Abstract
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. Pathological examination of a male fetus in the 18th gestational week revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities. 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 sister fetus. Through RNA analyses, we characterized exon 4 skipping affecting the PNKP forkhead-associated (FHA) and phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the paternal c.498G>A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic PNKP-variants to compare prenatal/postnatal phenotypes. Both carry the splice donor variant c.1029+2T>C intrans with a variant in the FHA domain (c.311T>C, p.(Leu104Pro); c.151G>C, p.(Val51Leu)). RNA-seq showed complex splicing for c.1029+2T>C and c.151G>C. Structural modeling revealed significant clustering of missense variants in the FHA domain with variants generating structural damage. Our clinical description extends the PNKP-continuum to the prenatal stage. Investigating possible PNKP-variant effects using RNA and structural modeling, we highlight the mutational complexity and exemplify a PNKP-variant characterization framework.
Highlights
Microcephaly, or rather micrencephaly in the narrow sense, is defined as an occipitofrontal circumference (OFC) below –2 SD of the mean for age and sex and can occur in isolated form or in a syndromic context [1]. It is classified as primary microcephaly (PM) in contrast to secondary microcephaly developing after birth
Before our report, polynucleotide kinase 3’-phosphatase (PNKP) was already associated with a wide phenotypic spectrum, which could be related to its multidomain architecture
The FHA domain recruits PNKP to DNA damage sites [25], where it is involved in repair of both single- and doublestrand breaks through its enzymatically active kinase and phosphatase domains [26, 27]
Summary
Or rather micrencephaly (abnormally small brain) in the narrow sense, is defined as an occipitofrontal circumference (OFC) below –2 SD of the mean for (gestational) age and sex and can occur in isolated form or in a syndromic context [1]. If detected prenatally, it is classified as primary microcephaly (PM) in contrast to secondary microcephaly developing after birth. Three additional neurological and neurodevelopmental diseases have been associated with PNKP variants.
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