Compound Heterozygous Mutations in PNKP Gene in an Iranian Child with Microcephaly, Seizures, and Developmental Delay

Abstract

Background

Pathogenic variants within polynucleotide kinase 3′phosphatase (PNKP) gene cause microcephaly, seizures, and developmental delay (MCSZ) and ataxia-oculomotor apraxia type 4 (AOA4) disorders due to unrepaired DNA lesions.

Methods

Whole exome sequencing was performed on a child with microcephaly, seizures, developmental delay, callosal dysgenesis on MRI, intellectual disability, speech disorder, hyperactivity, and ataxic gait.

Results

Two heterozygous mutations in the PKNP gene, a novel intronic frameshift variant c.1298 + 33_1299-24del and a previously reported duplication, c.1253_1269dup; p.Thr424Glyfs*49 in exon 14 were identified. Both of these mutations affect the DNA kinase domain of PKNP.

Conclusions

Our finding along with previous studies provide more evidence of the clinical heterogeneity of diseases caused by mutations in PNKP which makes its clinical diagnosis difficult and highlights the importance of genetic testing to unravel the cause of these diseases.

KEYWORDS:

• microcephaly
• seizures
• developmental delay
• intellectual disability
• ataxic gait

Acknowledgments

Authors would like to thank the patient’s family for collaboration in this research.

Conflict of interest

The authors declare that they have no competing interests.

Funding

None to declare.