Joubert syndrome–related disorders (JSRDs) are a group of clinically and genetically pleiotropic conditions that share a midbrain-hindbrain malformation, the pathognomonic molar tooth sign (MTS) visible on brain imaging, with variable involvement of other organs and systems mainly the eyes and the kidneys. Nevertheless, the definition of JSRDs remained problematical due to the extreme phenotypic heterogeneity, often with intrafamilial variability, and the significant clinical overlap among distinct forms. Here we describe two siblings with nephronophthisis (NPHP), the elder is best categorized as JSRD. Nevertheless, his younger sibling lacked the characteristic molar tooth sign; hence best categorized as NPHP- related ciliopathy. Both siblings had NPHP as the common renal phenotype, yet with variable neurological and ocular involvement. Genetic linkage and mutation analysis revealed a novel homozygous, potential loss of function mutation (c.2618dupA, pH is 873Glnfs*14) in the gene NPHP4 in both siblings. This finding extends the phenotypic spectrum associated with NPHP4 mutations, with discernible clinical heterogeneity and intrafamilial variability.
Citation: Nabhan MM, Brenzinger S, Carlsson J, Saleem SN, Otto EA, Hildebrandt F, et al. (2015) Intrafamilial Variability and Clinical Heterogeneity in Two Siblings with NPHP4 loss of Function Mutations. J Mol Biomark Diagn 6:217.