Deep phenotyping and whole-exome sequencing improved the diagnostic yield for nuclear pedigrees with neurodevelopmental disorders.
deep phenotyping
genetic diagnosis
neurodevelopmental disorders
whole exome sequencing
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
revised:
18
02
2022
received:
07
09
2021
accepted:
25
02
2022
pubmed:
11
3
2022
medline:
27
4
2022
entrez:
10
3
2022
Statut:
ppublish
Résumé
Neurodevelopmental disorders, a group of early-onset neurological disorders with significant clinical and genetic heterogeneity, remain a diagnostic challenge for clinical genetic evaluation. Therefore, we assessed the diagnostic yield by combining standard phenotypes and whole-exome sequencing in families with these disorders that were "not yet diagnosed" by the traditional testing methods. Using a standardized vocabulary of phenotypic abnormalities from human phenotype ontology (HPO), we performed deep phenotyping for 45 "not yet diagnosed" pedigrees to characterize multiple clinical features extracted from Chinese electronic medical records (EMRs). By matching HPO terms with known human diseases and phenotypes from model organisms, together with whole-exome sequencing data, we prioritized candidate mutations/genes. We made probable genetic diagnoses for the families. We obtained a diagnostic yield of 29% (13 out of 45) with probably genetic diagnosis, of which compound heterozygosity and de novo mutations accounted for 77% (10/13) of the diagnosis. Of note, these pedigrees are accompanied by a more significant number of non-neurological features. Deep phenotyping and whole-exome sequencing improve the etiological evaluation for neurodevelopmental disorders in the clinical setting.
Sections du résumé
BACKGROUND
Neurodevelopmental disorders, a group of early-onset neurological disorders with significant clinical and genetic heterogeneity, remain a diagnostic challenge for clinical genetic evaluation. Therefore, we assessed the diagnostic yield by combining standard phenotypes and whole-exome sequencing in families with these disorders that were "not yet diagnosed" by the traditional testing methods.
METHODS
Using a standardized vocabulary of phenotypic abnormalities from human phenotype ontology (HPO), we performed deep phenotyping for 45 "not yet diagnosed" pedigrees to characterize multiple clinical features extracted from Chinese electronic medical records (EMRs). By matching HPO terms with known human diseases and phenotypes from model organisms, together with whole-exome sequencing data, we prioritized candidate mutations/genes. We made probable genetic diagnoses for the families.
RESULTS
We obtained a diagnostic yield of 29% (13 out of 45) with probably genetic diagnosis, of which compound heterozygosity and de novo mutations accounted for 77% (10/13) of the diagnosis. Of note, these pedigrees are accompanied by a more significant number of non-neurological features.
CONCLUSIONS
Deep phenotyping and whole-exome sequencing improve the etiological evaluation for neurodevelopmental disorders in the clinical setting.
Identifiants
pubmed: 35266334
doi: 10.1002/mgg3.1918
pmc: PMC9034680
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1918Informations de copyright
© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
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