Our in vivo and in vitro functional studies establish POLRMT as a candidate disease gene that should be considered in the genetic diagnostic workup of patients that present with global developmental delay, speech/intellectual disabilities, hypotonia, short stature, PEO and multiple OXPHOS defects, and suggest that defects in the human mitochondrial transcription machinery may be more prevalent than previously thought. The gene discussed is POLRMT; the disease is Intellectual disability.