Phenotypic and Genotypic Features of a Chinese Cohort with Retinal Hemangioblastoma
Abstract
:1. Introduction
2. Methods
2.1. Study Subjects
2.2. Clinical Evaluation
2.3. VHL Gene Screening
2.4. In Silico Analysis
2.5. Literature Review and Data Combination for Mutation Frequency Calculation
3. Results
3.1. Demographic Features of the RH Cohort (Table 1)
Nbr | Gender | Age | VHL Genotypes | Kindred Phenotypes | Affected Eyes | Systemic Phenotypes | Clinical VHL | |
---|---|---|---|---|---|---|---|---|
CNS | Abdominal Organs | |||||||
P1 | F | 19 | ND | N | RE | N | N | N |
P2 | F | 47 | ND | N | RE | N | N | N |
P3 | M | 35 | ND | N | RE | N | N | N |
P4 | M | 20 | ND | N | RE | N | N | N |
P5 | F | 34 | ND | N | LE | N | N | N |
P6 | M | 40 | ND | N | RE | N | N | N |
P7 | F | 32 | ND | N | LE | N | N | N |
P8 | M | 51 | ND | N | RE | N | N | N |
P9 | F | 22 | ND | N | LE | N | N | N |
P10 | F | 45 | ND | N | RE | N | N | N |
P11 | M | 19 | ND | N | RE | N | N | N |
P12 | M | 21 | ND | N | RE | N | N | N |
P13 | M | 40 | ND | N | LE | N | N | N |
P14 | M | 43 | ND | N | LE | N | N | N |
P15 | F | 36 | ND | N | RE | NA | NA | N |
P16 | F | 8 | ND | Y,C | BE | N | N | Y |
P17 | F | 57 | ND | Y,C | BE | N | N | Y |
P18 | M | 22 | p.Ser65Leu | Y,C | LE | N | N | Y |
P19 | M | 22 | p.Ser65Trp | Y,C | RE | N | Pancreatic cysts | Y |
P20 | M | 13 | p.Ser65Trp | N | RE | N | NA | N |
P21 | M | 51 | p.Glu70Lys | N | BE | N | N | Y |
P22 | F | 11 | p.Asn78IIe | Y,C | BE | N | N | Y |
P23 | F | 40 | p.Asn78Ser | Y,C | RE | N | N | Y |
P24 | F | 28 | p.Arg79Pro | N | BE | Y | N | Y |
P25 | M | 25 | p.Pro86Ser | Y,C,R,K | BE | Y | N | Y |
P26 | M | 14 | p.Leu85Leufs*46 | Y,C | LE | NA | NA | Y |
P27 | F | 25 | p.Pro86Thr | N | RE | NA | NA | N |
P28 | F | 16 | p.Leu89Pro | Y,C,R | BE | N | N | Y |
P29 | F | 9 | p.Gly93Asp | N | BE | N | N | Y |
P30 | F | 13 | p.Tyr98* | Y,C,K | LE | Y | N | Y |
P31 | M | 30 | p.His110fs*49 | Y,C,R | BE | Y | N | Y |
P32 | F | 58 | p.Tyr112Ser | Y,C | RE | Y | Liver, kidney cysts | Y |
P33 | M | 18 | p.Trp117Gly | Y,C,R,K | BE | Y | NA | Y |
P34 | F | 29 | p.Asn131Lys | N | RE | N | NA | N |
P35 | F | 19 | p.Thr157IIe | Y,C,R,K | BE | N | N | Y |
P36 | F | 22 | p.Lys159Glu | Y,C | BE | N | NA | Y |
P37 | F | 23 | p.Arg161* | Y,C,R | BE | Y | Pancreatic cysts | Y |
P38 | M | 22 | p.Arg161* | N | BE | Y | Pancreatic cysts | Y |
P39 | M | 15 | p.Arg167Gln | N | BE | N | N | Y |
P40 | F | 32 | p.Arg167Trp | Y,C,R | BE | N | N | Y |
P41 | F | 13 | p.Arg167Trp | Y,C | BE | Y | N | Y |
P42 | M | 48 | p.Arg167Trp | Y,C,R | BE | N | Pheochromocytoma | Y |
P43 | F | 24 | p.Pro172Argfs*30 | Y,R | BE | Y | N | Y |
P44 | M | 35 | p.176delArg | Y,C | RE | N | N | Y |
P45 | F | 32 | c.463+3 A>G | Y,R | BE | Y | Pheochromocytoma | Y |
