CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders

Abstract

Joubert syndrome-related disorders (JSRDs) are a group of clinically and genetically heterogeneous conditions that share a midbrain-hindbrain malformation, the molar tooth sign (MTS) visible on brain imaging, with variable neurological, ocular, and renal manifestations. Mutations in the CEP290 gene were recently identified in families with the MTS-related neurological features, many of which showed oculo-renal involvement typical of Senior-Loken syndrome (JSRD-SLS phenotype). Here, we performed comprehensive CEP290-mutation analysis on two nonoverlapping cohorts of JSRD-affected patients with a proven MTS. We identified mutations in 19 of 44 patients with JSRD-SLS. The second cohort consisted of 84 patients representing the spectrum of other JSRD subtypes, with mutations identified in only two patients. The data suggest that CEP290 mutations are frequently encountered and are largely specific to the JSRD-SLS subtype. One patient with mutation displayed complete situs inversus, confirming the clinical and genetic overlap between JSRDs and other ciliopathies.

Figure 1.

Schematic of distribution of mutations identified in this study across the 54 exons of CEP290. Numbers of patients with mutations are listed in parentheses.

Figure 2.

Brain magnetic resonance imaging results for 12 of 21 probands with mutations, showing the typical midbrain-hindbrain malformation known as the MTS. All panels display axial sections at the pontine or pontomesencephalic junction showing the MTS. A–L, respectively, patients MTI012, MTI286, COR002a, COR083, COR145, COR109, COR084, COR125, MTI333b, MTI154, MTI125, and MTI487.

Figure 3.

Patient MTI273, homozygous for the S1595fsX1599 mutation in exon 36 of the CEP290 gene and presenting with JSRD-SLS associated with complete situs inversus. Sagittal (A) and axial (B) brain magnetic resonance imaging sections show the MTS malformation. C, Face showing absence of specific dysmorphic features. D, Kidney ultrasound displaying multiple renal cysts and increased echogenicity. E, Chest x-ray showing complete situs inversus, with stomach bubble and heart apex on the patient's right side (R).