Broadening the Phenotypic Spectrum of MAFB-Related Disease: Renal, Auricular, Ocular, and Nervous System Involvement

Focal segmental glomerulosclerosis (FSGS) is a leading cause of renal disease presenting with steroid-resistant nephrotic syndrome (SNRS) and variable stages of chronic kidney disease (CKD). Monogenic etiologies for FSGS are increasingly recognized, particularly in pediatric and familial cases. Missense variants in the MAF BZIP Transcription Factor B (MAFB) gene cause a dominantly inherited condition with variable phenotype, ranging from isolated ocular or renal manifestations to syndromic FSGS.

Detailed clinical and genetic investigations were conducted in an extended family presenting with a spectrum of renal and extra-renal manifestations.

Using Exome Sequencing (ES), a heterozygous variant, c.797T>C; p.(Leu266Pro) in the MAFB gene was identified in multiple affected family members. Variant segregation confirmed its presence in additional family members. The proband exhibited CKD accompanied by congenital auricular anomalies, hearing loss, and neurodevelopmental delay. An affected sibling presented with nephrotic-range proteinuria, Duane retraction syndrome (DRS) and neurodevelopmental involvement, while another family member had an isolated renal phenotype. Several of these features have not been previously associated with MAFB. Tools for structural modeling and stability predictions supported the functional impact of this variant.

Our findings expand the phenotypic spectrum of MAFB-associated disease and further emphasize its variability.