Lin Dan, Lin Na, Zhou Yao, Li Qi, Ma Yanlin
Key Laboratory of Reproductive Health Diseases Research and Translation of Ministry of Education & Key Laboratory of Human Reproductive Medicine and Genetic Research of Hainan Province & Hainan Provincial Clinical Research Center for Thalassemia, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, 571101, Hainan, China.
Hereditas. 2025 Sep 24;162(1):183. doi: 10.1186/s41065-025-00552-y.
To investigate a Chinese family with epidermolysis bullosa palmoplantar keratosis, analyze the mutation loci in this family lineage, and perform preimplantation genetic testing using assisted reproductive technology to enable affected members of this Chinese family to have unaffected offspring.
Clinical information and blood samples were collected from all affected family members to extract genomic DNA. We detected a mutation site in the KRT9 gene through whole-exome sequencing, then verified this family line's Keratin-9 gene variant locus using Sanger sequencing. After the pathogenicity was clarified, blastocyst trophoblast cells were extracted for Preimplantation Genetic Testing for Monogenic (PGT-M)(Single Gene) Disorders using the in vitro fertilization embryo transfer technique, and suitable embryos were selected for transfer. Amniocentesis was performed to extract fetal exfoliated cells for prenatal diagnosis at 18 weeks of fetal development.
A heterozygous mutation c.503T > C (p. Leu168Ser), which results in the substitution of a leucine for a serine (p. Leu168Ser), was detected in the KRT9 gene in the proband and his father, which is located in the highly conserved helix 1 A region of Keratin 9, resulting in an abnormal function of the intermediate filamentous proteins expressed by Keratin 9 encodes genes which are expressed in the palmo-plantar regions of the epidermis, and the patients of the family present with pronounced palmar-plantar keratoderma.
We identified the c.503T > C (p. Leu168Ser) missense mutation in exon 1 of the KRT9 gene as the cause of KRT9-palmoplantar epidermal differentiation disorder (KRT9-pEDD) in a Chinese family. Under the guidance of comprehensive genetic counseling, employing PGT-M, we successfully prevented the transmission of the KRT9-pEDD pathogenic variant, resulting in the birth of a healthy child.
研究一个患有掌跖角化性大疱性表皮松解症的中国家庭，分析该家系中的突变位点，并利用辅助生殖技术进行植入前基因检测，使这个中国家庭的患病成员能够生育未患病的后代。
收集所有患病家庭成员的临床信息和血液样本以提取基因组DNA。通过全外显子组测序检测到KRT9基因中的一个突变位点，然后使用桑格测序法验证该家系的角蛋白9基因变异位点。在明确致病性后，采用体外受精胚胎移植技术提取囊胚滋养层细胞进行单基因疾病植入前基因检测（PGT-M），并选择合适的胚胎进行移植。在胎儿发育18周时进行羊膜穿刺术提取胎儿脱落细胞进行产前诊断。
在先证者及其父亲的KRT9基因中检测到一个杂合突变c.503T＞C（p.Leu168Ser），该突变导致亮氨酸被丝氨酸替代（p.Leu168Ser），位于角蛋白9高度保守的螺旋1A区域，导致角蛋白9编码基因表达的中间丝蛋白功能异常，该基因在表皮的掌跖区域表达，该家系患者表现为明显的掌跖角化病。
我们鉴定出KRT9基因外显子1中的c.503T＞C（p.Leu168Ser）错义突变是一个中国家庭中KRT9-掌跖表皮分化障碍（KRT9-pEDD）的病因。在全面遗传咨询的指导下，采用PGT-M，我们成功阻断了KRT9-pEDD致病变异的传递，生育了一个健康的孩子。
