Predicted Protein Structure Variations Indicate the Clinical Presentation of Cyp4v2-Related Bietti Crystalline Dystrophy

Abstract

Supplemental Digital Content is Available in the Text.Through protein structure prediction, more severe impairment of CYP4V2 protein led to a more severe disease course with earlier progression and poorer preservation of central vision. This is the first cohort study of Bietti crystalline dystrophy in Taiwan, and the results could be helpful in identifying a therapeutic window.

Correspondence

“…Although the authors did not mention whether phase determination was conducted in patients with compound heterozygous variants to differentiate between paternal and maternal variant inheritance, 11 we assume that all these cases were in trans compound heterozygous variants. Regarding Figure 4 (Patient 18), 1 we noted that the fundus autofluorescence images differ from previously reported patient cases. 12 The area encompassed by the hyper-AF ring in the macula 1 contrasts previous literature, where lobular hypo-AF patches are typically observed and associated with retinal pigment epithelial atrophy and BCD (Fig.…”

“…Regarding Figure 4 (Patient 18), 1 we noted that the fundus autofluorescence images differ from previously reported patient cases. 12 The area encompassed by the hyper-AF ring in the macula 1 contrasts previous literature, where lobular hypo-AF patches are typically observed and associated with retinal pigment epithelial atrophy and BCD (Fig. 10.3).…”

“…It is not surprising that CYP4V2 truncating variants are deleterious and have higher severity scores as shown in Table 1. 1 As mentioned by the authors, since the c.237G>T and c.367A>G variants were relatively far from the CYP4V2 ligand binding site, the severity scores were 1. 1 In fact, these two variants should be classified as a “variant of unknown significance (VUS)” instead of “likely pathogenic” in Table 1, 1 according to current ACMG classification guidelines.…”

“…1 As mentioned by the authors, since the c.237G>T and c.367A>G variants were relatively far from the CYP4V2 ligand binding site, the severity scores were 1. 1 In fact, these two variants should be classified as a “variant of unknown significance (VUS)” instead of “likely pathogenic” in Table 1, 1 according to current ACMG classification guidelines. 4 In ClinVar, both variants (Variation IDs: 39,259 and 39,264) were submitted from several groups as benign or VUS except one by GeneReviews as pathogenic, which cited an article by Li et al, 5 which listed a case with these two variants in Table 2.…”

“…In summary, the authors have presented a unique set of CYP4V2 disease-causing variants. Because of limited information in this study and evidence from past literature, both the c.237G>T and c.367A>G variants should be classified as a “variant of unknown significance (VUS)” instead of “likely pathogenic” in Table 1, 1 according to current ACMG classification guidelines. We hope our perspectives are helpful and aid in advancing their investigation.…”