Genetic heterogeneity and consanguinity lead to a "double hit": homozygous mutations of MYO7A and PDE6B in a patient with retinitis pigmentosa

Abstract

Purpose: Retinitis pigmentosa (RP), the most genetically heterogeneous disorder in humans, actually represents a group of pigmentary retinopathies characterized by night blindness followed by visual-field loss. RP can appear as either syndromic or nonsyndromic. One of the most common forms of syndromic RP is Usher syndrome, characterized by the combination of RP, hearing loss, and vestibular dysfunction.

Methods: The underlying cause of the appearance of syndromic and nonsyndromic RP in three siblings from a consanguineous Israeli Muslim Arab family was studied with whole-genome homozygosity mapping followed by whole exome sequencing.

Results: THE FAMILY WAS FOUND TO SEGREGATE NOVEL MUTATIONS OF TWO DIFFERENT GENES: myosin VIIA (MYO7A), which causes type 1 Usher syndrome, and phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B), which causes nonsyndromic RP. One affected child was homozygous for both mutations. Since the retinal phenotype seen in this patient results from overlapping pathologies, one might expect to find severe retinal degeneration. Indeed, he was diagnosed with RP based on an abnormal electroretinogram (ERG) at a young age (9 months). However, this early diagnosis may be biased, as two of his older siblings had already been diagnosed, leading to increased awareness. At the age of 32 months, he had relatively good vision with normal visual fields. Further testing of visual function and structure at different ages in the three siblings is needed to determine whether the two RP-causing genes mutated in this youngest sibling confer increased disease severity.

Conclusions: This report further supports the genetic heterogeneity of RP, and demonstrates how consanguinity could increase intrafamilial clustering of multiple hereditary diseases. Moreover, this report provides a unique opportunity to study the clinical implications of the coexistence of pathogenic mutations in two RP-causative genes in a human patient.

Figure 1

Pedigree and mutation analysis. A: Shown is a consanguineous Israeli Muslim Arab family segregating autosomal recessive sensorineural hearing loss (SNHL) and retinitis pigmentosa (RP). Double lines indicate a consanguineous union. Filled symbols represent affected individuals, whereas clear symbols represent unaffected individuals. The genotypes of each family member at the myosin VIIA (MYO7A) and the phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B) genes are indicated. m, mutant allele; +, wt allele. B: Nucleotide sequence traces in non-carrier individuals (WT) and in affected individuals (MUT) homozygous for the c.2308delC mutation of MYO7A or the c.1417delC mutation of PDE6B.

Figure 2

Fundus photographs and optical coherence tomography (OCT) of affected individuals from family TB128. A, B: Fundus photographs of individual II:1 at the age of 15 years demonstrate normal optic disc and blood vessels with peripheral temporal degenerative changes and atrophy of the retina. C: Fundus photograph of individual II:3 at the age of 13 years demonstrates waxy pallor of the tilted optic discs with severe attenuation of the retinal blood vessels, and bone spicule-like pigmentation in the entire retinal periphery. D: Fundus photograph of individual II:4 at the age of 32 months demonstrates oval optic disc with temporal peripapillary atrophy, normal color, mild attenuation of retinal blood vessels, and no pigmentary changes in the retina at this stage. E, F: Optical coherence tomography (OCT) of the right and left eyes (RE and LE, respectively) of individual II:1 demonstrates normal retinal thickness. Macular thickness: RE 274 μm, LE 260 μm. Mean optic nerve fiber layer thickness: RE 101 μm, LE 104 μm. G, H: OCT of RE and LE, respectively, of individual II:3 demonstrates normal retinal thickness. Macular thickness: RE 262 μm, LE 246 μm. Mean optic nerve fiber layer thickness: RE 105 μm, LE 97 μm.