TY - JOUR
T1 - Molecular analysis of low-level mosaicism of the IKBKG mutation using the X Chromosome Inactivation pattern in Incontinentia Pigmenti
AU - Kawai, Miki
AU - Kato, Takema
AU - Tsutsumi, Makiko
AU - Shinkai, Yasuko
AU - Inagaki, Hidehito
AU - Kurahashi, Hiroki
N1 - Funding Information:
The authors thank the patients, their families, and their attending physicians for participating in this study. The authors also thank in particular Dr. M. Miyata, Dr. H. Nishizawa, Dr. R. Suda, Dr. Y. Fukui, H. Dr. Wakita, F. Dr. Tanaka, Dr. T. Inozume, Dr. A. Noguchi, Dr. T. Hukuda, Dr. A. Sugimoto, Dr. K. Yamane, Dr. T. Nishimura, Dr. T. Kusaka, Dr. Y. Kosugi, Dr. M. Matsuo, Dr. H. Arai, Dr. R. Matsunaga, Dr. S. Akashi, Dr. Y. Murai. Dr. T. Nishimura, Dr. T. Kaji, Dr. S. Kato, Dr. A. Yara, and Dr. S. Kanai, Dr. H. Sueoka, T. Fujii, and Dr. Y. Fukuhara. Additionally, the authors also thank Asami Kuno and Narumi Kamiya for technical assistance.
PY - 2020/12
Y1 - 2020/12
N2 - Background: 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. Methods: 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. Results: 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. Conclusion: 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.
AB - Background: 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. Methods: 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. Results: 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. Conclusion: 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.
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U2 - 10.1002/mgg3.1531
DO - 10.1002/mgg3.1531
M3 - Article
AN - SCOPUS:85092895635
VL - 8
JO - Molecular genetics & genomic medicine
JF - Molecular genetics & genomic medicine
SN - 2324-9269
IS - 12
M1 - e1531
ER -