Karaoglan Murat
Department of Pediatric Endocrinology, Gaziantep University Faculty of Medicine, 27070 Gaziantep, Turkey.
J Pediatr Endocrinol Metab. 2019 Dec 18;32(12):1311-1320. doi: 10.1515/jpem-2019-0187.
Background The genotype-phenotype relationship shows regional variability in 21-hydroxylase deficiency (21-OHD) caused by mutations in the CYP21A2 gene. This study focuses on the genotype-phenotype compatibility between patients and their siblings in a region where consanguineous marriage is common. Methods The most common mutations (I2G-P30L-I172N-V237E-M239K-V281L-Q318X-R356W-F306 + nt) were studied in 60 children with 21-OHD and 40 siblings (12 symptomatic and 28 asymptomatic; mean age 5.89 ± 4.63 and 8.34 ± 2.22 years, respectively). The allele number (patients; 93 siblings; 70 alleles) was counted for each case. Salt wasting (SW; n = 38), simple virilizing (SV; n = 11) and non-classical congenital adrenal hyperplasia (NCCAH; n = 11) types were compared with their genotypes classified into groups Null-AB-C-D-E based on enzyme impairment. Results Disease-causing mutations were identified in unrelated alleles: 80 out of 93 alleles (86%) in the patients: SW, 51/56 (91%); SV, 14/16 (87.4%) and NCCAH, 15/21 (71.4%). There were 43 out of 70 alleles (61.4%) in the siblings (asymptomatic, 25/50 [50%]; symptomatic, 18/20 [90%]). The most frequently detected mutations in the patients were: I2G (22%), Q318X-P30L-V281L (13% each). The distribution of the most common mutations by clinical types was: SW: I2G-Q318X (30.2%-19.6%), SV: I172NI2G (37.5%-18.7%), NCCAH: V281L-P30L (33.3%-28.5%). In patients and symptomatic siblings, the concordance percentages by genotype groups were: Null (100%-100%), A (85%-60%), B (100%-Not applicable), C (41.6%-50%). Eleven out of 28 asymptomatic siblings had disease-causing mutations (four, severe; one, moderate; six, mild). The distribution of genotypes by phenotypes were: SW: Null-A (88%), SV: B-A (50%-41.6%), NCCAH: C (100%). Conclusions This study showed that the most common alleles were IN2G-Q381X-R356W-P30L-V281L in the children with 21-OHD and asymptomatic siblings, and that the phenotype can be predicted from the genotype except for the P30L-V281L. This result suggests that the most common mutations in 21-OHD are similar to previous reports, but that the genotype-phenotype compatibility is good except for group C showing regional variability, and that genotyping of siblings discovered new patients.
背景 CYP21A2 基因突变导致的 21 - 羟化酶缺乏症（21 - OHD）的基因型 - 表型关系存在区域差异。本研究聚焦于近亲婚姻常见地区患者与其兄弟姐妹之间的基因型 - 表型相容性。方法 对 60 例 21 - OHD 患儿及 40 名兄弟姐妹（12 例有症状，28 例无症状；平均年龄分别为 5.89 ± 4.63 岁和 8.34 ± 2.22 岁）研究最常见的突变（I2G - P30L - I172N - V237E - M239K - V281L - Q318X - R356W - F306 + nt）。统计每个病例的等位基因数（患者 93 个；兄弟姐妹 70 个等位基因）。将失盐型（SW；n = 38）、单纯男性化型（SV；n = 11）和非经典型先天性肾上腺皮质增生症（NCCAH；n = 11）根据酶损伤情况分为 Null - AB - C - D - E 组，比较其基因型。结果 在不相关的等位基因中鉴定出致病突变：患者 93 个等位基因中有 80 个（86%）：SW 型，51/56（91%）；SV 型，14/16（87.4%）；NCCAH 型，15/21（71.4%）。兄弟姐妹 共 70 个等位基因中有 43 个（61.4%）（无症状者，25/50 [50%]；有症状者，18/20 [90%]）。患者中最常检测到的突变是：I2G（22%），Q318X - P30L - V281L（各 13%）。按临床类型划分最常见突变的分布为：SW 型：I2G - Q318X（30.2% - 19.6%），SV 型：I172N - I2G（37.5% - 18.7%），NCCAH 型：V281L - P30L（33.3% - 28.5%）。在患者和有症状的兄弟姐妹中，按基因型组划分的一致性百分比为：Null（100% - 100%），A（85% - 60%），B（100% - 不适用），C（41.6% - 50%）。28 例无症状兄弟姐妹中有 11 例有致病突变（4 例严重；1 例中度；6 例轻度）。按表型划分的基因型分布为：SW 型：Null - A（88%），SV 型：B - A（50% - 41.6%），NCCAH 型：C（100%）。结论 本研究表明，21 - OHD 患儿及无症状兄弟姐妹中最常见的等位基因为 IN2G - Q381X - R356W - P30L - V281L，除 P30L - V281L 外，可从基因型预测表型。该结果表明与既往报道相比，21 - OHD 最常见的突变相似，但除 C 组显示区域差异外，基因型 - 表型相容性良好，对兄弟姐妹进行基因分型发现了新患者。
