FBXO11 Variants are Associated with Intellectual Disability and Variable Clinical Manifestation in Chinese Patients

Abstract

F-box protein 11 (FBXO11) is a member of F-Box protein family, which has recently been proved to be associated with intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA, OMIM: 618089). In this study, 12 intellectual disability patients from 5 Chinese ID families were collected, and whole exome sequencing (WES), sanger sequencing, and RNA sequencing (RNA-seq) were conducted. Almost all the patients presented with mild to severe intellectual disability (12/12), global developmental delay (10/12), speech and language development delay (8/12) associated with a range of alternate features including increased body weight (7/12), short stature (6/12), seizures (3/12), reduced visual acuity (4/12), hypotonia (1/12), and auditory hallucinations and hallucinations (1/12). Distinguishingly, malformation was not observed in all the patients. WES analysis showed 5 novel FBXO11 variants, which include an inframe deletion variant, a missense variant, two frameshift variants, and a partial deletion of FBXO11 (exon 22-23). RNA-seq indicated that exon 22-23 deletion of FBXO11 results in a new mRNA structure. Conservation and protein structure prediction demonstrated deleterious effect of these variants. The DEGs analysis revealed 488 differentially expressed genes shared among 6 patients, which were associate with genes of immune system, metabolism, protein binding, cytosol, and nucleoplasm. Among them, 272 genes were down-regulated and 216 were up-regulated. Our research is the first report of FBXO11-associated IDDFBA in Chinese patients, which expands the genetic and clinical spectrum of this newly identified NDD/ID syndrome and advances understanding of molecular pathogenesis of FBXO11.