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. 2023 Jul;11(7):e2167.
doi: 10.1002/mgg3.2167. Epub 2023 Mar 26.

Individualised human phenotype ontology gene panels improve clinical whole exome and genome sequencing analytical efficacy in a cohort of developmental and epileptic encephalopathies

Olivia J Henry  1 , Tommy Stödberg  2   3 , Sofia Båtelson  3 , Chiara Rasi  4 , Henrik Stranneheim  1   4   5 , Anna Wedell  1   5
Affiliations

Individualised human phenotype ontology gene panels improve clinical whole exome and genome sequencing analytical efficacy in a cohort of developmental and epileptic encephalopathies

Olivia J Henry et al. Mol Genet Genomic Med. 2023 Jul.

Abstract

Background: The majority of genetic epilepsies remain unsolved in terms of specific genotype. Phenotype-based genomic analyses have shown potential to strengthen genomic analysis in various ways, including improving analytical efficacy.

Methods: We have tested a standardised phenotyping method termed 'Phenomodels' for integrating deep-phenotyping information with our in-house developed clinical whole exome/genome sequencing analytical pipeline. Phenomodels includes a user-friendly epilepsy phenotyping template and an objective measure for selecting which template terms to include in individualised Human Phenotype Ontology (HPO) gene panels. In a pilot study of 38 previously solved cases of developmental and epileptic encephalopathies, we compared the sensitivity and specificity of the individualised HPO gene panels with the clinical epilepsy gene panel.

Results: The Phenomodels template showed high sensitivity for capturing relevant phenotypic information, where 37/38 individuals' HPO gene panels included the causative gene. The HPO gene panels also had far fewer variants to assess than the epilepsy gene panel.

Conclusion: We have demonstrated a viable approach for incorporating standardised phenotype information into clinical genomic analyses, which may enable more efficient analysis.

Keywords: deep phenotyping; epilepsy; human phenotype ontology; precision medicine; whole exome sequencing; whole genome sequencing.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

FIGURE 1
FIGURE 1
The Phenomodels standardised epilepsy phenotyping template. Blue indicates the information content of the term. ADEAF, Autosomal dominant epilepsy with auditory features; ADNFLE, Autosomal dominant nocturnal frontal lobe epilepsy; CAE, childhood absence epilepsy; CECTS, childhood epilepsy with centrotemporal spikes; EE CSWS, Epileptic encephalopathy with continuous spike‐and‐wave during sleep; EIMFS, epilepsy of infancy with migrating focal seizures; EME, early myoclonic encephalopathy; FBTC, focal to bilateral tonic clonic seizure; FCD, focal cortical dysplasia; FFVF, Familial focal epilepsy with variable foci; GEFS+, genetic epilepsy with febrile seizures plus; GTCSA, Generalised tonic clonic seizures alone; JAE, Juvenile absence epilepsy; JME, Juvenile myoclonic epilepsy; LGS, Lennox Gastaut syndrome; LKS, Landau Kleffner Syndrome; MAE, epilepsy with myoclonic atonic seizures; MEI, myoclonic epilepsy in infancy; Other familial TLE, Other familial temporal lobe epilepsies; PME, Progressive myoclonic epilepsies; SelFIE, self‐limited familial infantile epilepsy; SelNE, self‐limited neonatal epilepsy.
FIGURE 2
FIGURE 2
Total whole genome sequencing variants in the clinical epilepsy gene panel and the individualised HPO IC ≥ 3 gene panels. The red dots indicate the median value. The box contains the interquartile range. Values outside the whiskers are outliers.
FIGURE 3
FIGURE 3
Whole genome sequencing rank ratio in the clinical epilepsy gene panel and the individualised HPO IC ≥ 3 gene panels. Red dots indicate median value. The box contains the interquartile range. Values outside the whiskers are outliers. Extreme outliers 0.212 from the epilepsy gene panel and 0.063 from HPO ≥ 3 gene panel have been removed for visualisation purposes.
FIGURE 4
FIGURE 4
Total whole exome sequencing variants in the clinical epilepsy gene panel and the individualised HPO IC ≥ 3.75 gene panels. The red dots indicate the median value. The box contains the interquartile range. Values outside the whiskers are outliers.
FIGURE 5
FIGURE 5
Whole exome sequencing rank ratio in the clinical epilepsy gene panel and the individualised HPO IC ≥ 3.75 gene panels. The red dots indicate the median value. The box contains the interquartile range. Values outside the whiskers are outliers.
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