Clinical and molecular genetic characterisation of a family segregating autosomal dominant retinitis pigmentosa and sensorineural deafness

Abstract

Aims/background: To characterise clinically a large kindred segregating retinitis pigmentosa and sensorineural hearing impairment in an autosomal dominant pattern and perform genetic linkage studies in this family. Extensive linkage analysis in this family had previously excluded the majority of loci shown to be involved in the aetiologies of RP, some other forms of inherited retinal degeneration, and inherited deafness.

Methods: Members of the family were subjected to detailed ophthalmic and audiological assessment. In addition, some family members underwent skeletal muscle biopsy, electromyography, and electrocardiography. Linkage analysis using anonymous microsatellite markers was performed on DNA samples from all living members of the pedigree.

Results: Patients in this kindred have a retinopathy typical of retinitis pigmentosa in addition to a hearing impairment. Those members of the pedigree examined demonstrated a subclinical myopathy, as evidence by abnormal skeletal muscle histology, electromyography, and electrocardiography. LOD scores of Zmax = 3.75 (theta = 0.10), Zmax = 3.41 (theta = 0.10), and Zmax = 3.25 (theta = 0.15) respectively were obtained with the markers D9S118, D9S121, and ASS, located on chromosome 9q34-qter, suggesting that the causative gene in this family may lie on the long arm (q) of chromosome 9.

Conclusions: These data indicate that the gene responsible for the phenotype in this kindred is located on chromosome 9 q. These data, together with evidence that a murine deafness gene is located in a syntenic area of the mouse genome, should direct the research community to consider this area as a candidate region for retinopathy and/or deafness genes.

Figure 1

Family TCD ZMK 92. All living individuals were used in molecular genetic analysis.

Figure 2

Rod isolated responses recorded from the dark adapted eye in response to single flashes of −3. 5 log unit intensity.

Figure 3

Cone isolated responses recorded from the light adapted eye in response to single flashes of maximal intensity.

Figure 4

Dark adaptation profiles to red and blue targets. The normal means and standard deviations were calculated from 23 normal individuals.

Figure 5

Pure tone audiometry.

Figure 6

Mid to far retinal periphery of patient IV11, aged 24 years, showing retinal pigment epithelial mottling and pigmentary disturbance.

Figure 7

Photograph of the posterior pole of patient V2, aged 16 years, showing marked optic disc pallor, extreme vascular attenuation, retinal pigment epithelial thinning, and mid peripheral pigmentary deposits.

Figure 8

Electrocardiogram tracings from patient V6, aged 13 years, showing inferoseptal and inferolateral ST depression and right axis deviation. The ECG lead order is: top row: I, AVR, VI, V4; middle row: II, AVL, V2, V5; and bottom row: III, AVF, V3, V6.

Figure 9

(A) Electron micrograph of a muscle biopsy from patient IV7 showing excessive numbers of mitochondria under the sarcolemmal membrane. (B) Electron micrograph of a muscle biopsy from a normal individual. In both (A) and (B) the sarcolemmal membrane is indicated by the black arrow, the mitochondria by the white arrow. Magnification × 1925 in each case.