Identification of four novel mutations in the CYP21 gene in congenital adrenal hyperplasia in the Chinese

More than 90% of the cases of congenital adrenal hyperplasia are caused by mutations of the CYP21 gene. Approximately 75% of the defective CYP21 genes are generated through intergenic recombination, termed apparent gene conversion, from the neighboring CYP21P pseudogene. Among them, mutation of the aberrant splicing donor site of IVS2 –12A/C>G at nucleotide (nt) 655 is believed to be a result derived from this mechanism and is the most prevalent case among all ethnic groups. However, mutation of 707–714delGAGACTAC rarely exists alone, although this locus is a distance of 53 nt away from IVS2 –12A/C>G. From the molecular characterization of the mutation of IVS2 –12A/C>G combined with 707–714delGAGACTAC in patients with congenital adrenal hyperplasia, we found that it appeared to be in a 3.2-rather than a 3.7-kb fragment generated by Taq I digestion in a PCR product of the CYP21 gene. Interestingly, the 5′ end region of such a CYP21 haplotype had CYP21P-specific sequences. Our results indicate that the coexistence of these two mutations is caused by deletion of the CYP21P, XA, RP2, and C4B genes and intergenic recombination in the C4-CYP21 repeat module. Surprisingly, this kind of the haplotype of the mutated CYP21 gene has not been reported as a gene deletion.

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Phenotypic, metabolic, and molecular genetic characterization of six patients with congenital adrenal hyperplasia caused by novel mutations in the CYP11B1 gene

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/j.jsbmb.2015.10.011 ◽

2016 ◽

Vol 155 ◽

pp. 126-134 ◽

Cited By ~ 8

Author(s):

Huy-Hoang Nguyen ◽

Antje Eiden-Plach ◽

Frank Hannemann ◽

Ewa M. Malunowicz ◽

Michaela F. Hartmann ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Genetic Characterization ◽

Molecular Genetic ◽

Adrenal Hyperplasia ◽

Novel Mutations ◽

Molecular Genetic Characterization

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Study of a Kindred with Classic Congenital Adrenal Hyperplasia: Diagnostic Challenge due to Phenotypic Variance1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.83.6.4887 ◽

1998 ◽

Vol 83 (6) ◽

pp. 1940-1945

Author(s):

Daisy Chin ◽

Phyllis W. Speiser ◽

Julianne Imperato-McGinley ◽

Naznin Dixit ◽

Naveen Uli ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Newborn Screening ◽

Point Mutation ◽

Phenotypic Expression ◽

Variable Degree ◽

Adrenal Hyperplasia ◽

Cyp21 Gene ◽

Classic Congenital Adrenal Hyperplasia ◽

Genital Ambiguity ◽

21 Hydroxylase Deficiency

We sought to determine the concordance of the phenotype and genotype in a kindred with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The variation in phenotypic expression within this family underscores the difficulty of establishing the diagnosis in the absence of newborn screening, even with a heightened index of suspicion. Steroidogenic profiles were obtained for the three affected siblings. The available clinical history of the two affected aunts was retrieved. Genotyping was performed on several members of the kindred. Detailed sequencing of the entire CYP21 gene of two clinically dissimilar subjects in this family was undertaken to explore the possibility of other mutations or polymorphisms. PCR with ligase detection reaction analysis of CYP21 revealed that the affected family members III-2, III-3, III-4, II-3, and II-4, all were compound heterozygotes carrying the intron 2 point mutation known to interfere with splicing (nucleotide 656 A to G) and the exon 4 point mutation causing a nonconservative substitution of asparagine for isoleucine at codon 172 (I172N). Detailed sequencing of the gene was performed for the two most phenotypically dissimilar subjects. A single silent polymorphism was found in the third nucleotide for codon 248 in patient II-4, but not in patient III-4, and no additional mutations were found. Classic congenital adrenal hyperplasia remains a difficult diagnosis to make in the absence of newborn screening because of the variability of phenotypic expression. Likewise, the variable degree of genital ambiguity in affected females in this family serves to question universal advocacy of prenatal steroid treatment in pregnancies at risk for congenital adrenal hyperplasia. Extensive molecular exploration did not provide an explanation of the phenotypic heterogeneity and supports the possibility of influences other than the CYP21 gene for the observed divergence.

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