PURPOSE: The aim of the present work is the molecular diagnosis of three patients with deafness and retinal degeneration. METHODS: Three patients from two unrelated families were initially analyzed with custom gene panels for Usher genes, non-syndromic hearing loss, or inherited syndromic retinopathies and further investigated by means of clinical or whole exome sequencing. RESULTS: The study allowed us to detect likely pathogenic variants in PEX6, a gene typically involved in peroxisomal biogenesis disorders (PBDs). Beside deaf-blindness, both families showed additional features: Siblings from Family 1 showed enamel alteration and abnormal peroxisome. In addition, the brother had mild neurodevelopmental delay and nephrolithiasis. The case II:1 from Family 2 showed intellectual disability, enamel alteration, and dysmorphism. CONCLUSIONS: We have reported three new cases with pathogenic variants in PEX6 presenting with milder forms of the Zellweger spectrum disorders (ZSD). The three cases showed distinct clinical features. Thus, expanding the phenotypic spectrum of PBDs and ascertaining exome sequencing is an effective strategy for an accurate diagnosis of clinically overlapping and genetically heterogeneous disorders such as deafness-blindness association.

This work was financially supported by grants of the Institute of Health Carlos III (ISCIII /FEDER), (Ref.: PI13/00638 PI16/00415, PI16/00539 and CIBER-ER 06/07/0036; Biobank FJD (RD09/0076/00101),); Fundación ONCE (Ref.: 2015/0398) ONCE & Fundaluce, Sponsored Chair IIS-FJD, UAM of Genomics Medicine. CNAG's 2013 call “300 exomes to elucidate rare diseases.” Institutional Development Fund at CAG from The Children’s Hospital of Philadelphia. CFG, ISN and MCP are recipients of fellowships from the ISCIII (Ref.: IFI14/00021; Sara Borrell CD13–00085 and Miguel Servet CPII17_00006 respectively)