Molecular autopsy leading to the diagnosis of TBCK-associated disorder

Brunet, T. (2023). Molecular autopsy leading to the diagnosis of TBCK-associated disorder (Version 1) [DataSet]. GestaltMatcher Database.

We report on a female patient with profound neurodevelopmental disorder who died 30 years ago at the age of three years. Her clinical presentation included severe muscular hypotonia, global developmental delay, feeding difficulties, absent speech, and recurrent respiratory infections. Dysmorphic features such as epicanthus, strabismus, broad nose, short neck, and hyperextensible joints were noted. Despite early suspicion of a syndromic disorder, no diagnosis was made at that time. Decades later, genome sequencing of preserved muscle tissue identified biallelic pathogenic variants in TBCK: a novel frameshift mutation and a recurrent single-exon (exon 23) deletion, which had been missed by previous exome sequencing. This confirmed the diagnosis of TBCK syndrome, an autosomal recessive neurodevelopmental disorder. The case highlights the diagnostic value of molecular autopsy, which can provide a genetic diagnosis postmortem and enable genetic counseling for relatives. Importantly, photographs taken more than 30 years ago proved useful for phenotypic interpretation and supported the retrospective diagnosis.