P46 | M | 20 | deletion of Exon 1 | Y,C,R,K | BE | Y | Pancreatic cysts | Y |
P47 | M | 38 | deletion of Exon 1 | Y,C,R,P | BE | N | Kidney carcinoma, pancreatic cysts | Y |
P48 | M | 17 | deletion of Exon 2 | Y,C,R | BE | Y | N | Y |
P49 | M | 16 | deletion of Exon 2, 3 | Y,C,R | BE | Y | N | Y |
P50 | M | 24 | deletion of Exon 2, 3 | Y,C,R | BE | Y | N | Y |
P51 | F | 23 | deletion of Exon 2, 3 | NA | RE | NA | NA | NA |
3.2. Genotype
3.3. Ocular Phenotype
3.4. Phenotype–Genotype Analysis
4. Discussion
4.1. Genotypic Features
4.2. Phenotypic Features
5. Limitations
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Variant Type | Location | cDNA Change | Protein Change | Domain | ALIGN GVGD | Polyphen2 | Mutation Taster | ACMG * ^ | In Silico | Cosegregation | Novelty | Nbr of Cases |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Point | Exon 1 | c.194C>G | p.Ser65Trp | β | 176.58 | Probably damaging | Deleterious | PS1 | C65 | AD | 2 | |
Exon 1 | c.194C>T | p.Ser65Leu | β | 144.08 | Possibly damaging | Deleterious | PS1 | C65 | AD | 1 | ||
Exon 1 | c.208G>A | p.Glu70Lys | β | 56.87 | Benign | Deleterious | PS1 | C55 | Sporadic | 1 | ||
Exon 1 | c.233A>G | p.Asn78Ser | β | 46.24 | Probably damaging | Deleterious | PS1 | C45 | AD | 1 | ||
Exon 1 | c.233A>T | p.Asn78IIe | β | 148.91 | Probably damaging | Deleterious | PS1 | C65 | AD | 1 | ||
Exon 1 | c.236G>C | p.Arg79Pro | β | 102.71 | Probably damaging | Deleterious | PS1 | C65 | AD | 1 | ||
Exon 1 | c.256C>A | p.Pro86Thr | β | 37.56 | Probably damaging | Deleterious | PS1 | C35 | Sporadic | 1 | ||
Exon 1 | c.256C>T | p.Pro86Ser | β | 73.35 | Probably damaging | Deleterious | PS1 | C65 | AD | 1 | ||
Exon 1 | c.266T>C | p.Leu89Pro | β | 97.78 | Probably damaging | Deleterious | PS1 | C65 | AD | 1 | ||
Exon 1 | c.278G>A | p.Gly93Asp | β | 93.77 | Probably damaging | Deleterious | PS1 | C65 | Sporadic | 1 | ||
Exon 1 | c.335A>C | p.Tyr112Ser | β | 143.11 | Probably damaging | Deleterious | PM1, PP2, PM2, PM5, PP3, PP5 | C65 | AD | Novel | 1 | |
Exon 1 | c.349T>G | p.Trp117Gly | β | 183.79 | Possibly damaging | Deleterious | PS1 | C65 | AD | 1 | ||
Exon 1 | c.393C>A | p.Asn131Lys | β | 93.88 | Probably damaging | Deleterious | PS1 | C65 | Sporadic | 1 | ||
Exon 3 | c.470C>T | p.Thr157IIe | α | 89.28 | Probably damaging | Deleterious | PS1 | C65 | AD | 1 | ||
Exon 3 | c.475A>G | p.Lys159Glu | α | 56.87 | Probably damaging | Deleterious | PS1 | C55 | AD | 1 | ||
Exon 3 | c.499C>T | p.Arg167Trp | α | 101.29 | Probably damaging | Deleterious | PS1 | C65 | 2 AD, 1 sporadic | 3 | ||
Exon 3 | c.500G>A | p.Arg167Gln | α | 42.81 | Probably damaging | Deleterious | PS1 | C35 | Sporadic | 1 | ||
In-frame deletion | Exon 3 | c.528_530delGAG | p.176delArg | α | - | Deleterious | PM2, PM4, PM1, | - | AD | Novel | 1 | |
