VP.09 Clinical characteristics and gene analysis of 10 rare cases with coexistence of double genetic diseases

Abstract

Coexistence of double genetic diseases in one patient is quite rare. In this study, we aimed to analyse the clinical and genetic characteristics of patients with double genetic diseases. Clinical and genetical data of patients with double genetic diseases from January 2021 to February 2022 in Peking University First Hospital were collected and analyzed. Among these 10 children, 7 were boys and 3 were girls, with last follow-up ages ranging from 2.0 to 7.9 years old. Cases 1-5, all boys, showed myopathic gait, poor running and jumping, and significantly increased serum creatine kinase level, as well as pathogenic variations in DMD gene, and were diagnosed as DMD/BMD. However, all of them had other symptoms and signs that were inconsistent with DMD/BMD. Further trio-based whole exome sequencing was performed. The 5 patients also had a second genetic disease, including hypertrophic osteoarthropathy, spinal muscular atrophy, fragile X syndrome, Phelmn-McDerimid syndrome and intracranial cavernous hemangioma. The remaining five cases had complicated clinical manifestations, or disease development that could not be explained by the first diagnosed disease. Type IX collagen gene related disease, and neurofibromatosis type 1 were identified in case 6. Collagen VI-related myopathy with and osteogenesis imperfecta type XV was identified in case 7. Turner syndrome with chromosome karyotype of 45,X, and Segawa syndrome were identified in case 8. Chromosome 22q11.2 microduplication syndrome with a 2.64Mb microduplication, and autosomal dominant lower extremity-predominant spinal muscular atrophy-1 caused by <i>DYNC1H1</i> gene mutation were confirmed in case 9. KBG syndrome due to <i>ANKRD11</i> gene mutation, and neurodevelopmental disorder with regression, abnormal movement, language loss and epilepsy caused by <i>IRF2BPL</i> gene mutation were identified in case 10. We found between the two pathogenic genes, either or both of them were <i>de novo</i> mutations. The clinical manifestations of patients with double genetic diseases were complex and diverse. Whole exome sequencing of the core pedigree combining with a variety of molecular genetic tests would be helpful for accurate diagnosis, genetic counseling and individualized management. This study provides important information and basis for the diagnosis of patients with coexistence of double genetic diseases.