Compound heterozygosity for a novel and a recurrent MFRP gene mutation in a family with the nanophthalmos-retinitis pigmentosa complex

PURPOSE To report a new familial case of the recently described autosomal recessive syndrome of nanophthalmos-retinitis pigmentosa-foveoschisis-optic disc drusen, which arises from compound heterozygosity for Membrane Frizzled-Related Protein (MFRP) mutations in a sibling pair of Mexican origin. METHODS Ophthalmological assessment included slit-lamp and dilated fundus examination, applanation tonometry, fundus photography, A-mode and B-mode ultrasound examination, electroretinogram, fluorescein retinal angiography, optical coherence tomography, and electrooculogram in both affected siblings. Molecular genetic analysis consisted of PCR amplification and direct automated sequence of the complete coding region of the MFRP gene. In addition, allele-specific cloning and sequencing techniques were used to characterize a heterozygous MFRP frameshift mutation. RESULTS Clinical examination revealed high hyperopia of > +16 diopters while electroretinographic and fluorangiographic studies demonstrated a retinal dystrophy compatible with retinitis pigmentosa. Ultrasound examination showed nanophthalmos (eye axial length <15 mm) and optic disc drusen while optical coherence tomography evidenced cystoid macular edema. Nucleotide sequencing in DNA from both affected siblings disclosed the presence of two MFRP mutations: a novel heterozygous point mutation predicting a nonsense change from tyrosine (TAC) to a stop signal (TAA) at codon 317, and a heterozygous 1 bp deletion in exon 5, predicting a prematurely truncated protein (p.Asn167ThrfsX25). DISCUSSION The third known family with the syndrome of nanophthalmos-retinitis pigmentosa-foveoschisis-optic disc drusen is presented. This is the first demonstration of compound heterozygosity for MFRP mutations as the source of the disease. The affected siblings described here are the youngest patients with the disease reported to date and the comparison of their clinical data with previous individuals with this syndrome suggest that some aspects of the phenotype are probably age-dependent.