Frameshift/Nonsense | Exon 1 | c.254insT | p.Leu85Leufs*46 | β | - | Deleterious | PVS1, PM2, | - | AD | Novel | 1 | |
Exon 1 | c.294C>G | p.Tyr98* | β | - | Deleterious | PS1 | - | AD | 1 | |||
Exon 1 | c.329Adel | p.His110fs*49 | β | - | Deleterious | PVS1, PM2, | - | AD | 1 | |||
Exon 3 | c.481C>T | p.Arg161* | α | - | Probably damaging | Deleterious | PS1 | - | 1 AD, 1 sporadic | 2 | ||
Exon 3 | c.515delCinsGCT | p.Pro172Argfs*30 | α | - | Deleterious | PVS1, PM2, | - | AD | Novel | 1 | ||
Splicing | Intron 2 | c.463+3 A>G | Deleterious | AD | 1 | |||||||
Large deletions | Exon 1 | PVS1 | AD | 2 | ||||||||
Exon 2 | PVS1 | AD | 1 | |||||||||
Exons 2 and 3 | PVS1 | AD | 3 |
Largest RH Diameter | ≤1.5 mm (n = 11) | 1.5–4.5 mm (n = 24) | ≥4.5 mm (n = 18) | Total (n = 53) | p (<0.013 Corrected) | |||||
---|---|---|---|---|---|---|---|---|---|---|
Nbr (Eyes) | Percentage | Nbr (Eyes) | Percentage | Nbr (Eyes) | Percentage | Nbr (Eyes) | Percentage | |||
Retinal Complications (Baseline) | ERD | 0a | 0% | 3a | 12.50% | 14b | 77.78% | 17 | 32.08% | <0.001 |
TRD | 0 | 0% | 4 | 16.67% | 3 | 16.67% | 7 | 13.21% | NS | |
PVR | 0 | 0% | 5 | 20.83% | 4 | 22.22% | 9 | 16.98% | NS | |
RRD | 0 | 0% | 1 | 4.17% | 1 | 5.56% | 2 | 3.77% | NS | |
Macular Complications (Baseline) | Macular involvement | 0a | 0% | 14b | 58.33% | 16b | 88.89% | 30 | 56.60% | <0.001 |
ME | 0 | 0% | 7 | 29.17% | 3 | 16.67% | 10 | 18.87% | NS | |
ERM | 0 | 0% | 2 | 8.33% | 3 | 16.67% | 5 | 9.43% | NS | |
Exudate | 0 | 0% | 5 | 20.83% | 8 | 44.44% | 13 | 24.53% | NS | |
RD in macula | 0 | 0% | 4 | 16.67% | 6 | 33.33% | 10 | 18.87% | NS | |
Invasive Treatment (Follow-Up) | RV without SO | 0 | 0% | 1 | 4.17% | 1 | 5.56% | 2 | 3.77% | NS |
RV SO | 2 | 18% | 3 | 12.50% | 7 | 38.89% | 12 | 22.64% | NS | |
Final Visit Status | SO Removed | 1 | 9% | 1 | 4.17% | 5 | 27.78% | 7 | 13.21% | NS |
Long-term SO tamponade | 1 | 9% | 2 | 8.33% | 2 | 11.11% | 5 | 9.43% | NS | |
NVG/NLP | 0 | 0% | 2 | 8.33% | 3 | 16.67% | 5 | 9.43% | NS |
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Gao, L.; Zhang, F.; Hejtmancik, J.F.; Jiao, X.; Jia, L.; Peng, X.; Ma, K.; Li, Q. Phenotypic and Genotypic Features of a Chinese Cohort with Retinal Hemangioblastoma. Genes 2024, 15, 1192. https://doi.org/10.3390/genes15091192
Gao L, Zhang F, Hejtmancik JF, Jiao X, Jia L, Peng X, Ma K, Li Q. Phenotypic and Genotypic Features of a Chinese Cohort with Retinal Hemangioblastoma. Genes. 2024; 15(9):1192. https://doi.org/10.3390/genes15091192
Chicago/Turabian StyleGao, Liqin, Feng Zhang, J. Fielding Hejtmancik, Xiaodong Jiao, Liyun Jia, Xiaoyan Peng, Kai Ma, and Qian Li. 2024. "Phenotypic and Genotypic Features of a Chinese Cohort with Retinal Hemangioblastoma" Genes 15, no. 9: 1192. https://doi.org/10.3390/genes15091192