Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan.
Department of Clinical Genetics, Fujita Health University Hospital, Toyoake, Japan.
Mol Genet Genomic Med. 2020 Dec;8(12):e1531. doi: 10.1002/mgg3.1531. Epub 2020 Oct 21.
Incontinentia pigmenti (IP) is a rare X-linked disorder affecting the skin and other ectodermal tissues that is caused by mutation of the IKBKG/NEMO gene. Previous studies have reported that the overall mutation detection rate in IP is ~75%. We hypothesized that a low-level mosaicism existed in the remaining cases.
Genomic variations in the IKBKG gene were examined in 30 IP probands and their family members. Standard mutational analyses were performed to detect common deletions, nucleotide alterations, and copy number variations. To assess skewing of the X chromosome inactivation (XCI) pattern, a HUMARA assay was performed. We compared the results of this analysis with phenotype severity.
Pathogenic variants were identified in 20 probands (66.7%), the rate of detection was suboptimal. The remaining 10 probands tended to manifest a mild phenotype with no skewed X chromosome inactivation that is generally observed in IP patients. Quantitative nested PCR and digital droplet PCR were performed for the 10 patients and mosaicism of the common IKBKG deletion were identified in five patients.
Overall, we detected 25 IKBKG mutations (83.3%). Determination of the XCI value in advance of mutational analyses for IP could improve the mutation detection rate. Our improved detection rate for these mutations, particularly those with a low-level mosaicism, may present opportunities for appropriate genetic counseling.
色素失禁症（IP）是一种罕见的 X 连锁疾病，影响皮肤和其他外胚层组织，由 IKBKG/NEMO 基因突变引起。先前的研究报告称，IP 的总体突变检测率约为 75%。我们假设在其余病例中存在低水平嵌合体。
对 30 名 IP 先证者及其家庭成员的 IKBKG 基因进行基因组变异检测。进行标准突变分析以检测常见缺失、核苷酸改变和拷贝数变异。为评估 X 染色体失活（XCI）模式的偏斜，进行 HUMARA 测定。我们将该分析的结果与表型严重程度进行比较。
在 20 名先证者（66.7%）中鉴定出致病性变异，检测率不理想。其余 10 名先证者表现出轻度表型，没有 IP 患者通常观察到的 X 染色体失活偏斜。对 10 名患者进行了定量嵌套 PCR 和数字液滴 PCR，在 5 名患者中鉴定出常见 IKBKG 缺失的嵌合体。
总体而言，我们检测到 25 个 IKBKG 突变（83.3%）。在进行 IP 的突变分析之前确定 XCI 值可以提高突变检测率。我们对这些突变的检测率提高，特别是那些低水平嵌合体的检测率提高，可能为适当的遗传咨询提供机会。
