all-trans retinal accumulation in photoreceptor outer segments and in retinal pigment epithelium cells. The present study broadens the mutational spectrum of the ABCA4 responsible for STGD1. A combination of whole exome sequencing and Sanger sequencing is likely to be a time-saving and cost-efficient approach to screen pathogenic variants in genetic disorders caused by sizable genes, as well as avoiding misdiagnosis. These results perhaps refine genetic counseling and ABCA4-targetted treatments for families affected by STGD1.

The mitochondrial tRNAMet/tRNAGlnA4401G and tRNACysG5821A mutations may be associated with hypertension in two Han Chinese families

2014 ◽  
Vol 36 (2) ◽  
pp. 127-134
Author(s):  
Xu Meifen ◽  
He Yiqun ◽  
Geng Junwei ◽  
Meng Yanzi ◽  
Yu Han ◽  
...  
Keyword(s):  
Han Chinese ◽  
Chinese Families

scholarly journals Contribution of SLC22A12 on hypouricemia and its clinical significance for screening purposes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Do Hyeon Cha ◽  
Heon Yung Gee ◽  
Raul Cachau ◽  
Jong Mun Choi ◽  
Daeui Park ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Kidney Injury ◽  
Genetic Identification ◽  
Diagnostic Screening ◽  
Renal Hypouricemia ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Causal Variants ◽  
Coding Variants ◽  
Independent Cohort

Abstract Differentiating between inherited renal hypouricemia and transient hypouricemic status is challenging. Here, we aimed to describe the genetic background of hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis using two founder variants in primary screening. We selected all cases (N = 31) with extreme hypouricemia (<1.3 mg/dl) from a Korean urban cohort of 179,381 subjects without underlying conditions. WES and corresponding downstream analyses were performed for the discovery of rare causal variants for hypouricemia. Two known recessive variants within SLC22A12 (p.Trp258*, pArg90His) were identified in 24 out of 31 subjects (77.4%). In an independent cohort, we identified 50 individuals with hypouricemia and genotyped the p.Trp258* and p.Arg90His variants; 47 of the 50 (94%) hypouricemia cases were explained by only two mutations. Four novel coding variants in SLC22A12, p.Asn136Lys, p.Thr225Lys, p.Arg284Gln, and p.Glu429Lys, were additionally identified. In silico studies predict these as pathogenic variants. This is the first study to show the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two ethnic-specific variants (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of Korean patients with monogenic hypouricemia. Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise.

scholarly journals Novel deep intronic mutation in PLA2G6 causing early-onset Parkinson’s disease with brain iron accumulation through pseudo-exon activation

Neurogenetics ◽  
2021 ◽  
Author(s):  
Chiara Cavestro ◽  
Celeste Panteghini ◽  
Chiara Reale ◽  
Alessia Nasca ◽  
Silvia Fenu ◽  
...  
Keyword(s):  
Early Onset ◽  
Cerebellar Atrophy ◽  
Iron Accumulation ◽  
Brain Iron ◽  
Causative Gene ◽  
Coding Regions ◽  
Aberrant Transcript ◽  
Pathogenic Variants ◽  
Intronic Mutation ◽  
Mrna Analysis

AbstractPLA2G6 is the causative gene for a group of autosomal recessive neurodegenerative disorders known as PLA2G6-associated neurodegeneration (PLAN). We present a case with early-onset parkinsonism, ataxia, cognitive decline, cerebellar atrophy, and brain iron accumulation. Sequencing of PLA2G6 coding regions identified only a heterozygous nonsense variant, but mRNA analysis revealed the presence of an aberrant transcript isoform due to a novel deep intronic variant (c.2035-274G > A) leading to activation of an intronic pseudo-exon. These results expand the genotypic spectrum of PLAN, showing the paramount importance of detecting possible pathogenic variants in deep intronic regions in undiagnosed patients.

Mitochondrial genome variations and functional characterization in Han Chinese families with schizophrenia

2016 ◽  
Vol 171 (1-3) ◽  
pp. 200-206 ◽  
Author(s):  
Rui Bi ◽  
Jinsong Tang ◽  
Wen Zhang ◽  
Xiao Li ◽  
Shi-Yi Chen ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Functional Characterization ◽  
Han Chinese ◽  
Chinese Families ◽  
Genome Variations

scholarly journals A scalable EHR-based approach for phenotype discovery and variant interpretation for hereditary cancer genes

2021 ◽  
Author(s):  
Chenjie Zeng ◽  
Lisa A Bastarache ◽  
Ran Tao ◽  
Eric Venner ◽  
Scott Hebbring ◽  
...  
Keyword(s):  
Hereditary Cancer ◽  
Meta Analysis ◽  
Genetic Disorders ◽  
Genomic Medicine ◽  
Risk Scores ◽  
Cancer Genes ◽  
Pathogenic Variants ◽  
Emerge Network ◽  
Uncertain Significance ◽  
Potential Pathogenicity

Knowledge of the clinical spectrum of rare genetic disorders helps in disease management and variant pathogenicity interpretation. Leveraging electronic health record (EHR)-linked genetic testing data from the eMERGE network, we determined the associations between a set of 23 hereditary cancer genes and 3017 phenotypes in 23544 individuals. This phenome-wide association study replicated 45% (184/406) of known gene-phenotype associations (P = 5.1 ×10-125). Meta-analysis with an independent EHR-derived cohort of 3242 patients confirmed 14 novel associations with phenotypes in the neoplastic, genitourinary, digestive, congenital, metabolic, mental and neurologic categories. Phenotype risk scores (PheRS) based on weighted aggregations of EHR phenotypes accurately predicted variant pathogenicity for at least 50% of pathogenic variants for 8/23 genes. We generated a catalog of PheRS for 7800 variants, including 5217 variants of uncertain significance, to provide empirical evidence of potential pathogenicity. This study highlights the potential of EHR data in genomic medicine.

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