Family-based whole-genome sequencing identifies compound heterozygous protein-coding and noncoding mutations in tetralogy of Fallot

Gene ◽  
2020 ◽  
Vol 741 ◽  
pp. 144555
Author(s):  
Yifeng Wang ◽  
Tao Jiang ◽  
Pushi Tang ◽  
Yifei Wu ◽  
Zhu Jiang ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Tetralogy Of Fallot ◽  
Genome Sequencing ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Protein Coding ◽  
Family Based

scholarly journals Effective variant filtering and expected candidate variant yield in studies of rare human disease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Brent S. Pedersen ◽  
Joe M. Brown ◽  
Harriet Dashnow ◽  
Amelia D. Wallace ◽  
Matt Velinder ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Rare Disease ◽  
Genome Sequencing ◽  
Autosomal Dominant ◽  
De Novo ◽  
Autosomal Dominant Inheritance ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Dominant Inheritance ◽  
Family Based

AbstractIn studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.

scholarly journals Clinical and Genetic Features in 31 Serial Chinese Children With Gitelman Syndrome

2021 ◽  
Vol 9 ◽  
Author(s):  
Lingxia Zhang ◽  
Ke Huang ◽  
Shugang Wang ◽  
Haidong Fu ◽  
Jingjing Wang ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Muscle Weakness ◽  
Growth Retardation ◽  
Gitelman Syndrome ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Whole Exome ◽  
Laboratory Test Results

Gitelman syndrome (GS, OMIM 263800) is a genetic congenital tubulopathy associated with salt loss, which is characterized by hypokalemic metabolic toxicity, hypocalciuria, and hypomagnesemia. GS, which is typically detected in adolescence or adulthood, has long been considered a benign tubular lesion; however, the disease is associated with a significant decrease in the quality of life. In this study, we assessed the genotype–phenotype correlations based on the medical histories, clinical symptoms, laboratory test results, and whole-exome sequencing profiles from pediatric patients with GS. Between January 2014 and December 2020, all 31 consecutively enrolled patients complained of fatigue, salt craving, and muscle weakness. Sixteen patients demonstrated growth retardation, and five patients presented with nocturia and constipation. All patients presented with hypokalemic metabolic alkalosis, normal blood pressure, hyperaldosteronism, and a preserved glomerular filtration rate, and 24 of the 31 (77.4%) patients had hypomagnesemia. Homozygous, compound heterozygous, and heterozygous mutations in SLC12A3 were detected in 4, 24, and 3 patients, respectively. GS patients often present with muscle weakness and fatigue caused by hypokalemia and hypomagnesemia. Therefore, early diagnosis of GS is important in young children to reduce the possibility of growth retardation, tetany, and seizures. Next-generation sequencing such as whole-exome or whole-genome sequencing provides a practical tool for the early diagnosis and improvement of GS prognosis. Further whole-genome sequencing is expected to reveal more variants in SLC123A among GS patients with single heterozygous mutations.

scholarly journals Identification of a Rare Case With Nagashima-Type Palmoplantar Keratoderma and 18q Deletion Syndrome via Exome Sequencing and Low-Coverage Whole-Genome Sequencing

2021 ◽  
Vol 12 ◽  
Author(s):  
Qianqian Li ◽  
Xiaofan Zhu ◽  
Conghui Wang ◽  
Jingjing Meng ◽  
Duo Chen ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Exome Sequencing ◽  
Genome Sequencing ◽  
Deletion Syndrome ◽  
Compound Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Palmoplantar Keratoderma ◽  
18Q Deletion Syndrome ◽  
Low Coverage

