Salt-Losing 21-Hydroxylase Deficiency Caused by Double Homozygosity for Two “Mild” Mutations | Zendy

Jacob Ilany | Zendy; Jiayan Liu | Zendy; Christoph Welsch | Zendy; Haike ReznikWolf | Zendy; Ephrat LevyLahad | Zendy; Richard J. Auchus | Zendy

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Salt-Losing 21-Hydroxylase Deficiency Caused by Double Homozygosity for Two “Mild” Mutations

Author(s) -

Jacob Ilany,

Jiayan Liu,

Christoph Welsch,

Haike ReznikWolf,

Ephrat LevyLahad,

Richard J. Auchus

Publication year - 2020

Publication title -

the journal of clinical endocrinology and metabolism

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.206

H-Index - 353

eISSN - 1945-7197

pISSN - 0021-972X

DOI - 10.1210/clinem/dgaa875

Subject(s) - 21 hydroxylase , heterozygote advantage , phenotype , compound heterozygosity , context (archaeology) , genetic counseling , allele , mutation , genetics , genotype , loss function , congenital adrenal hyperplasia , in silico , biology , gene , paleontology

Context Congenital adrenal hyperplasia due to 21-hydroxylase deficiency presents with different severities that correlate with the genotype. The salt-losing phenotype requires 2 alleles with “severe” mutations. Case Description We present a case of salt-losing 21-hydroxylase deficiency that was found to be homozygous for 2 “mild” pathogenic variants: V281L and S301Y. Both in silico and heterologous expression functional analysis demonstrated that co-occurrence of these 2 mutations in cis severely impairs the function of the 21-hydroxylase enzyme. Conclusions This case has important implications for genetic counseling. Regarding this combination of 2 “mild” variants as having mild phenotypic effects could lead to inappropriate counseling of heterozygote carriers.

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