Rare compound heterozygous variants in PNKP identified by whole exome sequencing in a German patient with ataxia-oculomotor apraxia 4 and pilocytic astrocytoma
Ataxia-oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive neurologic disorder. The phenotype is characterized by ataxia, oculomotor apraxia, peripheral neuropathy and dystonia. AOA4 is caused by biallelic pathogenic variants in the PNKP gene encoding a polynucleotide kinase 3′-phosphatas...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article (Journal) Editorial |
| Language: | English |
| Published: |
2 March 2018
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| In: |
Clinical genetics
Year: 2018, Volume: 94, Issue: 1, Pages: 185-186 |
| ISSN: | 1399-0004 |
| DOI: | 10.1111/cge.13216 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1111/cge.13216 Verlag, lizenzpflichtig, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1111/cge.13216 
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| Author Notes: | C. Scholz, M.M. Golas, R.G. Weber, C. Hartmann, U. Lehmann, F. Sahm, G. Schmidt, B. Auber, M. Sturm, B. Schlegelberger, T. Illig, D. Steinemann, W. Hofmann |
| Summary: | Ataxia-oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive neurologic disorder. The phenotype is characterized by ataxia, oculomotor apraxia, peripheral neuropathy and dystonia. AOA4 is caused by biallelic pathogenic variants in the PNKP gene encoding a polynucleotide kinase 3′-phosphatase with an important function in DNA-damage repair. By whole exome sequencing, we identified 2 variants within the PNKP gene in a 27-year-old German woman with a clinical AOA phenotype combined with a cerebellar pilocytic astrocytoma diagnosed at 23 years of age. One variant, a duplication in exon 14 resulting in the frameshift c.1253_1269dup p.(Thr424fs*49), has previously been described as pathogenic, for example, in cases of AOA4. The second variant, representing a nonsense mutation in exon 17, c.1545C>G p.(Tyr515*), has not yet been described and is predicted to cause a loss of the 7 C-terminal amino acids. This is the first description of AOA4 in a patient with central European descent. Furthermore, the occurrence of a pilocytic astrocytoma has not been described before in an AOA4 patient. Our data demonstrate compound heterozygous PNKP germline variants in a German patient with AOA4 and provide evidence for a possible link with tumor predisposition. Localization of the 2 variants in human PNKP NP_009185.2. NM_007254.3:c.1253_1269dup p.(Thr424fs*49) is predicted to cause a frameshift within the kinase domain, NM_007254.3:c.1545C>G p.(Tyr515*) is predicted to cause loss of 2 C-terminal amino acids of the kinase domain and 5 additional C-terminal amino acids. |
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| Item Description: | Gesehen am 22.04.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1399-0004 |
| DOI: | 10.1111/cge.13216 |