case_images: PMC11799048_01
case_images: Pedigree of family.
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case_images: The proband, a 24-year-old female, had no history of consanguineous marriages within three generations of her family, and denied any family history of hereditary diseases (Figure 2).
case_images: Ocular examination of proband and family member. (a) II-1 Fundus Examination: No visible peripheral osteocyte-like pigmentation was observed. (b) FAF: An expanded area of hypofluorescence at the macular fovea, surrounded by hyperfluorescent rings on the temporal side. (c) Optical coherence tomography (OCT): Thinning of the outer retina and interrupted continuity of the ellipsoid zone and external limiting membrane, with visible hyperreflective masses in the RPE/Bruch complex zone. (d)Visual field:Central and paracentric scotoma. (e) ERG: Severe decrease in rod and cone response. (f) Anterior Segment Photography: Coral-like opacity noted in the lens. (j, k) In the proband's father (I-1): Autofluorescence revealed an expanded area of hypofluorescence at the macular fovea. OCT indicated thinning of the outer retina and disruption in the ellipsoidal zone at the fovea centralis. No abnormalities in ERG or visual field were detected. (i-p) In the proband's mother (I-2): No ophthalmic abnormalities were detected. (q-u) In the proband's brother (II-2): No ophthalmic abnormalities were detected.
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case_images: Both eyes exhibited transparent corneas, normal-depth anterior chambers, clear-textured irises, round pupils approximately 2.5 mm in diameter, light reflex sensitivity, and coral-like lens opacities (Figure 3f). There were no visible peripheral osteocyte-like pigmentation by fundus examination (Figure 3a). Autofluorescence (FAF) revealed an expanded area of hypofluorescence at the macular fovea, surrounded by hyperfluorescent rings on the temporal side (Figure 3b). OCT demonstrated thinning of the outer retina and disruption in the continuity of the ellipsoid zone and external limiting membrane, with hyperreflective masses evident in the RPE/Bruch complex zone (Figure 3c). The visual field displayed central and paracentric scotoma (Figure 3d), accompanied by a marked reduction in rod and cone response in the ERG (Figure 3e). In the proband's father (I-1), autofluorescence revealed an expanded area of hypofluorescence at the macular fovea; OCT demonstrated thinning of the outer retina and disruption of the ellipsoidal zone in the fovea centralis; no abnormalities were observed in the ERG and visual field (Figure 3j,k). No ophthalmic abnormalities were detected in the proband's mother and younger brother (Figure 3i-u).
case_images: M1 and M2 mutations verification and analysis. (a) Sequence Chromatograms of M1 Mutations: Both the proband and the father carried the M1 variant in the ABHD12 gene (c.477G>A:P.W159*), which was not detected in the mother and younger brother. (b) qPCR Validation Results of the Target Gene Region in the Proband's Family: QPCR was performed on all family members, confirming the presence of the M2 variant (seq[GRCh38] del(20) (p11.21) chr20:G. 25302218_25320318del) in the proband, younger brother, and mother. (c) M1 Nonsense Variant Producing Truncated Protein and Affecting Protein Function. The ABHD12 gene, composed of 398 amino acids, features a three-dimensional structure with 14 alpha-helices, 8 beta-folds, and 18 loop regions. The p.W159* mutation results in the termination of gene translation at tryptophan 159, reducing the protein to 5 alpha-helices, 2 beta-folds, and 8 irregular loops. A: Wild type (purple: beta-fold; blue: alpha-helix; pink: Irregular loop zone); B: Mutant (red: alpha-helix, yellow: beta-fold, green: Irregular loop region); C: Folded structure of the protein, showing a transition to an alpha-helix structure in the wild-type N-terminal loop region post-mutation. This loss of components leads to significant changes in protein function and structure. The blue box highlights a major structural change post-absence. (d) The Homology of Amino Acid Sequences Between Human ABHD12 and Other Species: The amino acid at position 159 is highly conserved among species, and the mutated residue at position 159 is marked with a black arrow.
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case_images: mgg370055-fig-0004
case_images: ABHD12 gene (c.477G > A:p.W159*), not detected in the mother and younger brother, as previously reported (Figure 4a) (Nguyen et al. ). qPCR was conducted on all family members, confirming the presence of the M2 variant (seq[GRCh38] del(20) (p11.21) chr20:g.25302218_25320318del) in the proband, younger brother, and mother. According to Mendel's laws of inheritance, the M1 variant (c.477G > A:p.W159*) originated from the father, while the M2 variant (copy number loss in the region chr20:25302218-25320318) originated from the mother (Figure 4b). M1 nonsense variant c.477G > A(p.Trp159Ter) resulted in the 159th codon changing from encoded tryptophan to terminating codon, this amino acid position exhibits high conservation across various species, thus producing truncated protein and affecting the function of the protein thereby and indicating Pathogenic Very Strong (PVS1) (Figure 4c,d).