PNKP was first reported in relation to autosomal recessive Microcephaly, seizures, and developmental delay in 2010 (Shen et al., 2010). At least 34 variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data.
Variants in this gene have been reported in at least 11 unrelated probands with Microcephaly, seizures, and developmental delay in 4 publications (20118933, 23224214, 29243230, 25728773). Variants in this gene segregated with disease in 7 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached.
The mechanism for disease is homozygous loss of function (Shen et al., 2010) Of note, this gene has also been implicated in autosomal recessive Ataxia-oculomotor apraxia. In particular c.1253_1269dup17 is associated with both conditions. This condition will be assessed separately.
This gene-disease association is supported by in vitro functional assays (McKinnon and Caldecott, 2007; Mani et al, 2010; Reynolds et al, 2010).
In summary, PNKP is definitively associated with autosomal recessive Microcephaly, seizures, and developmental delay. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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