Background:
Inborne errors of metabolism are a common cause of neonatal death.
This study evaluated the acute early-onset metabolic derangement and
death in two unrelated neonates.
Methods:
WES, Sanger sequencing, homology modeling, and in silico
bioinformatics analysis were employed to assess the effects of variants
on protein structure and function.
Results:
WES revealed a novel homozygous variant, p.G303Afs*40 and p.R156P,
in the PC gene of each neonate, which both were confirmed by Sanger
sequencing. Based on the ACMG guidelines, the p.G303Afs*40 was likely
pathogenic, and the p.R156P was a VUS. Nevertheless, a known variant at
position 156, the p.R156Q, was also a VUS. Protein secondary structure
prediction showed changes in p.R156P and p.R156Q variants compared to
the wild-type protein. However, p.G303Afs*40 depicted significant
changes at C-terminal. Furthermore, comparing the interaction of
wild-type and variant proteins with the ATP ligand during simulations,
revealed a decreased affinity to the ATP in all the variants. Moreover,
analysis of SNP impacts on PC protein using Polyphen-2, SNAP2, FATHMM,
and SNPs&GO servers predicted both R156P and R156Q as damaging
variants. Likewise, free energy calculations demonstrated the
destabilizing effect of both variants on PC.
Conclusion:
This study confirmed the pathogenicity of both variants and
suggested them as a cause of type B PCD. The results of this study would
provide the family with prenatal diagnosis and expand the variant
spectrum in the PC gene,which is beneficial for geneticists and
endocrinologists.