Autosomal-dominant nystagmus, foveal hypoplasia and presenile cataract associated with a novel PAX6 mutation

Abstract

Autosomal-dominant idiopathic infantile nystagmus has been linked to 6p12 (OMIM 164100), 7p11.2 (OMIM 608345) and 13q31-q33 (OMIM 193003). PAX6 (11p13, OMIM 607108) mutations can also cause autosomal-dominant nystagmus, typically in association with aniridia or iris hypoplasia. We studied a large multigenerational white British family with autosomal-dominant nystagmus, normal irides and presenile cataracts. An SNP-based genome-wide analysis revealed a linkage to a 13.4-MB region on chromosome 11p13 with a maximum lod score of 2.93. A mutation analysis of the entire coding region and splice junctions of the PAX6 gene revealed a novel heterozygous missense mutation (c.227C4G) that segregated with the phenotype and is predicted to result in the amino-acid substitution of proline by arginine at codon 76 p.(P76R). The aminoacid variation p.(P76R) within the paired box domain is likely to destabilise the protein due to steric hindrance as a result of the introduction of a polar and larger amino acid. Eye movement recordings showed a significant intrafamilial variability of horizontal, vertical and torsional nystagmus. High-resolution in vivo imaging of the retina using optical coherence tomography (OCT) revealed features of foveal hypoplasia, including rudimentary foveal pit, incursion of inner retinal layers, short photoreceptor outer segments and optic nerve hypoplasia. Thus, this study presents a family that segregates a PAX6 mutation with nystagmus and foveal hypoplasia in the absence of iris abnormalities. Moreover, it is the first study showing detailed characteristics using eye movement recordings of autosomal-dominant nystagmus in a multigenerational family with a novel PAX6 mutation.

The clinical evaluation of infantile nystagmus: what to do first, and why

“…PAX6 disease may present with complete aniridia or with cataract, ellipsoid iris or other mild iris anomalies (33,34). Waardenburg syndrome patients may also have iris transillumination and may possibly have foveal hypoplasia and nystagmus as well; one patient in our foveal dysplasia category has Waardenburg syndrome with an MITF mutation, and foveal hypoplasia.…”

Clinical utility gene card for: Aniridia

“…15 3.2 Predictive Setting: The tested person is clinically unaffected but carries an increased risk based on family history (To be answered if in 1.9 'B' was marked)…”

“…6,7,10,11 Phenotypically subtle PAX6 variants have been documented, [12][13][14] including those that segregate with nystagmus, foveal hypoplasia and autosomal dominant keratitis in the absence of iris abnormalities supporting the concept of gene dosage effects, variable expressivity and gonadal mosaicism. 15 Deep phenotyping studies have revealed smaller corpus callosum area on brain volumetry following magnetic resonance imaging, and subtle hearing difficulties associated with interhemispheric transfer problems. 16 The clinical examination alone in atypical phenotypes would not lead to a PAX6-related molecular diagnosis, highlighting the importance of genetic testing.…”

Congenital aniridia: etiology, manifestations and management

“…Incidence of nystagmus is as high as 90%, where the majority of these eyes show horizontal pendular nystagmus [1, 63]. Vertical nystagmus as a phenotype variant with foveal hypoplasia, presenile cataract and intact irides has been recently described [68]. …”