A Novel De Novo Frameshift Variant of TBL1XR1 Leads to Neurodevelopmental Disorders and Treatment Experience

Neurodevelopmental disorders were a wide range of cognitive and behavioural disorders. Its pathogenic genes, transduction beta like 1 X-linked receptor 1 (TBL1XR1), had been a hot research topic recently. However, reports involving treatment and long-term follow-up were still limited.

Exome sequencing of the family was performed. The clinical data and genetic variants, treatment and long-term follow-up were summarized. Moreover, treatment of published cases was also summarized to systematically understand its treatment strategies.

Genetic screening revealed a de novo variant of TBL1XR1 [NM_024665.7: c.1372_1387dup, p.Asp463Glyfs*6]. The variant was a 16-bp nucleotide duplication in exon 14, caused a conversion of the aspartic amino acids to glycine amino acids at the 463rd and finally generated a stop codon 6 amino acids after the 462nd amino acids. It was classified as a variant of pathogenic (P) according to the ACMG (American College of Medical Genetics and Genomics) guidelines. Valproic acid was administered up to 20 mg/kg/day, which resulted in satisfactory seizure control. Long-term follow-up confirmed the complete disappearance of seizures at 5 and 6 months of age, although hyperactivity, attention deficit and global developmental delay persisted.

Our results expanded the pathogenic variant spectrum and treatment of TBL1XR1-related neurodevelopmental disorders.