RRP12 loss-of-function phenotype was explored through Western blot and immunocytofluorescence studies on patient-derived fibroblasts and in a knockdown zebrafish model.<h4>Results</h4>A combined approach of exome sequencing and homozygosity mapping allowed the prioritization of a rare homozygous variant in RRP12 (c.1558C>T, p.R520C) in two apparently unrelated Pakistani patients from consanguineous families, presenting with infantile-onset generalized dystonia, spasticity, and widespread brain calcifications. Here, RRP12 is linked to generalized dystonia.