Genesis by meiotic unequal crossover of a de novo deletion that contributes to steroid 21-hydroxylase deficiency.

Представлено описание клинико-генетических характеристик ребенка 2 лет с двумя моногенными заболеваниями: сольтеряющей формой адрено--генитального синдрома с аутосомно-рецессивным типом наследования и узловой гетеротопий мозга 7 типа, наследующейся аутосомно-доминантно, диагностированных с использованием двух различных молекулярно-генетических методов. Наличие адрено-генитального синдрома диагностировано в первые дни жизни на основании типичных клинических проявлений и подтверждено путём прямой ДНК-диагностики, в результате которой обнаружена гомозиготная мутация p.R356W в гене CYP21А2. Наличие второго моногенного заболевания предполагалось на основании диагностики грубой задержки психомоторного и речевого развития и аномалий строения головного мозга, обнаруженных при проведении магнитно-резонансной томографии. При секвенировании клинического экзома выявлена ранее не описанная нуклеотидная замена с.2015С>T (р.W672I) в гене NEDD4L. Патогенные варианты в домене HECT данного белка приводят к перивентрикулярной узловой гетеротопии 7 типа (OMIM:617021). Анализ данного варианта методом прямого секвенирования по Сэнгеру в семье показал его происхождение de novo. We report 2-year-old girl with two monogenic diseases - adrenogenital syndrome with autosomal recessive inheritance mode and periventricular nodular heterotopia type 7 with autosomal dominant, diagnosed by two different molecular genetic methods. The presence of adreno-genital syndrome diagnosed in the first days of life based on typical clinical manifestations and the homozygous mutation was detected p.R356Wby direct DNA testing CYP21А2 gene. The presence of the second monogenic disease was proposed base on the observation the severe delay of psychomotor and speech development and abnormalities of the brain structure detected by MRI. Clinical exome sequencing identified previously not described single nucleotide substitution c.2015С>T (p.W672I) in NEDD4L gene. Pathogenic variants in HECT domain of this protein lead to periventricular nodular heterotopia type 7 (OMIM:617021). Analysis of segregation this variant in the family by direct sequencing of Sanger showed its origin de novo.

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Divergent Phenotype of Two Siblings Human Leukocyte Antigen Identical, Affected by Nonclassical and Classical Congenital Adrenal Hyperplasia Caused by 21-Hydroxylase Deficiency

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-0779 ◽

2006 ◽

Vol 91 (11) ◽

pp. 4510-4513 ◽

Cited By ~ 6

Author(s):

O. Porzio ◽

V. Cunsolo ◽

M. Malaponti ◽

E. De Nisco ◽

A. Acquafredda ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Human Leukocyte Antigen ◽

De Novo ◽

Human Leukocyte ◽

Compound Heterozygote ◽

Variable Degree ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Leukocyte Antigen ◽

21 Hydroxylase Deficiency

Abstract Context: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders most often caused by enzyme 21-hydroxylase deficiency. Most mutations causing enzymatic deficiency are generated by recombinations between the active gene CYP21 and the pseudogene CYP21P. Only 1–2% of affected alleles result from spontaneous mutations. The phenotype of CAH varies greatly, usually classified as classical or nonclassical, depending on variable degree in 21-hydroxylase activity. Here we report a divergent phenotype of two human leukocyte antigen identical siblings, affected by nonclassical and classical CAH caused by 21-hydroxylase deficiency due to different genotype. Patients and Methods: Using direct sequencing method and Southern blot, we studied two children (one male and one female), affected, respectively, by nonclassical and classical CAH and their parents. Results: The mother was heterozygous for the Q318X mutation, and the father was heterozygous for the V281L mutation. The brother was a compound heterozygote for the mutations V281L and Q318X, whereas the proband was compound heterozygote for the Q318X mutation and a large conversion. The two children are human leukocyte antigen identical (A*02;B*14;DRB1*01/A*33;B*14;DRB1*03). Conclusions: Different phenotype of the proband is the result of compound heterozygosity for the maternal mutation Q318X and a de novo large conversion.

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de novo mutation causes steroid 21-hydroxylase deficiency in one family of HLA-identical affected and unaffected siblings.

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.77.1.8325964 ◽

1993 ◽

Vol 77 (1) ◽

pp. 86-89

Author(s):

T Tajima ◽

K Fujieda ◽

Y Fujii-Kuriyama

Keyword(s):

De Novo ◽

De Novo Mutation ◽

Hydroxylase Deficiency ◽

21 Hydroxylase Deficiency

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Comprehensive Genetic Analysis of 182 Unrelated Families with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-0319 ◽

2011 ◽

Vol 96 (1) ◽

pp. E161-E172 ◽

Cited By ~ 92

Author(s):

Gabriela P. Finkielstain ◽

Wuyan Chen ◽

Sneha P. Mehta ◽

Frank K. Fujimura ◽

Reem M. Hanna ◽

...

Keyword(s):

Genetic Analysis ◽

Congenital Adrenal Hyperplasia ◽

Mutation Analysis ◽

De Novo ◽

Uniparental Disomy ◽

Compound Heterozygous ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Study Objective ◽

21 Hydroxylase Deficiency

Background: Genetic analysis is commonly performed in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Study Objective: The objective of the study was to describe comprehensive CYP21A2 mutation analysis in a large cohort of CAH patients. Methods: Targeted CYP21A2 mutation analysis was performed in 213 patients and 232 parents from 182 unrelated families. Complete exons of CYP21A2 were sequenced in patients in whom positive mutations were not identified by targeted mutation analysis. Copy number variation and deletions were determined using Southern blot analysis and PCR methods. Genotype was correlated with phenotype. Results: In our heterogeneous U.S. cohort, targeted CYP21A2 mutation analysis did not identify mutations on one allele in 19 probands (10.4%). Sequencing identified six novel mutations (p.Gln262fs, IVS8+1G>A, IVS9-1G>A, p.R408H, p.Gly424fs, p.R426P) and nine previously reported rare mutations. The majority of patients (79%) were compound heterozygotes and 69% of nonclassic (NC) patients were compound heterozygous for a classic and a NC mutation. Duplicated CYP21A2 haplotypes, de novo mutations and uniparental disomy were present in 2.7% of probands and 1.9 and 0.9% of patients from informative families, respectively. Genotype accurately predicted phenotype in 90.5, 85.1, and 97.8% of patients with salt-wasting, simple virilizing, and NC mutations, respectively. Conclusions: Extensive genetic analysis beyond targeted CYP21A2 mutational detection is often required to accurately determine genotype in patients with CAH due to the high frequency of complex genetic variation.

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