Limits...
Whole-Exome Sequencing in the Differential Diagnosis of Primary Adrenal Insufficiency in Children.

Chan LF, Campbell DC, Novoselova TV, Clark AJ, Metherell LA - Front Endocrinol (Lausanne) (2015)

Bottom Line: However, with the availability, and increasing cost effectiveness of whole-exome sequencing, there is the potential for this to become a powerful diagnostic tool.Here, we report the results of whole-exome sequencing of 43 patients referred to us with a diagnosis of familial glucocorticoid deficiency (FGD) who were mutation negative for MC2R, MRAP, and STAR the most commonly mutated genes in FGD.The diagnosis of isolated or familial glucocorticoid deficiency was only confirmed in 3 of the 17 patients, other genetic diagnoses were adrenal hypo- and hyperplasia, Triple A, and autoimmune polyendocrinopathy syndrome type I, emphasizing both the difficulty of phenotypically distinguishing between disorders of PAI and the utility of WES as a tool to achieve this.

View Article: PubMed Central - PubMed

Affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London , London , UK.

ABSTRACT
Adrenal insufficiency is a rare, but potentially fatal medical condition. In children, the cause is most commonly congenital and in recent years a growing number of causative gene mutations have been identified resulting in a myriad of syndromes that share adrenal insufficiency as one of the main characteristics. The evolution of adrenal insufficiency is dependent on the variant and the particular gene affected, meaning that rapid and accurate diagnosis is imperative for effective treatment of the patient. Common practice is for candidate genes to be sequenced individually, which is a time-consuming process and complicated by overlapping clinical phenotypes. However, with the availability, and increasing cost effectiveness of whole-exome sequencing, there is the potential for this to become a powerful diagnostic tool. Here, we report the results of whole-exome sequencing of 43 patients referred to us with a diagnosis of familial glucocorticoid deficiency (FGD) who were mutation negative for MC2R, MRAP, and STAR the most commonly mutated genes in FGD. WES provided a rapid genetic diagnosis in 17/43 sequenced patients, for the remaining 60% the gene defect may be within intronic/regulatory regions not covered by WES or may be in gene(s) representing novel etiologies. The diagnosis of isolated or familial glucocorticoid deficiency was only confirmed in 3 of the 17 patients, other genetic diagnoses were adrenal hypo- and hyperplasia, Triple A, and autoimmune polyendocrinopathy syndrome type I, emphasizing both the difficulty of phenotypically distinguishing between disorders of PAI and the utility of WES as a tool to achieve this.

No MeSH data available.


Related in: MedlinePlus

Pie chart indicating the percentage of FGD cases due to gene mutations in the Melanocortin 2 receptor (MC2R), MC2R accessory protein (MRAP), Mini chromosome maintenance deficient 4 (MCM4), Nicotinamide nucleotide transhydrogenase (NNT), Steroidogenic acute regulatory protein (STAR), Cytochrome p450 11A1 (CYP11A1), Thioredoxin reductase 2 (TXNRD2), Glutathione peroxidase 1 (GPX1), and Peroxiredoxin 3 (PRDX3) in our patient cohort.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4525066&req=5

Figure 1: Pie chart indicating the percentage of FGD cases due to gene mutations in the Melanocortin 2 receptor (MC2R), MC2R accessory protein (MRAP), Mini chromosome maintenance deficient 4 (MCM4), Nicotinamide nucleotide transhydrogenase (NNT), Steroidogenic acute regulatory protein (STAR), Cytochrome p450 11A1 (CYP11A1), Thioredoxin reductase 2 (TXNRD2), Glutathione peroxidase 1 (GPX1), and Peroxiredoxin 3 (PRDX3) in our patient cohort.

Mentions: Many of the genetic disorders listed in Table 1 may present with PAI. Some of these conditions will have additional features and investigations will reveal abnormal findings, for example, adrenal cortex auto-antibodies or perturbed levels of 17-hydroxyprogesterone and very-long chain fatty acids to name a few [reviewed in Ref. (8)]. However, with recent discoveries of new genes and novel mutations in known genes causing PAI, it is becoming increasingly clear that considerable phenotypic overlap between genetic disorders occurs. This is applicable to the condition FGD, once thought to be fairly distinct from other causes of PAI (see Figure 1). FGD patients present with isolated glucocorticoid deficiency and normal mineralocorticoid production. Biochemical results in FGD point toward ACTH resistance, with serum cortisol often undetectable and extremely high plasma ACTH (11). As we learn more about the genetic causes of FGD, the boundaries between different PAI disorders or diagnostic features of FGD are being challenged (12–20).


