期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 109, 期 3, 页码 498-507出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2022.01.008
关键词
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资金
- Foundation Fighting Blindness USA [PPA-0517-0717-RAD, BR-GE-0120-0775-LUMC]
- RetinaUK [GR591]
- Fighting Blindness Ireland [FB18CRE]
- Stichting Blindenhulp
- Stichting voor Ooglijders
- Stichting tot Verbetering van het Lot der Blinden
- ProRetina, Germany
- Groupement de Cooperation Sanitaire Interregional G4 qui reunit les Centres Hospital-iers Universitaires Amiens, Caen, Lille et Rouen (GCS G4)
- Fondation Stargardt France
- European Union's Horizon 2020 research and innovation program Marie Sklodowska-Curie Innovative Training Networks (ITN) StarT [813490]
- European Union [739534-ERN-EYE]
- Ghent University [BOF20/GOA/023]
- FWO [G0A9718N]
- Foundation JED
- Foundation John W. Mouton Pro Retina
- Foundation Fighting Blindness USA
- [EJPRD19-234]
In this study, personalized recurrence risk calculations were established for patients with Stargardt disease (STGD1) based on the analysis of ABCA4 gene variants. The risk estimates provide valuable information for accurate risk assessment and personalized counseling for individuals affected by STGD1.
Recurrence risk calculations in autosomal recessive diseases are complicated when the effect of genetic variants and their population frequencies and penetrances are unknown. An example of this is Stargardt disease (STGD1), a frequent recessive retinal disease caused by bi-allelic pathogenic variants in ABCA4. In this cross-sectional study, 1,619 ABCA4 variants from 5,579 individuals with STGD1 were collected and categorized by (1) severity based on statistical comparisons of their frequencies in STGD1-affected individuals versus the general population, (2) their observed versus expected homozygous occurrence in STGD1-affected individuals, (3) their occurrence in combination with established mild alleles in STGD1-affected individuals, and (4) previous functional and clinical studies. We used the sum allele frequencies of these severity categories to estimate recurrence risks for offspring of STGD1-affected individuals and carriers of pathogenic ABCA4 variants. The risk for offspring of an STGD1-affected individual with the severe vertical bar severegenotype or a severe vertical bar mild with complete penetrancegenotype to develop STGD1 at some moment in life was estimated at 2.8%-3.1% (1 in 36-32 individuals) and 1.6%-1.8% (1 in 62-57 individuals), respectively. The risk to develop STGD1 in childhood was estimated to be 2-to 4-fold lower: 0.68%-0.79% (1 in 148-126) and 0.34%-0.39% (1 in 296-252), respectively. In conclusion, we established personalized recurrence risk calculations for STGD1-affected individuals with different combinations of variants. We thus propose an expanded genotype-based personalized counseling to appreciate the variable recurrence risks for STGD1-affected individuals. This represents a conceptual breakthrough because risk calculations for STGD1 may be exemplary for many other inherited diseases.
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