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Multiomic analysis elucidates Complex I deficiency caused by a deep intronic variant in NDUFB10
Author(s) -
Helman Guy,
Compton Alison G.,
Hock Daniella H.,
Walkiewicz Marzena,
Brett Gemma R.,
Pais Lynn,
Tan Tiong Y.,
De PaoliIseppi Ricardo,
Clark Michael B.,
Christodoulou John,
White Susan M.,
Thorburn David R.,
Stroud David A.,
Stark Zornitza,
Simons Cas
Publication year - 2021
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24135
Subject(s) - biology , exome sequencing , genetics , exome , exon , deep sequencing , genome , intron , gene , transcriptome , computational biology , proteomics , gene expression , mutation
Abstract The diagnosis of Mendelian disorders following uninformative exome and genome sequencing remains a challenging and often unmet need. Following uninformative exome and genome sequencing of a family quartet including two siblings with suspected mitochondrial disorder, RNA sequencing (RNAseq) was pursued in one sibling. Long‐read amplicon sequencing was used to determine and quantify transcript structure. Immunoblotting studies and quantitative proteomics were performed to demonstrate functional impact. Differential expression analysis of RNAseq data identified significantly decreased expression of the mitochondrial OXPHOS Complex I subunit NDUFB10 associated with a cryptic exon in intron 1 of NDUFB10 , that included an in‐frame stop codon. The cryptic exon contained a rare intronic variant that was homozygous in both affected siblings. Immunoblot and quantitative proteomic analysis of fibroblasts revealed decreased abundance of Complex I subunits, providing evidence of isolated Complex I deficiency. Through multiomic analysis we present data implicating a deep intronic variant in NDUFB10 as the cause of mitochondrial disease in two individuals, providing further support of the gene‐disease association. This study highlights the importance of transcriptomic and proteomic analyses as complementary diagnostic tools in patients undergoing genome‐wide diagnostic evaluation.