关键词: 结节性硬化症, TSC2基因, 镶嵌变异, 低比例变异, 产前诊断, 皮肤表现

Abstract: 【Abstract】    Objective    To analyze the clinical characteristics of and gene mutation in a patient with tuberous sclerosis complex （TSC） caused by somatic mosaicism in the TSC2 gene, and to provide guidance for prenatal diagnosis. Methods    In August 2022, peripheral blood samples were collected from a patient with clinically suspected TSC and his parents at the Institute of Medical Genetics, Henan Provincial People's Hospital, and DNA was extracted. Whole exome sequencing, whole genome high resolution optical mapping, and full length TSC1/TSC2 gene sequencing were sequentially performed to identify the genetic variant, and the proportion of the mosaic variant in the patient′s somatic cells was calculated based on the frequencies of the wild type and variant alleles in high depth sequencing. Sanger sequencing was performed to validate the variant in peripheral blood DNA from the patient and his parents, as well as in DNA from the patient′s normal skin tissues and lesional skin tissues. DNA was extracted from the peripheral blood and amniotic fluid of the patient′s spouse, and the target variant in the TSC2 gene was detected by PCR and Sanger sequencing. Results    The 26-year-old male patient presented with hypopigmented macules on the back for 26 years, facial angiofibromas for 22 years, and periungual fibromas on the toes for 10 years. His parents and spouse were healthy with no similar symptoms. Full-length TSC1/TSC2 gene sequencing revealed a heterozygous mutation c.774+1G>A in the TSC2 gene in the patient, with a mosaic proportion of approximately 8.86%. This variant was absent in the peripheral blood DNA of the patient′s parents, but existed in DNA from the patient′s normal skin tissues and lesional skin tissues （facial angiofibromas and periungual fibromas）, with Sanger sequencing chromatograms showing a minor mutant peak. The variant was not detected in peripheral blood DNA from the patient′s spouse or in DNA from amniotic fluid. The infant had been followed up for over one year since birth, with no abnormalities in growth, development, skin, or nervous system. Conclusions    The somatic mosaic mutation c.774+1G>A in the TSC2 gene was the cause of the TSC phenotype in this patient. Identification of the pathogenic variant can effectively guide prenatal diagnosis and promote healthy birth and fetal development. 

Key words: Tuberous sclerosis complex, TSC2 gene, Mosaic mutation, Low proportional mutation, Prenatal diagnosis, Skin manifestations