RMND1 mutations are associated with autosomal recessive syndromic nephropathy

Aim: To investigate the genetic aetiology of deafness, lactic acidosis (LA) and nephropathy in Australian patients.
Background: RMND1 is an integral inner membrane mitochondrial protein. Mutations in RMND1 cause an autosomal recessive mitochondrial oxidative phosphorylation deficiency disorder recently phenotypically expanded to encompass syndromic nephropathy.
Methods: Two Australian patients with global developmental delay (GDD),deafness, LA and nephropathy underwent whole exomic sequencing (WES).
Results: Patient 1 presented in the neonatal period with seizures and sensorineural hearing loss (SNHL) having been born at 24 weeks gestation. The child had tubulopathy with polyuria, hyponatraemia, hyperkalaemia, metabolic acidosis (LA), positive sweat test (negative CFTR analysis) and progressive renal impairment. Renal ultrasound showed normal sized echogenic kidneys. Renal biopsy demonstrated chronic tubulointerstitial nephritis and nephronophthisis. WES identified compound heterozygous RMND1 mutations (c.[713A>G][829_830del];p.[ Asn238Ser][ Glu277Glyfs*20]). At 4years, GDD continues to improve, bilateral cochlear implants have been successful and renal impairment continues to progress (eGFR 33 ml/min/1.73 m2). Patient 2 was born at term by normal delivery and had unremarkable neonatal course except for bilateral SNHL. At 5 months of age, he was noted to have generalised hypotonia, poor weight gain, GDD, LA and 3-methylglutaconic aciduria in the context of a viral illness. A homozygous RMND1 mutation (c.[1349G>C];p.[*450Serext*32]) was identified by WES (Melbourne Genomics Health Alliance). Subsequent screening for renal disease showed hyperkalemia and renal hypodysplasia. At 18months, he is globally delayed and hypotonic.
Conclusions: These cases reinforce the relationship between RMND1 mutations and autosomal recessive nephropathy associated with SNHL and LA, whilst demonstrating the utility of WES in diagnosis. Tubulointersitital changes on renal biopsy suggest a potential relationship with other forms of ciliopathy. This and how oxidative phosphorylation deficiencies mediate renal disease require further investigation.