Whole-Exome Sequencing in the Differential Diagnosis of Primary Adrenal Insufficiency in Children.

Chan LF, Campbell DC, Novoselova TV, Clark AJ, Metherell LA - Front Endocrinol (Lausanne) (2015)

Pie chart indicating the percentage of FGD cases due to gene mutations in the Melanocortin 2 receptor (MC2R), MC2R accessory protein (MRAP), Mini chromosome maintenance deficient 4 (MCM4), Nicotinamide nucleotide transhydrogenase (NNT), Steroidogenic acute regulatory protein (STAR), Cytochrome p450 11A1 (CYP11A1), Thioredoxin reductase 2 (TXNRD2), Glutathione peroxidase 1 (GPX1), and Peroxiredoxin 3 (PRDX3) in our patient cohort.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525066&req=5

Figure 1: Pie chart indicating the percentage of FGD cases due to gene mutations in the Melanocortin 2 receptor (MC2R), MC2R accessory protein (MRAP), Mini chromosome maintenance deficient 4 (MCM4), Nicotinamide nucleotide transhydrogenase (NNT), Steroidogenic acute regulatory protein (STAR), Cytochrome p450 11A1 (CYP11A1), Thioredoxin reductase 2 (TXNRD2), Glutathione peroxidase 1 (GPX1), and Peroxiredoxin 3 (PRDX3) in our patient cohort.
Mentions: Many of the genetic disorders listed in Table 1 may present with PAI. Some of these conditions will have additional features and investigations will reveal abnormal findings, for example, adrenal cortex auto-antibodies or perturbed levels of 17-hydroxyprogesterone and very-long chain fatty acids to name a few [reviewed in Ref. (8)]. However, with recent discoveries of new genes and novel mutations in known genes causing PAI, it is becoming increasingly clear that considerable phenotypic overlap between genetic disorders occurs. This is applicable to the condition FGD, once thought to be fairly distinct from other causes of PAI (see Figure 1). FGD patients present with isolated glucocorticoid deficiency and normal mineralocorticoid production. Biochemical results in FGD point toward ACTH resistance, with serum cortisol often undetectable and extremely high plasma ACTH (11). As we learn more about the genetic causes of FGD, the boundaries between different PAI disorders or diagnostic features of FGD are being challenged (12–20).

Bottom Line: However, with the availability, and increasing cost effectiveness of whole-exome sequencing, there is the potential for this to become a powerful diagnostic tool.Here, we report the results of whole-exome sequencing of 43 patients referred to us with a diagnosis of familial glucocorticoid deficiency (FGD) who were mutation negative for MC2R, MRAP, and STAR the most commonly mutated genes in FGD.The diagnosis of isolated or familial glucocorticoid deficiency was only confirmed in 3 of the 17 patients, other genetic diagnoses were adrenal hypo- and hyperplasia, Triple A, and autoimmune polyendocrinopathy syndrome type I, emphasizing both the difficulty of phenotypically distinguishing between disorders of PAI and the utility of WES as a tool to achieve this.

View Article: PubMed Central - PubMed

Affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London , London , UK.

ABSTRACT
Adrenal insufficiency is a rare, but potentially fatal medical condition. In children, the cause is most commonly congenital and in recent years a growing number of causative gene mutations have been identified resulting in a myriad of syndromes that share adrenal insufficiency as one of the main characteristics. The evolution of adrenal insufficiency is dependent on the variant and the particular gene affected, meaning that rapid and accurate diagnosis is imperative for effective treatment of the patient. Common practice is for candidate genes to be sequenced individually, which is a time-consuming process and complicated by overlapping clinical phenotypes. However, with the availability, and increasing cost effectiveness of whole-exome sequencing, there is the potential for this to become a powerful diagnostic tool. Here, we report the results of whole-exome sequencing of 43 patients referred to us with a diagnosis of familial glucocorticoid deficiency (FGD) who were mutation negative for MC2R, MRAP, and STAR the most commonly mutated genes in FGD. WES provided a rapid genetic diagnosis in 17/43 sequenced patients, for the remaining 60% the gene defect may be within intronic/regulatory regions not covered by WES or may be in gene(s) representing novel etiologies. The diagnosis of isolated or familial glucocorticoid deficiency was only confirmed in 3 of the 17 patients, other genetic diagnoses were adrenal hypo- and hyperplasia, Triple A, and autoimmune polyendocrinopathy syndrome type I, emphasizing both the difficulty of phenotypically distinguishing between disorders of PAI and the utility of WES as a tool to achieve this.

No MeSH data available.


Related in: MedlinePlus