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A case of early‐onset epileptic encephalopathy with a homozygous TBC1D24 variant caused by uniparental isodisomy
Author(s) -
Nakashima Mitsuko,
Negishi Yutaka,
Hori Ikumi,
Hattori Ayako,
Saitoh Shinji,
Saitsu Hirotomo
Publication year - 2019
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61056
Subject(s) - exome sequencing , compound heterozygosity , genetics , loss of heterozygosity , exome , biology , medicine , allele , mutation , gene
TBC1D24 ‐related disorders are rare neurodevelopmental disorders that show a broad range of neuropsychiatric deficits and are mostly inherited in an autosomal recessive manner. Here we describe a case with early‐onset epileptic encephalopathy, in whom exome sequencing detected a novel pathogenic homozygous c.442G>A, p.(Glu148Lys) variant in TBC1D24 . She showed severe developmental delay, congenital sensorineural hearing loss and seizures, but the combination of a high dose phenobarbital and potassium bromide was very effective for the seizures. Sanger sequencing revealed that her mother was a heterozygous carrier of the TBC1D24 variant, but her father showed only wild‐type alleles. Homozygosity mapping analysis using exome data showed loss of the heterozygosity region at 16p13.3–p13.13 encompassing TBC1D24 . Genotyping analysis using rare variants within loss of the heterozygosity region indicated that the patient has a homozygous haplotype inherited from her mother, indicating maternal segmental uniparental isodisomy (UPiD). These data clearly show that exome sequencing is a powerful tool to perform comprehensive genetic analysis.