The diagnostic yield of whole exome sequencing as a first approach in consanguineous Omani renal ciliopathy syndrome patients

Autor: Miguel Barroso-Gil, John A. Sayer, Eric Olinger, Intisar Al Alawi, Mohammed S. Al Riyami, Issa Al Salmi, Laura Powell
Rok vydání: 2021
Předmět:
0301 basic medicine
Oman
viruses
Population
030232 urology & nephrology
Computational biology
BBS9
Genetic analysis
General Biochemistry
Genetics and Molecular Biology
Consanguinity
03 medical and health sciences
symbols.namesake
0302 clinical medicine
Exome Sequencing
renal ciliopathy
medicine
Humans
Exome
Copy-number variation
General Pharmacology
Toxicology and Pharmaceutics
Child
education
Exome sequencing
Sanger sequencing
education.field_of_study
General Immunology and Microbiology
business.industry
virus diseases
Syndrome
Articles
General Medicine
biochemical phenomena
metabolism
and nutrition
medicine.disease
Disease gene identification
Ciliopathies
digestive system diseases
Ciliopathy
030104 developmental biology
symbols
business
cystic kidney disease
Research Article
whole exomes sequencing
Zdroj: F1000Research
ISSN: 2046-1402
DOI: 10.12688/f1000research.40338.2
Popis: Background: Whole exome sequencing (WES) is becoming part of routine clinical and diagnostic practice. In the investigation of inherited cystic kidney disease and renal ciliopathy syndromes, WES has been extensively applied in research studies as well as for diagnostic utility to detect various novel genes and variants. The yield of WES critically depends on the characteristics of the patient population. Methods: In this study, we selected 8 unrelated Omani children, presenting with renal ciliopathy syndromes with a positive family history and originating from consanguineous families. We performed WES in affected children to determine the genetic cause of disease and to test the yield of this approach, coupled with homozygosity mapping, in this highly selected population. DNA library construction and WES was carried out using SureSelect Human All Exon V6 Enrichment Kit and Illumina HiSeq platform. For variants filtering and annotation Qiagen Variant Ingenuity tool was used. Nexus copy number software from BioDiscovery was used for evaluation of copy number variants and whole gene deletions. Patient and parental DNA was used to confirm mutations and the segregation of alleles using Sanger sequencing. Results: Genetic analysis identified 4 potential causative homozygous variants each confirmed by Sanger sequencing in 4 clinically relevant ciliopathy syndrome genes, (TMEM231, TMEM138, WDR19 and BBS9), leading to an overall diagnostic yield of 50%. Conclusions: WES coupled with homozygosity mapping provided a diagnostic yield of 50% in this selected population. This genetic approach needs to be embedded into clinical practise to allow confirmation of clinical diagnosis, to inform genetic screening as well as family planning decisions. Half of the patients remain without diagnosis highlighting the technical and interpretational hurdles that need to be overcome in the future.
Databáze: OpenAIRE
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