A Child with Epidermolytic Ichthyosis from a Parent with Epidermolytic Nevus: Risk Evaluation of Transmission from Mosaic to Germline Michihiro Kono,

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A Child with Epidermolytic Ichthyosis from a Parent with Epidermolytic Nevus: Risk Evaluation of Transmission from Mosaic to Germline Michihiro Kono, Yasushi Suga, Tomohiro Akashi, Yasutomo Ito, Takuya Takeichi, Yoshinao Muro, Masashi Akiyama Journal of Investigative Dermatology Volume 137, Issue 9, Pages 2024-2026 (September 2017) DOI: 10.1016/j.jid.2017.04.036 Copyright © 2017 The Authors Terms and Conditions

Figure 1 Clinical and histopathological features of the skin lesions of epidermolytic ichthyosis (EI) in the proband and epidermolytic nevus (EN) in the father. (a) The proband has diffuse hyperkeratosis with scales and multiple erosions on the whole body. (b) Hyperkeratotic lesions appear on the right upper arm, the right hands, and the right half of the lumbar and groin areas in the proband’s father. The lesions on the trunk seem to follow Blaschko’s lines. (c, d) Close-up photographs of the skin lesion on (c) the right hand and (d) the groin areas in the proband’s father. (e) Histological examination of the scaly lesion on the paraumbilical abdomen of the proband’s father shows thick orthokeratotic hyperkeratosis and granular degeneration in the epidermis. Those features were identical to those seen in his daughter. Hematoxylin and eosin stain. Scale bar = 100 μm. Photographs published with consent. Journal of Investigative Dermatology 2017 137, 2024-2026DOI: (10.1016/j.jid.2017.04.036) Copyright © 2017 The Authors Terms and Conditions

Figure 2 KRT10 mutation detection in the proband and her parents by direct sequencing and mutant allele frequency measurements by NGS. (a) The heterozygous mutation c.446C>T (p.Arg156Cys), which is in the helix initiation region of the 1A domain and is critical for the assembly of keratin filaments, is detected in exon 1 of KRT10 in the gDNA sample from the proband’s peripheral blood. The identical KRT10 mutation p.Arg156Cys is detected in the gDNA sample from the EN lesion of her father as a lower peak on the chromatograph than that of wild-type KRT10 (the mutant allele frequency = ∼14.9% from the ratio of heights of each peak of chromatograph). A peak of the mutant allele is unrecognizable in gDNA samples from the father’s blood and semen. No pathogenic KRT1 mutation was found in the proband and her parents, and no pathogenic KRT10 mutation was found in her mother. (b) The accuracy of mutant allele frequency measurements is confirmed by NGS. Six points of the mutant allele frequencies of standard samples (12.8%, 5.16%, 2.35%, 1.12%, 0.55%, 0.27%) prepared by the mixture of gDNA from the proband and a healthy control sample were measured. Horizontal axis: theoretical values of the mutant allele frequency. Vertical axis: actual values of the mutant allele frequency (%) measured by NGS. The approximation curve is y = 0.8724x – 0.0678, and the determination coefficient is approximately 1. (c) The mutant allele frequency in gDNA samples from the saliva of the proband and from the EN lesion, blood, and sperm of the proband’s father was determined by amplicon sequencing. Approximately 3.9% of the father’s sperm has the causative mutation (mutant allele frequency = 3.9 ± 0.17%), and the mutant allele frequency in his peripheral blood cells is 5.3 ± 0.11%, as obtained by deep sequencing (122,653 reads for the semen and 100,053 reads for the blood cells). The mutant allele frequency in his EN lesion, including the dermis, as determined by deep sequencing (108,441 reads) is 12.0 ± 0.47%. The mutant allele frequency in the proband’s saliva is 49.6 ± 0.47% as determined by deep sequencing (100,825 reads). A, adenine; C, cytosine; EN, epidermolytic nevus; G, guanine; gDNA, genomic DNA; NGS, next-generation sequencing; T, thymine. Journal of Investigative Dermatology 2017 137, 2024-2026DOI: (10.1016/j.jid.2017.04.036) Copyright © 2017 The Authors Terms and Conditions