A KRT6A mutation p.Ile462Asn in a Chinese family with pachyonychia congenita, and identification of maternal mosaicism: a case report.

BACKGROUND: Pachyonychia congenita (PC, OMIM #167200, #167210, #615726, #615728, and #615735) is a rare autosomal dominant disorder caused by keratin gene mutations in KRT6A,KRT6B,KRT6C,KRT16 or KRT17. It is characterized with nail dystrophy and palmoplantar keratoderma (PPK). The most prominent manifestation is plantar pain. This is a further unusual case of parental mosaicism in PC. Although very rare, germ cell mosaicism should be considered when providing genetic counselling for unaffected parents of a child with PC. CASE PRESENTATION: We report the case of a 5-year-old boy with thickening nails and oral leukokeratosis at birth. He began to develop palmoplantar keratoderma at 2 years old and his sister has similar clinical manifestation characterized with nail discoloration and thickening. A previously reported heterozygous mutation, p.Ile462Asn, was identified in KRT6A in the proband and his affected sister. SNaPshot sequencing revealed mosaicism at a level of 2.5% and 4.7% in DNA from blood and hair bulbs from the unaffected mother. HiSeq deep sequencing demonstrated low-grade mosaicism in the patient's younger sister and parents. CONCLUSION: These findings indicate the ability of WES and SNaPshot sequencing to detect low-frequency mosaic mutations. Although very rare, germinal mosaicism should be considered when genetic counseling is given to families with presumed spontaneous cases of PC.

Novel desmoplakin mutations in a child with Carvajal syndrome / 中华皮肤科杂志

Objective:To detect genetic mutations in a child with woolly hair and keratotic skin lesions on the knees, palms and soles but without cardiac symptoms.Methods:Clinical data were collected from the patient and her parents, and DNA was extracted from peripheral blood of the patient, her parents and 100 unrelated healthy controls. A next-generation skin-targeted sequencing panel was used to detect gene mutations, and Sanger sequencing was performed for verification.Results:The 3-year-old female patient had presented with curly hair since birth, palmoplantar keratoderma with knee involvement since the age of 8 months. Phenotypes of the patient′s parents were normal. Sequencing revealed a frameshift mutation c.5152dupT (p.L1718Ffs*15) in exon 23 and a nonsense mutation c.C6478T (p.R2160X) in exon 24 of the desmoplakin (DSP) gene in the patient. The frameshift mutation c.5152dupT was also identified in her mother, but no mutation was found in exon 24 of the DSP gene in her mother. No mutation was found in the patient′s father or the 100 healthy controls. The patient was diagnosed with Carvajal syndrome.Conclusion:Compound heterozygous mutations in the DSP gene were identified in the patient with Carvajal syndrome, including c.5152dupT (p.L1718Ffs*15) and c.C6478T (p.R2160X) mutations, which may contribute to the occurrence of Carvajal syndrome.