A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative.
Genet Med
; 21(1): 161-172, 2019 01.
Article
in En
| MEDLINE
| ID: mdl-29907797
ABSTRACT
PURPOSE:
Sixty to seventy-five percent of individuals with rare and undiagnosed phenotypes remain undiagnosed after exome sequencing (ES). With standard ES reanalysis resolving 10-15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals.METHODS:
In 38 ES negative patients an individualized genomic-phenotypic approach was employed utilizing (1) phenotyping; (2) reanalyses of FASTQ files, with innovative bioinformatics; (3) targeted molecular testing; (4) genome sequencing (GS); and (5) conferring of clinical diagnoses when pathognomonic clinical findings occurred.RESULTS:
Certain and highly likely diagnoses were made in 18/38 (47%) individuals, including identifying two new developmental disorders. The majority of diagnoses (>70%) were due to our bioinformatics, phenotyping, and targeted testing identifying variants that were undetected or not prioritized on prior ES. GS diagnosed 3/18 individuals with structural variants not amenable to ES. Additionally, tentative diagnoses were made in 3 (8%), and in 5 individuals (13%) candidate genes were identified. Overall, diagnoses/potential leads were identified in 26/38 (68%).CONCLUSIONS:
Our comprehensive approach to ES negatives maximizes the ES and clinical data for both diagnoses and candidate gene identification, without GS in the majority. This iterative approach is cost-effective and is pertinent to the current conundrum of ES negatives.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Developmental Disabilities
/
Genetic Predisposition to Disease
/
Exome
Type of study:
Diagnostic_studies
/
Prognostic_studies
Limits:
Child
/
Female
/
Humans
/
Male
Language:
En
Journal:
Genet Med
Journal subject:
GENETICA MEDICA
Year:
2019
Type:
Article
Affiliation country:
United States