Semi-dominant mutations in MFN2-related neuropathy and implications for genetic counselling.

MFN2 is a complicated gene diagnostically. It has a large number of variants of uncertain pathogenicity and three described patterns of inheritance including dominant, semi-dominant and recessive which can cause difficulties for genetic counselling. We report a family in which two affected brothers both carried a p.R250Q and p.T362R mutation of MFN2 in trans. Both brothers developed an early onset, sensory motor neuropathy. The father, who is presumed to carry the p.R250Q mutation, died aged 63 and had no symptoms of a neuropathy. The mother who carries the p.T362R mutation has a very mild neuropathy. In both our case and that reported by Piscosquito and colleagues in this journal, these two variants appear to cause a late onset symptomatic axonal neuropathy in the heterozygous state but a more severe, early onset neuropathy in the compound heterozygous state. This raises the question as to whether clinicians should be offering routine diagnostic testing of the MFN2 gene to partners of patients with known mutations in MFN2 wishing to start a family.