Nagashima-type palmoplantar keratoderma (NPPK) is characterized by non-progressive, diffuse, and cross-gradient hyperkeratosis caused by mutations in the SERPINB7 gene on chromosome 18q21.33. Chromosome 18q deletion syndrome (18q- syndrome) is a terminal deletion or microdeletion syndrome characterized by intellectual disability and congenital malformations. This paper describes an 18-year-old man with palmoplantar keratoderma and diffuse white matter abnormalities in the brain. Trio-based exome sequencing (ES) revealed a suspected mosaic compound heterozygous mutation for c.796C>T (p.Arg266∗) in exon 8 inherited from the mother and a de novo exons 4–6 deletion of SERPINB7. Additional copy number variant (CNV) analysis of the ES data indicated a heterozygous gross deletion of 18q22.3-q23. The two SERPINB7 gene variants were verified by Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR). Finally, low-coverage whole-genome sequencing (WGS) confirmed the 18q22.3-q23 deletion and additionally detected a mosaic 18q21.33-q22.3 deletion, together explaining NPPK and the neurological phenotypes of the proband. The gross deletion of all exons of SERPINB7 was revealed for the first time. More rarely, c.796C>T (p.Arg266∗) was likely to be mosaic, while the exon deletion was mosaic. In conclusion, the combination of multiple molecular genetic testing methods provides comprehensive informative molecular findings and promotes the diagnosis of complex diseases, as in this case.

scholarly journals Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Víctor Raggio ◽  
Nicolas Dell’Oca ◽  
Camila Simoes ◽  
Alejandra Tapié ◽  
Conrado Medici ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Molecular Diagnosis ◽  
Rare Diseases ◽  
High Throughput Sequencing ◽  
Heart Defects ◽  
Large Deletion ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Artery Disease

Abstract Background Rare diseases are pathologies that affect less than 1 in 2000 people. They are difficult to diagnose due to their low frequency and their often highly heterogeneous symptoms. Rare diseases have in general a high impact on the quality of life and life expectancy of patients, which are in general children or young people. The advent of high-throughput sequencing techniques has improved diagnosis in several different areas, from pediatrics, achieving a diagnostic rate of 41% with whole genome sequencing (WGS) and 36% with whole exome sequencing, to neurology, achieving a diagnostic rate between 47 and 48.5% with WGS. This evidence has encouraged our group to pursue a molecular diagnosis using WGS for this and several other patients with rare diseases. Results We used whole genome sequencing to achieve a molecular diagnosis of a 7-year-old girl with a severe panvascular artery disease that remained for several years undiagnosed. We found a frameshift variant in one copy and a large deletion involving two exons in the other copy of a gene called YY1AP1. This gene is related to Grange syndrome, a recessive rare disease, whose symptoms include stenosis or occlusion of multiple arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities. Bioinformatic analyses propose these mutations as the most likely cause of the disease, according to its frequency, in silico predictors, conservation analyses, and effect on the protein product. Additionally, we confirmed one mutation in each parent, supporting a compound heterozygous status in the child. Conclusions In general, we think that this finding can contribute to the use of whole genome sequencing as a diagnosis tool of rare diseases, and in particular, it can enhance the set of known mutations associated with different diseases.

scholarly journals Novel Compound Heterozygous Mutation in TRAPPC9 Gene: The Relevance of Whole Genome Sequencing

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 557
Author(s):  
Maria Isabel Alvarez-Mora ◽  
Jordi Corominas ◽  
Christian Gilissen ◽  
Aurora Sanchez ◽  
Irene Madrigal ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Missense Variant ◽  
Autism Spectrum ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Whole Exome ◽  
Considerable Impact

Advances in high-throughput technologies and its implementation worldwide have had a considerable impact on the elucidation of the molecular causes underlying neurodevelopmental psychiatric disorders, especially for autism spectrum disorder and intellectual disability (ID). Nevertheless, etiology remains elusive in close to 50% of cases, even in those families with multiple affected individuals, strongly hinting at a genetic cause. Here we present a case report of two siblings affected with severe ID and other comorbidities, who embarked on a genetic testing odyssey until diagnosis was reached by using whole genome sequencing (WGS). WGS identified a maternally inherited novel missense variant (NM_031466.7:c.1037G > A; p.Gly346Glu) and a paternally inherited 90 kb intragenic deletion in TRAPPC9 gene. This report demonstrates the clinical utility of WGS in patients who remain undiagnosed after whole exome sequencing.

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