title: A novel homozygous insertion and review of published mutations in the NNT gene causing familial glucocorticoid deficiency (FGD).
abstract: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by low levels of cortisol despite high adrenocorticotropin (ACTH) levels, due to the reduced ability of the adrenal cortex to produce cortisol in response to stimulation by ACTH. FGD is a heterogeneous disorder for which causal mutations have been identified in MC2R, MRAP, MCM4 and TXNRD2. Also mutations in STAR and CYP11A1 can sometimes present with a phenotype resembling FGD. Recently, it has been indicated that FGD can also be caused by mutations in NNT (nicotinamide nucleotide transhydrogenase). We identified a 6.67 Mb homozygous region harboring the NNT gene by SNP haplotyping in a 1-year old Dutch boy presenting with FGD, but without mutations in MC2R and MRAP. Exome-sequencing revealed a novel homozygous mutation (NM_012343.3: c.1259dupG) in NNT that was predicted to be disease-causing. The mutation is located in exon 9 and creates a frameshift leading to a premature stop-codon (p.His421Serfs*4) that is known to result in FGD. Both parents were shown to be heterozygous carriers. We reviewed the literature for all the reported NNT mutations and their clinical presentation. The median age of disease onset in 23 reported patients, including the present patient, was 12 months (range 3 days-39 months). There was no difference in age of disease onset between truncating and non-truncating NNT mutations. Based on recent literature, we advise to monitor patients with FGD due to NNT mutations for possible combined mineralocorticoid insufficiency and extra-adrenal manifestations.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Omid
authors.initials: O
authors.lastname: Jazayeri
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Xuanzhu
authors.initials: X
authors.lastname: Liu
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Cleo C
authors.initials: CC
authors.lastname: van Diemen
authors.affiliation: University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Department of Pediatric Endocrinology, The Netherlands.
authors.forename: Willie M
authors.initials: WM
authors.lastname: Bakker-van Waarde
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Birgit
authors.initials: B
authors.lastname: Sikkema-Raddatz
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sinke
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands. Electronic address: c.m.a.van.ravenswaaij@umcg.nl.
authors.forename: Conny M A
authors.initials: CM
authors.lastname: van Ravenswaaij-Arts
mesh_terms: D000309:Adrenal Insufficiency / Q000175:diagnosis* / Q000235:genetics*; D000483:Alleles; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D003241:Consanguinity; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics; D016254:Mutagenesis, Insertional; D009154:Mutation; D061087:NADP Transhydrogenase, AB-Specific / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D024101:Mitochondrial Proteins; D061087:NADP Transhydrogenase, AB-Specific; C556045:NNT protein, human
keywords: Exome sequencing; Familial glucocorticoid deficiency; Mutation; NNT; Review