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

Bitarafan, Fatemeh; Khodaeian, Mehrnoosh; Almadani, Navid; Kalhor, Alireza; Sardehaei, Elham Amjadi; Garshasbi, Masoud

doi:10.1080/15513815.2019.1686784

Cited by 2 publications

(3 citation statements)

References 10 publications

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“…Smaller introns are associated with a higher likelihood of intron retention (35), a mechanism we proved for two novel variants here. RNA analyses of disease-associated PNKP variants were previously not reported, despite many intronic and splice sites affecting changes described (6,26,28,29,(36)(37)(38)(39)(40)(41)(42)(43). The results of our RNA splicing analyses for one novel silent variant, one known splice donor variant and moreover one variant annotated as missense point toward a likely underappreciated pathomechanism.…”

Section: Discussionmentioning

confidence: 62%

Prenatal phenotype of PNKP-related primary microcephaly associated with variants in the FHA and Phosphatase domain

Neuser

Krey

Schwan³

et al. 2021

Preprint

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Biallelic PNKP variants cause heterogeneous disorders ranging from neurodevelopmental disorder with microcephaly/seizures to adult-onset Charcot-Marie-Tooth disease. To date, only postnatal descriptions exist. We present the first prenatal diagnosis of PNKP-related primary microcephaly. Detailed pathological examination of a male fetus revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities in a sibling fetus. Prenatal trio exome sequencing identified compound-heterozygosity for the PNKP variants c.498G>A, p.[(=),0?] and c.302C>T, p.(Pro101Leu). Segregation confirmed both variants in the sibling fetus. Through RNA analyses, we characterized skipping of exon 4 affecting the PNKP Forkhead-associated (FHA) and Phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the c.498G>A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic PNKP-variants to compare prenatal/postnatal phenotypes. Both carry the same splice-donor variant c.1029+2T>C in trans with a variant in the FHA domain (c.311T>C, p.(Leu104Pro) and c.151G>C, p.(Val51Leu), respectively). RNA-seq showed complex splicing events for c.1029+2T>C and c.151G>C. Computational modelling and structural analysis revealed significant clustering of missense variants in the FHA domain, with some variants potentially generating structural damage. Our detailed clinical description extends the PNKP-continuum to the prenatal stage. Investigating possible PNKP-variant effects using RNA and structural modelling, we highlight the mutational complexity and exemplify a framework for variant characterization in this multi-domain protein.

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Section: Discussionmentioning

confidence: 62%

Prenatal phenotype of PNKP-related primary microcephaly associated with variants in the FHA and Phosphatase domain

Neuser

Krey

Schwan³

et al. 2021

Preprint

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“…14 As previously mentioned, PNKP is a modular protein with three domains: an amino-terminal FHA domain, a DNA phosphatase domain, and a DNA kinase domain. 16 These three domains have been affected by different mutations in the MCSZ (►Figs. 4 and 5).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the phosphatase or FHA domain have not been found in patients with AOA4. 14,16,17 The severity of the phenotype may be better linked to the type of mutations. Shen et al found that a splicing mutation is associated with more moderate symptoms and suggested a single common homozygous region on chromosome 19q in exon 14 (1250_1266dup c.526 C > T) for four of his five families, which is also repeated in the family described by Poulton et al 5,10 Other regions for MCSZ have also been described, affecting exons 11 (five and our case) and 15.…”

Section: Discussionmentioning

confidence: 99%

A Novel c.968C > T homozygous Mutation in the Polynucleotide Kinase 3′ − Phosphatase Gene Related to the Syndrome of Microcephaly, Seizures, and Developmental Delay

Vázquez¹,

Romero²,

Gutiérrez³

et al. 2020

J Pediatr Genet

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Microcephaly is defined by a head circumference that is at least two standard deviations below the mean for age and sex of the general population in a specific race. Primary microcephaly may occur as an isolated inborn error, which may damage to the central nervous system or as part of the congenital abnormalities associated with genetic syndrome, affecting multiple organ systems. One of the syndromic forms consists of microcephaly, seizures, and developmental delay caused by biallelic mutations in the gene that encode polynucleotide kinase 3′ − phosphatase protein (PNKP). We report here a newborn male who presented with microcephaly, severe developmental delay, and early-onset refractories seizures, caused by a novel homozygous mutation of the PNKP gene.

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

Cited by 2 publications

References 10 publications

Prenatal phenotype of PNKP-related primary microcephaly associated with variants in the FHA and Phosphatase domain

Prenatal phenotype of PNKP-related primary microcephaly associated with variants in the FHA and Phosphatase domain

A Novel c.968C > T homozygous Mutation in the Polynucleotide Kinase 3′ − Phosphatase Gene Related to the Syndrome of Microcephaly, Seizures, and Developmental Delay

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