Mutations in the CRB1 Gene Cause Leber Congenital Amaurosis

Abstract

To test the hypothesis that mutations in the CRB1 gene cause Leber congenital amaurosis (LCA) and, if so, to describe the ocular phenotype of patients with LCA who harbor CRB1 sequence variations. Patients: One hundred ninety probands with a clinical diagnosis of LCA were selected from a cohort of 233 probands ascertained in 5 different countries. The remaining 43 probands (18%) were excluded because they harbored sequence variations in previously identified LCA genes. Methods: One hundred ninety unrelated individuals with LCA were screened for coding sequence mutations in the CRB1 gene with single-strand conformation polymorphism analysis followed by automated DNA sequencing. Results: Twenty-one of the 190 probands (9% of the total cohort of 233) and 2 (1.4%) of 140 controls harbored amino acid-altering sequence variations in the CRB1 gene (P=.003). Conclusions: In our cohort of patients with LCA, coding sequence variations were observed in the CRB1 gene more frequently than in any of the other 5 known LCAassociated genes. Likely disease-causing sequence variations have now been identified in 64 (28%) of 233 subjects in this cohort. Clinical Relevance: Molecular diagnosis can confirm and clarify the diagnosis in an increasing fraction of patients with LCA. As genotype data accumulate, clinical phenotypes associated with specific mutations may be established. This will facilitate the counseling of patients regarding their visual prognosis and the likelihood of associated systemic anomalies.

Unraveling the genetic cause of hereditary ophthalmic disorders in Arab societies from Israel and the Palestinian Authority

“…Disease-associated variants in CRB1 imply that the affected subjects in our families most likely suffer from severe retinitis pigmentosa (RP12; ref. [22]) or Leber congenital amaurosis [23], which is well compatible with the symptomology described by the families. However, a definite diagnosis would require a detailed clinical workup by an ophthalmologist in these cases.…”

Unraveling the genetic cause of hereditary ophthalmic disorders in Arab societies from Israel and the Palestinian Authority

“…Disease-associated variants in CRB1 imply that the affected subjects in our families most likely suffer from severe retinitis pigmentosa (RP12; ref. [22]) or Leber congenital amaurosis [23], which is well compatible with the symptomology described by the families. However, a definite diagnosis would require a detailed clinical workup by an ophthalmologist in these cases.…”

Systematic assessment of the contribution of structural variants to inherited retinal diseases

“…Both were diagnosed with LCA. Loss-of-function pathogenic variants in CRB1 are known to cause AR Leber congenital amaurosis 8 (45), which is consistent with the phenotype of our patient. The patient carries a heterozygous c.3392_3879-492 deletion, which removes part of exon 9 and the entire exon 10 of CRB1 and results in a frameshift that was predicted to lead to NMD (Fig.…”

Study of the involvement of the RGR, CRPB1, and CRB1 genes in the pathogenesis of autosomal recessive retinitis pigmentosa

“…The most common change, located 12 bp upstream from the start of exon 2, has been previously reported to be identically distributed among the alleles of LCA probands and controls. 26 Similar results were obtained in our Spanish population. Analysis of the three new variants indicates that they represent polymorphisms in the human population, suggesting no particular relationship to retinal degeneration.…”

Unraveling the genetic cause of hereditary ophthalmic disorders in Arab societies from Israel and the Palestinian Authority

“…Disease-associated variants in CRB1 imply that the affected subjects in our families most likely suffer from severe retinitis pigmentosa (RP12; ref. [22]) or Leber congenital amaurosis [23], which is well compatible with the symptomology described by the families. However, a definite diagnosis would require a detailed clinical workup by an ophthalmologist in these cases.…”

Systematic assessment of the contribution of structural variants to inherited retinal diseases

“…Both were diagnosed with LCA. Loss-of-function pathogenic variants in CRB1 are known to cause AR Leber congenital amaurosis 8 (45), which is consistent with the phenotype of our patient. The patient carries a heterozygous c.3392_3879-492 deletion, which removes part of exon 9 and the entire exon 10 of CRB1 and results in a frameshift that was predicted to lead to NMD (Fig.…”

Study of the involvement of the RGR, CRPB1, and CRB1 genes in the pathogenesis of autosomal recessive retinitis pigmentosa

“…The most common change, located 12 bp upstream from the start of exon 2, has been previously reported to be identically distributed among the alleles of LCA probands and controls. 26 Similar results were obtained in our Spanish population. Analysis of the three new variants indicates that they represent polymorphisms in the human population, suggesting no particular relationship to retinal degeneration.…”

Unraveling the genetic cause of hereditary ophthalmic disorders in Arab societies from Israel and the Palestinian Authority

“…Disease-associated variants in CRB1 imply that the affected subjects in our families most likely suffer from severe retinitis pigmentosa (RP12; ref. [22]) or Leber congenital amaurosis [23], which is well compatible with the symptomology described by the families. However, a definite diagnosis would require a detailed clinical workup by an ophthalmologist in these cases.…”

Systematic assessment of the contribution of structural variants to inherited retinal diseases

“…Both were diagnosed with LCA. Loss-of-function pathogenic variants in CRB1 are known to cause AR Leber congenital amaurosis 8 (45), which is consistent with the phenotype of our patient. The patient carries a heterozygous c.3392_3879-492 deletion, which removes part of exon 9 and the entire exon 10 of CRB1 and results in a frameshift that was predicted to lead to NMD (Fig.…”

Study of the involvement of the RGR, CRPB1, and CRB1 genes in the pathogenesis of autosomal recessive retinitis pigmentosa

“…The most common change, located 12 bp upstream from the start of exon 2, has been previously reported to be identically distributed among the alleles of LCA probands and controls. 26 Similar results were obtained in our Spanish population. Analysis of the three new variants indicates that they represent polymorphisms in the human population, suggesting no particular relationship to retinal degeneration.…”