Molecular Screening of 43 Brazilian Families Diagnosed with Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy

Abstract

Leber congenital amaurosis (LCA) is a severe disease that leads to complete blindness in children, typically before the first year of life. Due to the clinical and genetic heterogeneity among LCA and other retinal diseases, providing patients with a molecular diagnosis is essential to assigning an accurate clinical diagnosis. Using our gene panel that targets 300 genes that are known to cause retinal disease, including 24 genes reported to cause LCA, we sequenced 43 unrelated probands with Brazilian ancestry. We identified 42 unique variants and were able to assign a molecular diagnosis to 30/43 (70%) Brazilian patients. Among these, 30 patients were initially diagnosed with LCA or a form of early-onset retinal dystrophy, 17 patients harbored mutations in LCA-associated genes, while 13 patients had mutations in genes that were reported to cause other diseases involving the retina.

Molecular Diagnosis of 34 Japanese Families with Leber Congenital Amaurosis Using Targeted Next Generation Sequencing

“…those for which potentially pathogenic variant(s) were not detected using the TS approach) were analysed via additional mutation screening (as described in the Methods section). None of the patients in these families carried the c.2991 + 1655A > G intronic variant in CEP290 that is frequently identified in European, Australian, and Brazilian families with LCA 5 , 7 , 8 . Neither were any of the analysed patients shown to harbour rare variants in five recently discovered LCA-associated genes ( CCT2 , CLUAP1 , DTHD1 , GDF6 , and IFT140 ) 20 – 24 , nor in exon 15 of RPGR , which is an alternative exon called ORF15 that contains highly repetitive purine-rich sequences (Supp.…”

Special Issue Introduction: Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations, and Inheritance Models

“…The remaining nine manuscripts deal with genotype–phenotype correlations. They range from very large genotyping studies (e.g., the Target5000 study by Dockery et al [ 87 ]) to targeted genotyping studies in pericentral RP (Comander et al [ 88 ]) and early-onset RP and LCA families (Di Iorio et al [ 89 ] and Porto et al [ 90 ]). Brandl et al [ 91 ] studied two genes encoding homologous proteins (IMPG1 and IMPG2) that are mutated in vitelliform macular dystrophies.…”

Pathogenicity Reclassification of RPE65 Missense Variants Related to Leber Congenital Amaurosis and Early-Onset Retinal Dystrophy

“…Two studies have already reported these variants, but they did not confirm or discuss the pathogenicity of c.247T>C (p.Phe83Leu) or c.560G>A (p.Gly187Glu) [22,46]; moreover, these two reported cases are Brazilian and are included in this study (family B and E probands). Based on current knowledge of these two RPE65 variants, no strong evidence has been identified, as there are no previously reported mutations which, regardless of nucleotide change, result in p.Phe83Leu or p.Gly187Glu, and no functional studies showing that these variants cause deleterious effects.…”

“…Both variants in this study have already been associated with rare recessive retinal dystrophies, each of which was identified in only one homozygous patient [22,46]. Therefore, the criterion regarding the identification of evaluated variants in trans with known pathogenic mutations was not met (ACMG/AMP pathogenic moderate level of evidence).…”

“…Two other moderate criteria that evaluate the position where the new missense mutation occurs were also not included: (i) outside of these two variants already reported [22,46], no other damaging missense variant in the amino acid residue Phe83 or Gly187 has been reported before and, (ii) the protein region where both variants occur is neither a mutational hot spot nor a well-established functional domain.…”