Exome Sequencing in an ADSHE Family: VUS Identification and Limits

Chiara Villa, Federica Arrigoni, Eleonora Rivellini, Marialuisa Lavitrano, Luca De Gioia, Luigi Ferini-Strambi and Romina Combi ()
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Chiara Villa: School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
Federica Arrigoni: Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
Eleonora Rivellini: School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
Marialuisa Lavitrano: School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
Luca De Gioia: Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
Luigi Ferini-Strambi: Department of Clinical Neurosciences, Neurology-Sleep Disorder Center, IRCCS San Raffaele Scientific Institute, 20127 Milan, Italy
Romina Combi: School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy

IJERPH, 2022, vol. 19, issue 19, 1-11

Abstract: Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is the familial form of a focal epilepsy characterized by hyperkinetic focal seizures, mainly arising during non-rapid eye movements (NREM) sleep. Mutations associated with ADSHE account for a small proportion of the genetically determined cases, suggesting the existence of other disease-causing genes. Here, we reported the results obtained by performing trio-based whole-exome sequencing (WES) in an Italian family showing ADSHE and investigated the structural impact of putative variants by in silico modeling analysis. We identified a p.(Trp276Gly) variant in MOXD1 gene encoding the monooxigenase DBH like 1 protein, cosegregating with the disease and annotated as VUS under the ACMG recommendations. Structural bioinformatic analysis predicted a high destabilizing effect of this variant, due to the loss of important hydrophilic bonds and an expansion of cavity volume in the protein hydrophobic core. Although our data support a functional effect of the p.(Trp276Gly) variant, we highlight the need to identify additional families carrying MOXD1 mutations or functional analyses in suitable models to clarify its role in ADSHE pathogenesis. Moreover, we discuss the importance of VUS reporting due to the low rate of pathogenic variant identification by NGS in epilepsy and for future reinterpretation studies.

Keywords: mutation; ADSHE; epilepsy; gene (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2022
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