Refining the phenotypic spectrum of PNKP-related microcephaly: a study of 27 new patients
Ghada M H Abdel-Salam1, Mohamed S Abdel-Hamid2, Sherif F Abdel-Ghafar2
1Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt ghada.abdelsalam@gmail.com.
Background:
Biallelic pathogenic variants in PNKP are associated with microcephaly and early-onset seizures (MCSZ), ataxia with oculomotor apraxia type 4 and Charcot-Marie-Tooth disease type 2B2.
Methods:
We describe the clinical and neuroimaging features of 27 new patients with PNKP variants. All patients presented with early-onset seizures, congenital microcephaly and intellectual disability. In addition, we compared our results with data in the literature.
Results:
Twenty-five patients presented with the classic MCSZ phenotype, while two showed a more severe clinical phenotype. The brain imaging features of the 25 patients varied significantly, but widening of the frontal lobe gyri with frontal hypoplasia and prominent cerebellar folia (consistent with atrophy) could point to PNKP-related microcephaly . In contrast, the two patients with severe phenotype showed additional brain MRI features of white matter loss and pontocerebellar hypoplasia fulfilling the criteria of microlissencephaly. Exome sequencing identified seven different PNKP variants, including two novel ones. The c.1253_1269dup p.(Thr424GlyfsTer49) and c.1381_1383dup p.(Asn461dup) variants, each was recurrent in 10 patients (37%), while the c.1381_1383del p.(Asn461del) variant was recurrent in four patients (14.8%). Haplotype analysis confirmed that the p.Asn461dup variant has a founder effect in our population. No genotype-phenotype correlation was observed in our cohort.
Conclusion:
Our results provide 'microlissencephaly' as an emerging distinct phenotype linked to PNKP variants. As such, PNKP variants could be associated with four overlapping subgroups that lie along a unifying phenotypic continuum.
Insights
Pathogenic variants in PNKP gene cause microcephaly with early-onset seizures (MCSZ) and intellectual disability. A distinct microlissencephaly phenotype is now recognized, expanding the spectrum of PNKP-related disorders.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Biallelic pathogenic variants in the PNKP gene are linked to microcephaly with early-onset seizures (MCSZ), ataxia with oculomotor apraxia type 4, and Charcot-Marie-Tooth disease type 2B2.
- PNKP is crucial for DNA repair, and its dysfunction can lead to neurodevelopmental disorders.
Purpose of the Study:
- To describe the clinical and neuroimaging characteristics of 27 new patients with PNKP variants.
- To compare these findings with existing literature and define the phenotypic spectrum of PNKP-related disorders.
Main Methods:
- Clinical assessment and neuroimaging (brain MRI) of 27 patients with PNKP variants.
- Exome sequencing to identify PNKP variants.
- Haplotype analysis to investigate founder effects.
- Comparison with previously reported cases.
Main Results:
- All 27 patients presented with early-onset seizures, congenital microcephaly, and intellectual disability.
- Twenty-five patients exhibited the classic MCSZ phenotype; two displayed a more severe phenotype with microlissencephaly, white matter loss, and pontocerebellar hypoplasia.
- Seven different PNKP variants were identified, including two novel ones, with specific recurrent variants noted (c.1253_1269dup and c.1381_1383dup).
- No genotype-phenotype correlation was observed within this cohort.
Conclusions:
- Microlissencephaly emerges as a distinct phenotype associated with PNKP variants.
- PNKP variants are associated with a phenotypic continuum encompassing four overlapping subgroups, including MCSZ and microlissencephaly.
