We wish to collaborate on three key areas of investigation:
1) Identification of additional NUBPL Complex I deficiency patients to further characterize the genotypic and phenotypic spectrum. Due to the relatively high frequency of the c.815-27T>C variant (~1% of European ancestry subjects) and the lack of some WES/WGS analysis pipelines to adequately assess splicing variants (other than splice donor and acceptor variants), we think NUBPL Complex I deficiency is likely underdiagnosed.
2) Identification of NUBPL c.815-27T>C homozygotes and assessment of their phenotypes. Due to the ~1% frequency of c.815-27T>C in European ancestry subjects, homozygous individuals have been reported in publicly available databases. For example, gnomAD v. 2.1 (https://gnomad.broadinstitute.org) reports ten c.815-27T>C homozygotes with European ancestry (7 Finnish and 3 non-Finnish). If affected, we suspect these individuals have milder and/or later onset of symptoms (see #3 below).
3) Is there a family history of late-onset movement disorders (e.g., Parkinson’s disease and essential tremor) in parents, grandparents, etc. of NUBPL Complex I deficiency patients? We have reported on one case of Parkinson’s disease (Eis et al. (2020)) in which the patient carries the Calvo et al. (2010) chromosomal rearrangement. We hypothe that carriers of one NUBPL mutation may have an increased risk of movement disorders (analogous to the increased risk of Parkinson’s disease in family members of Gaucher disease patients).
NUBPL