Clinical intrafamilial variability in lethal familial neonatal seizure disorder caused by TBC1D24 mutations

Reymundo Lozano, Kristin Herman, Melanie Rothfuss, Hillary Rieger, Pinar Bayrak-Toydemir, Davide Aprile, Floriana Fruscione, Federico Zara, Anna Fassio

Research output: Contribution to journalArticlepeer-review


TBC1D24-related disorders include a wide phenotypic ranging from mild to lethal seizure disorders, non-syndromic deafness, and composite syndromes such as DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures). The TBC1D24 gene has a role in cerebral cortex development and in presynaptic neurotransmission. Here, we present a familial case of a lethal early-onset epileptic encephalopathy, associated with two novel compound heterozygous missense variants on the TBC1D24 gene, which were detected by exome sequencing. The detailed clinical data of the three siblings is summarized in order to support the variability of the phenotype, severity, and progression of this disorder among these family members. Functional studies demonstrated that the identified novel missense mutations result in a loss of expression of the protein, suggesting a correlation between residual expression, and the disease severity. This indicates that protein expression analysis is important for interpreting genetic results when novel variants are found, as well as for complementing clinical assessment by predicting the functional impact. Further analysis is necessary to delineate the clinical presentation of individuals with TBC1D24 pathogenic variants, as well as to develop markers for diagnosis, prognosis, and potential targeted treatments.

Original languageEnglish
JournalAmerican Journal of Medical Genetics, Part A
Publication statusAccepted/In press - 2016


  • Deafness
  • Lethal seizure disorder
  • Neonatal seizure disorder
  • Non-syndromic deafness
  • Recessive seizures
  • TBC1D24

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


Dive into the research topics of 'Clinical intrafamilial variability in lethal familial neonatal seizure disorder caused by TBC1D24 mutations'. Together they form a unique fingerprint.

Cite this