A rare CYP21A2 mutation in a congenital adrenal hyperplasia kindred displaying genotype-phenotype nonconcordance.
Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is caused by the autosomal recessive inheritance of mutations in the gene CYP21A2. CYP21A2 mutations lead to variable impairment of the 21-hydroxylase enzyme, which, in turn, is associated with three clinical phenotypes, namely, salt wasting, simple virilizing, and nonclassical CAH. However, it is known that a given mutation can associate with different clinical phenotypes, resulting in a high rate of genotype-phenotype nonconcordance. We aimed to study the genotype-phenotype nonconcordance in a family with three siblings affected with nonclassical CAH. All had hormonal evidence of nonclassical CAH, but this phenotype could not be explained by the genotype obtained from commercial CYP21A2 genetic testing, which revealed heterozygosity for the maternal 30 kb deletion mutation. We performed Sanger sequencing of the entire CYP21A2 gene in this family to search for a rare mutation that was not covered by commercial testing and found in the three siblings a second, rare c.1097G>A (p.R366H) mutation in exon 8. Computational modeling confirmed that this was a mild mutation consistent with nonclassical CAH. We recommend that sequencing of entire genes for rare mutations should be carried out when genotype-phenotype nonconcordance is observed in patients with autosomal recessive monogenic disorders, including CAH.
Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
Ahmed
A
Khattab
Department of Medicine, The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, New York.
Tony
T
Yuen
Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
Sultan
S
Al-Malki
Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
Mabel
M
Yau
Department of Medicine, The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, New York.
Diya
D
Kazmi
Department of Medicine, The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, New York.
Li
L
Sun
Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
Madeleine
M
Harbison
School of Pharmacy, University College, London, United Kingdom.
Shozeb
S
Haider
Department of Medicine, The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, New York.
Mone
M
Zaidi
Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York.
Maria I
MI
New
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000312:Adrenal Hyperplasia, Congenital / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D019943:Amino Acid Substitution; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D002648:Child; D019295:Computational Biology; D004252:DNA Mutational Analysis; D004359:Drug Therapy, Combination; D005091:Exons; D005103:Expert Systems; D017353:Gene Deletion; D005938:Glucocorticoids / Q000627:therapeutic use; D006579:Heterozygote; D006801:Humans; D008297:Male; D008958:Models, Molecular; D010375:Pedigree; D017354:Point Mutation; D011487:Protein Conformation; D035781:Siblings; D013255:Steroid 21-Hydroxylase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
D047072:Aromatase Inhibitors; D005938:Glucocorticoids; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase
CYP21A2; Khattab, A., T. Yuen, S. Al-Malki, M. Yau, D. Kazmi, L. Sun, M. Harbison, S. Haider, M. Zaidi & M.I. New. 2015. A rare CYP21A2 mutation in a congenital adrenal hyperplasia kindred displaying genotype-phenotype nonconcordance. In “MARROW,” ed. by M. Za; congenital adrenal hyperplasia; genotype; p.R366H; phenotype