We used whole exome sequencing (WES) to identify the molecular basis of an early-onset mitochondrial syndrome—pathogenic biallelic variants in the HTRA2 gene, encoding a mitochondria-localised serine protease—in five subjects from two unrelated families characterised by seizures, neutropenia, hypotonia and cardio-respiratory problems. Here, HTRA2 is linked to Decreased total neutrophil count.