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Seizure. 2019 Mar;66:81-85. doi: 10.1016/j.seizure.2018.12.021. Epub 2018 Dec 23.

Compound heterozygous SZT2 mutations in two siblings with early-onset epilepsy, intellectual disability and macrocephaly.

Author information

1
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy. Electronic address: francisco.domingues@eurac.edu.
2
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy; Department of Biosciences, University of Salzburg, Salzburg, Austria.
3
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy.
4
Department of Biosciences, University of Salzburg, Salzburg, Austria.
5
NGS Core Facility, Life & Brain Center, University of Bonn, Bonn, Germany.
6
Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
7
Genetic Counseling Service, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy.
8
Child Neurology and Neurorehabilitation Unit, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy.
9
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy; Department of Neurology, University of Lübeck, Lübeck, Germany.

Abstract

PURPOSE:

Mutations in SZT2 have been previously reported in several cases of early onset epilepsy and intellectual disability. In this study we investigate potential causal mutations in two male siblings affected by early onset epilepsy, intellectual disability and macrocephaly.

METHODS:

We use family-based whole-exome sequencing to identify candidate variants.

RESULTS:

We report the identification of two potential causal SZT2 mutations in compound heterozygous state. We observe considerable differences in the clinical phenotype severity of the two affected individuals. The cerebral MRI revealed no abnormalities in the older affected brother, while in the youngest one it revealed a right frontal polymicrogiria. Moreover, while good seizure control was achieved in the older affected individual the younger brother is affected by pharmacoresistant epilepsy, progressive spastic paraplegia, cortical myoclonus and a more severe intellectual disability. We also analyzed the relative location of the reported pathogenic mutations in the SZT2 protein.

CONCLUSION:

Variable phenotypic expressivity is observed for this condition, while the location and type of mutations in SZT2 also has a potential impact on epilepsy severity. These findings extend our knowledge of epileptogenic conditions related to SZT2 and mTOR signaling.

KEYWORDS:

Epileptic and developmental encephalopathies; Intellectual disability; SZT2; Whole exome sequencing; mTORopathies

PMID:
30818181
DOI:
10.1016/j.seizure.2018.12.021
[Indexed for MEDLINE]
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