Deep phenotyping and whole-exome sequencing improved the diagnosis yield
for nuclear pedigrees with neurodevelopmental disorders
Abstract
Neurodevelopmental disorders, a group of early-onset neurological
disorders with significantly clinical and genetic heterogeneity, remain
a diagnostic odyssey for clinical genetic evaluation. In a total of 45
parent-child trios/quads with these disorders that was ‘not yet
diagnosed’ by the traditional testing methods, we assessed the
diagnostic yield by the combined use of standardized phenotypes and
whole-exome sequencing data. Using a standardized vocabulary of
phenotypic abnormalities from Human Phenotype Ontology (HPO), we
performed deep phenotyping for these pedigrees to characterize multiple
clinical features that was extracted from Chinese electronic medical
records (EMRs). By matching HPO terms with known human diseases or
cross-species comparison, together with whole-exome sequencing data, we
prioritized candidate mutations/genes that underlies these pedigrees. We
obtained a diagnostic yield of 49% (22 out of 45) with probably or
possibly genetic diagnosis, of which the compound heterozygosity and de
novo mutations accounted for the half of the diagnosis. Of note, the
pedigrees with probable or possible diagnosis accompanied with a greater
number of phenotypes implicated in non-nervous systems. The combined use
of deep phenotyping and whole-exome sequencing provide implications for
etiological evaluation for neurodevelopmental disorders in the clinical
setting.