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Personalized genetic counseling for Stargardt disease : offspring risk estimates based on variant severity

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Abstract
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 severe"genotype or a "severe vertical bar mild with complete penetrance"genotype 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.
Keywords
Genetics (clinical), Genetics, CONE-ROD DYSTROPHY, ABCA4 DISEASE, COMPLEX INHERITANCE, MUTATIONS, MILD, FREQUENT, ALLELES, ASSOCIATION, PROGRESSION

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Citation

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MLA
Cornelis, Stephanie, et al. “Personalized Genetic Counseling for Stargardt Disease : Offspring Risk Estimates Based on Variant Severity.” AMERICAN JOURNAL OF HUMAN GENETICS, vol. 109, no. 3, 2022, pp. 498–507, doi:10.1016/j.ajhg.2022.01.008.
APA
Cornelis, S., Runhart, E. H., Bauwens, M., Corradi, Z., De Baere, E., Roosing, S., … Cremers, F. P. M. (2022). Personalized genetic counseling for Stargardt disease : offspring risk estimates based on variant severity. AMERICAN JOURNAL OF HUMAN GENETICS, 109(3), 498–507. https://doi.org/10.1016/j.ajhg.2022.01.008
Chicago author-date
Cornelis, Stephanie, Esmee H. Runhart, Miriam Bauwens, Zelia Corradi, Elfride De Baere, Susanne Roosing, Lonneke Haer-Wigman, Claire-Marie Dhaenens, Anneke T. Vulto-van Silfhout, and Frans P.M. Cremers. 2022. “Personalized Genetic Counseling for Stargardt Disease : Offspring Risk Estimates Based on Variant Severity.” AMERICAN JOURNAL OF HUMAN GENETICS 109 (3): 498–507. https://doi.org/10.1016/j.ajhg.2022.01.008.
Chicago author-date (all authors)
Cornelis, Stephanie, Esmee H. Runhart, Miriam Bauwens, Zelia Corradi, Elfride De Baere, Susanne Roosing, Lonneke Haer-Wigman, Claire-Marie Dhaenens, Anneke T. Vulto-van Silfhout, and Frans P.M. Cremers. 2022. “Personalized Genetic Counseling for Stargardt Disease : Offspring Risk Estimates Based on Variant Severity.” AMERICAN JOURNAL OF HUMAN GENETICS 109 (3): 498–507. doi:10.1016/j.ajhg.2022.01.008.
Vancouver
1.
Cornelis S, Runhart EH, Bauwens M, Corradi Z, De Baere E, Roosing S, et al. Personalized genetic counseling for Stargardt disease : offspring risk estimates based on variant severity. AMERICAN JOURNAL OF HUMAN GENETICS. 2022;109(3):498–507.
IEEE
[1]
S. Cornelis et al., “Personalized genetic counseling for Stargardt disease : offspring risk estimates based on variant severity,” AMERICAN JOURNAL OF HUMAN GENETICS, vol. 109, no. 3, pp. 498–507, 2022.
@article{8743660,
  abstract     = {{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 severe"genotype or a "severe vertical bar mild with complete penetrance"genotype 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.}},
  author       = {{Cornelis, Stephanie and Runhart, Esmee H. and Bauwens, Miriam and Corradi, Zelia and De Baere, Elfride and Roosing, Susanne and Haer-Wigman, Lonneke and Dhaenens, Claire-Marie and Vulto-van Silfhout, Anneke T. and Cremers, Frans P.M.}},
  issn         = {{0002-9297}},
  journal      = {{AMERICAN JOURNAL OF HUMAN GENETICS}},
  keywords     = {{Genetics (clinical),Genetics,CONE-ROD DYSTROPHY,ABCA4 DISEASE,COMPLEX INHERITANCE,MUTATIONS,MILD,FREQUENT,ALLELES,ASSOCIATION,PROGRESSION}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{498--507}},
  title        = {{Personalized genetic counseling for Stargardt disease : offspring risk estimates based on variant severity}},
  url          = {{http://doi.org/10.1016/j.ajhg.2022.01.008}},
  volume       = {{109}},
  year         = {{2022}},
}

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