Prenatal to preimplantation genetic diagnosis of a novel compound heterozygous mutation in HSPA9 associated with Even-Plus syndrome.

BACKGROUND: Heat shock protein family A member 9 (HSPA9) prevents unfolded and dysfunctional protein accumulation, with genetic variants known to be pathogenic. Here, we determined the genetic cause of Even-Plus syndrome (OMIM: 616854) in a Chinese family. METHODS: We collected samples from two affected and two normal individuals. Whole-exome sequencing was performed to identify their genetic profiles. Potential variants were validated using Sanger sequencing. Assisted reproduction with mutation-free embryos successfully blocked the transmission of mutations. RESULTS: We identified novel inherited pathogenic complex heterozygous variations in the HSPA9 gene in the two affected fetuses. Three-dimensional spatial simulation of the HSPA9 protein after prediction of the mutated RNA splicing pattern abolished part of the substrate-binding domain of the protein. According to ACMG guidelines, c. 1822-1G>A and c. 1411-3T>G were classified as pathogenic and likely pathogenic, respectively. Mutation-free embryos were selected for transplantation and reconfirmed to possess no mutations. A healthy daughter was successfully born into the family. CONCLUSIONS: This study is the first to report complex heterozygous variations in the HSPA9 gene that influence alternative splicing in early pregnancy. Our findings expand on the mutational spectrum leading to Even-Plus syndrome and provide a basis for genetic counseling and future embryonic studies.

De Novo Mutation in KRT1 Leads to Epidermolytic Palmoplantar Keratoderma: from Chinese Traditional Treatment to Prenatal Diagnosis Using Whole-Exome Sequencing-Plus.

Congenital skin disorders are a class of complex genetic diseases that are difficult to diagnose and treat. We developed trio whole-exome sequencing-plus (WES-plus) for detecting de novo mutations and evaluated the use of traditional Chinese medicine (TCM) for treating congenital skin disorders. In this study, we successively performed panel-based next-generation sequencing (NGS) and Trio WES-plus in a child with frequent large blisters. Panel-based NGS revealed no pathogenic mutations. Trio WES-plus for resequencing based on cutaneous keratosis of the palms and feet detected a missense mutation (c.1436T>A, p.Ile479Asn) in the coding region of KRT1 in the child but not in his parents. Following prenatal diagnosis, a healthy second baby without the mutation was born. The disease symptoms of epidermolytic palmoplantar keratoderma (EPPK) application were improved by TCM and Western medicine. Our study revealed the pathogenicity of a de novo mutation in human KRT1, which expands the mutation spectrum of EPPK. Trio WES-plus is useful for diagnosing genetic diseases and providing genetic guidance from prenatal diagnosis to treatment.