Novel Compound Heterozygous NNT Variants in Familial Glucocorticoid Deficiency Type 4 Diagnosed by Whole Genome...

Familial glucocorticoid deficiency (FGD) type 4 is a rare autosomal recessive disorder caused by loss-of-function variants in NNT (nicotinamide nucleotide transhydrogenase), which encodes a mitochondrial NADPH-generating enzyme essential for protecting adrenocortical cells from oxidative stress. We report an 18-year-old Korean male who presented at 16 months of age with primary adrenal insufficiency characterized by markedly elevated ACTH and low cortisol. Over 18 years, sequential genetic investigations including a targeted panel that did not include NNT and identification of a POR variant of uncertain significance failed to establish a molecular diagnosis. Whole genome sequencing revealed two novel compound heterozygous NNT variants (NM_182977.3:c.1820dup, p.Gly608TrpfsTer11; and NM_182977.3:c.1861C>T, p.Gln621Ter), both classified as likely pathogenic, consistent with FGD type 4. This case expands the allelic spectrum of NNT-related disease and illustrates the diagnostic utility of whole genome sequencing in undiagnosed primary adrenal insufficiency.