Compound Heterozygous Mutations in PNKP Gene in an Iranian Child with Microcephaly, Seizures, and Developmental Delay
Fatemeh Bitarafan1, Mehrnoosh Khodaeian2, Navid Almadani3
1Department of Cellular and Molecular Biology, North Tehran Branch, Islamic Azad University, Tehran, Iran.
Insights
Genetic testing identified two mutations in the polynucleotide kinase 3'phosphatase (PNKP) gene in a child with severe neurological symptoms. These findings expand the known spectrum of PNKP-related disorders.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Pathogenic variants in the polynucleotide kinase 3'phosphatase (PNKP) gene are linked to microcephaly, seizures, developmental delay (MCSZ), and ataxia-oculomotor apraxia type 4 (AOA4).
- These genetic defects lead to unrepaired DNA lesions, impacting neurological function.
Observation:
- Whole exome sequencing was performed on a pediatric patient presenting with microcephaly, seizures, developmental delay, intellectual disability, speech disorder, hyperactivity, and ataxic gait.
- MRI revealed callosal dysgenesis in the patient.
Findings:
- Two heterozygous mutations in the PNKP gene were identified: a novel intronic frameshift variant (c.1298+33_1299-24del) and a previously reported duplication (c.1253_1269dup; p.Thr424Glyfs*49).
- Both identified mutations are located in the DNA kinase domain of the PNKP protein, suggesting a functional impact.
Implications:
- This study contributes to understanding the clinical heterogeneity of PNKP-related disorders.
- The findings underscore the diagnostic challenges associated with these conditions and emphasize the critical role of genetic testing in identifying the underlying causes.
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.
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