1 - Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, School of Biological Sciences, University of Manchester, Manchester, UK.
2 - Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.
3 - Medical Genetics Department, Hospital de Dona Estefânia, Centro Hospitalar Lisboa Central, Lisbon, Portugal.
4 - Division of Cellular and Molecular Function, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Letter to the editor.
Clin Genet. 2018 Aug;94(2):276-277. doi: 10.1111/cge.13255. Epub 2018 Apr 19. PMID: 29671881 DOI: 10.1111/cge.13255
Resumo:
Introduction: Perrault syndrome is a rare autosomal recessive condition characterized by sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency (POI) in 46, XX females. Additional phenotypes, especially progressive neurological features affect some individuals. Six genes have been identified as causative for Perrault syndrome: HSD17B4, HARS2, LARS2, CLPP, C10orf2 and ERAL1, the latter 5 of which function in mitochondrial translation.
Case Report: We present a case with clinical features of Perrault syndrome, in addition to renal dysfunction and short stature, associated with a known pathogenic variant, RMND1 c.713A>G p.(Asn238-Ser). The proband is from a non-consanguineous Portuguese family. SNHL was noted at 7 years of age and was moderate to severe at 16 years of age. At 10 years of age short stature, growth hormone deficiency and POI were observed. She also had distal renal tubular acidosis, renal dysfunction has not been previously associated with Perrault syndrome. Whole exome sequencing was performed on the proband, no putative pathogenic variants were identified in known Perrault syndrome genes. We classified the homozygous known pathogenic variant, RMND1 c.713A>G p.(Asn238Ser) (NM_017909) as the likely cause of the phenotype in the proband. The variant segregated with the phenotype.
Discussion: RMND1 has been proposed to tether the mitoribosome to the mitochondrial inner matrix. Variants in RMND1 are associated with a wide phenotypic range including SNHL, hypotonia, developmental delay, lactic academia and renal dysfunction. The variant RMND1 c.713A>G has been observed as homozygous in 2 unrelated families. In both families SNHL, developmental delay, hypotonia and peripheral spasticity were observed, one patient had renal dysfunction. All 3 affected individuals are prepubertal, including 1 affected female. POI has not been previously associated with variants in RMND1 but in most reported cases patients have been of pre-pubertal age so POI may not have yet become apparent.
Conclusion: We suggest that patients with Perrault syndrome are screened for variants in RMND1 alongside the known Perrault syndrome genes. Renal phenotypes in women with Perrault syndrome features may indicate the causative variant is in RMND1. We also suggest that POI may be an unrecognized feature of RMND1-related mitochondrial dysfunction and female patients should be monitored for POI.
Palavras Chave: Perrault syndrome, Primary Ovarian Insufficiency RMND1, Sensorineural hearing loss, Mitochondrial dysfunction