Premium
A phenotypically severe, biochemically “silent” case of HIBCH deficiency in a newborn diagnosed by rapid whole exome sequencing and enzymatic testing
Author(s) -
D'Gama Alissa M.,
Brucker William J.,
Zhang Tian,
Gubbels Cynthia S.,
Ferdinandusse Sacha,
Shi Jiahai,
Grant Patricia Ellen,
VanNoy Grace,
Genetti Casie A.,
Juusola Jane,
Yu Timothy W.,
Kritzer Amy,
Agrawal Pankaj B.
Publication year - 2020
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61498
Subject(s) - exome sequencing , newborn screening , mitochondrial disease , medicine , compound heterozygosity , phenotype , inborn error of metabolism , disease , global developmental delay , biology , bioinformatics , genetics , pediatrics , gene , mitochondrial dna
3‐Hydroxyisobutyryl‐CoA dehydrogenase (HIBCH) deficiency is a rare error in valine catabolism associated with a Leigh syndrome‐like phenotype, mitochondrial dysfunction, and increased C4‐OH. We report the most severe case to date in a full‐term female who presented with poor feeding and nystagmus on day of life (DOL) 1. Although initial neuroimaging findings were concerning for metabolic disease, further metabolic testing was nondiagnostic and she was discharged on DOL 18. She was readmitted on DOL 22 after severe apneic episodes requiring intubation, with EEG demonstrating multifocal seizures and MRI/MRS demonstrating worsening findings. Care was withdrawn DOL 27 and she expired. Rapid whole exome sequencing (WES) demonstrated compound heterozygous variants in HIBCH with a paternal pathogenic variant (c.852delA, p.L284FfsX10 ) and a maternal likely pathogenic variant (c.488G>T, p.C163F). Fibroblast enzymatic testing demonstrated marked reduction in HIBCH levels. This case demonstrates the importance of rapid WES and follow‐up functional testing in establishing a diagnosis when metabolic disease is suspected but lacks an expected biochemical signature.