TY - JOUR
T1 - Clinical intrafamilial variability in lethal familial neonatal seizure disorder caused by TBC1D24 mutations
AU - Lozano, Reymundo
AU - Herman, Kristin
AU - Rothfuss, Melanie
AU - Rieger, Hillary
AU - Bayrak-Toydemir, Pinar
AU - Aprile, Davide
AU - Fruscione, Floriana
AU - Zara, Federico
AU - Fassio, Anna
N1 - Publisher Copyright:
© 2016 Wiley Periodicals, Inc.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
KW - TBC1D24
KW - deafness
KW - lethal seizure disorder
KW - neonatal seizure disorder
KW - non-syndromic deafness
KW - recessive seizures
UR - http://www.scopus.com/inward/record.url?scp=84982237098&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.37933
DO - 10.1002/ajmg.a.37933
M3 - Article
C2 - 27541164
AN - SCOPUS:84982237098
SN - 1552-4825
VL - 170
SP - 3207
EP - 3214
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 12
ER -