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

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|severe" genotype or a "severe|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: STGD1, recurrence risk, ABCA4, genotype-phenotype correlation, personalized genetic counseling, autosomal recessive disease.

Graphical abstract

Figure 1

Estimates of ABCA4 genotype frequencies in the general population Mild^CP, mild ABCA4 variant with complete penetrance; mod., moderately severe effect; N1868I, mild ABCA4 variant with incomplete penetrance, c.5603A>T (p.Asn1868Ile); sev., severe effect; WT, wild type. Sum AFs are presented of different severity categories in the genetic ancestry-matched gnomAD dataset. Data include the sum AFs of causative variants of unknown severity divided over mild^CP, moderately severe and severe, and variants with unknown pathogenicity divided over benign, mild^CP, moderately severe, and severe. ↓ represents the underestimate and ↑ the overestimate of the sum AFs and the corresponding genotype frequencies. Genotype frequencies are calculated with Hardy-Weinberg’s principle, p² + 2 × p × q + q² = 1. Red shading indicates a genotype that results in an STGD1 phenotype; orange shading indicates a genotype that may result in an STGD1 phenotype; light blue shading indicates a genotype that is unlikely to result in an STGD1 phenotype but might contribute to a pathogenic genotype in offspring; white shading indicates a genotype does not result in an STGD1 phenotype and does not contribute to a pathogenic genotype in offspring.

Figure 2

Genotype estimates for offspring of a person with STGD1 or a carrier of a pathogenic ABCA4 variant and an unaffected partner with an unknown genotype (A and B) The blue boxes present the genotype scenarios for an individual with STGD1 (A) and a known ABCA4 variant carrier (B) who have a child with an unaffected individual harboring an unknown ABCA4 genotype (white box on the left side). Ranges indicate the estimates based on the pathogenic sum allele frequency underestimate and overestimate in the genetic ancestry-matched gnomAD. The risks are divided by genotype in the white boxes on the right side. The numbers in the blue boxes on the right represent the total risk of having affected offspring. Two different penetrance rates of p.Asn1868Ile (hereafter: N1868I) alleles were implemented: the N1868I allele in the general population has a penetrance of approximately 5%, whereas the N1868I allele within families with affected individuals shows higher penetrance, roughly estimated at 65%. The higher penetrance is therefore probably only applicable if the offspring inherited the N1868I allele from the affected parent (N1868I allele with underscore) or from the unaffected carrier of an ABCA4 variant in whose (first degree) family that same allele had been penetrant. The “}” specifies the risk of offspring with a severe|severe or severe|moderately severe genotype, who most likely manifest STGD1 in childhood. ∼, an individual with the severe|mild^CP or moderately severe|moderately severe genotype may be unaffected at the age they conceive a child and be diagnosed with STGD1 shortly or a long time thereafter. The presented risk estimates do not apply to situations where both (future) parents have STGD1, in which case it is generally feasibly to narrow down the possible inheritance scenarios on the basis of known ABCA4 genotypes of both (future) parents. Based on our data from Dutch individuals (E.H.R., unpublished data), 44% of STGD1-affected individuals with a severe|mild^CP genotype and 21% with the moderate|moderate genotype received the diagnosis after the average age of European parents of children born in 2018 (32 years). The allele frequencies for these genotypes are corrected for those percentages. N1868I, mild (p.Asn1868Ile) ABCA4 variant with incomplete penetrance. Mild^CP, mild ABCA4 variant with complete penetrance. Mod., ABCA4 variant with moderately severe effect on ABCA4 function. WT, wild-type ABCA4 allele.