Abstract
A de novo novel variant of uncertain significance p. (Arg532del) in the KLHL15 gene was identified by trio exome analysis in a child with global developmental delay, coarse facial features, repetitive behaviour, increased fatigability, poor feeding and gastro-oesophageal reflux. Comparative modelling and structural analysis were performed to gain insight into the effects of the variant on KLHL15 protein structure and function, with a view to aiding variant classification. The p. (Arg532del) variant affects a highly conserved residue within one of the Kelch repeats of the KLHL15 protein. This residue contributes to the stability of loop regions at the substrate binding surface of the protein; comparative modelling of the variant protein predicts altered topology at this surface, including at residue Tyr552, which is known to be important for substrate binding. We propose that it is highly probable that the p. (Arg532del) variant has a deleterious impact on KLHL15 structure, leading to a reduced level of protein function in vivo.
DOI
10.1016/j.ejmg.2023.104768
Publication Date
2023-04-12
Publication Title
European Journal of Medical Genetics
Publisher
Elsevier
ISSN
1769-7212
Embargo Period
2024-11-19
Recommended Citation
Pereira Baptista, J. (2023) 'Clinical findings and structural analysis involving a patient with a novel KLHL15 variant', European Journal of Medical Genetics, . Elsevier: Available at: https://doi.org/10.1016/j.ejmg.2023.104768
