title: Genetic heterogeneity and consanguinity lead to a "double hit": homozygous mutations of MYO7A and PDE6B in a patient with retinitis pigmentosa.
abstract: OBJECTIVE
  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.
authors.affiliation: The Krieger Eye Research Laboratory, Felsenstein Medical Research Center, Schneider Children's Medical Center, Beilinson Campus, Petah Tikva, Israel.
authors.forename: Nitza
authors.initials: N
authors.lastname: Goldenberg-Cohen
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.forename: Yael
authors.initials: Y
authors.lastname: Zalzstein
authors.forename: Ben
authors.initials: B
authors.lastname: Cohen
authors.forename: Ygal
authors.initials: Y
authors.lastname: Rotenstreich
authors.forename: Leah
authors.initials: L
authors.lastname: Rizel
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.forename: Tamar
authors.initials: T
authors.lastname: Ben-Yosef
mesh_terms: D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D005654:Fundus Oculi; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics*; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000235:genetics*; D041623:Tomography, Optical Coherence
chemical_list: C000631455:MYO7A protein, human; D000081412:Myosin VIIa; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517431:PDE6B protein, human; D009218:Myosins