In:
European Journal of Human Genetics, Springer Science and Business Media LLC, Vol. 30, No. 1 ( 2022-01), p. 101-110
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 in trans 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.
Type of Medium:
Online Resource
ISSN:
1018-4813
,
1476-5438
DOI:
10.1038/s41431-021-00982-y
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2022
detail.hit.zdb_id:
2005160-8
SSG:
12
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