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Jensen AM, Raska J, Fojtik P, Monti G, Lunding M, Vochyanova S, Pospisilova V, vanderLee SJ, VanDongen J, Bossaerts L, VanBroeckhoven C, Dols O, Lleo A, Benussi L, Ghidoni R, Hulsman M, Sleegers K, Bohaciakova D, Holstege H, Andersen O. The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease. 2023 Jul 13 10.1101/2023.07.09.23292253 (version 1) medRxiv.
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Rouen University Hospital
I think this variant is definitely a strong contributor to AD. However, the pedigrees also show that the patients with DNA available and carrying the variant also carry one APOE4 allele. Actually, APOE4 segregates as well as does SORL1 in these pedigrees. All affected individuals with DNA available are SORL1+/APOE4+. One unaffected individual is SORL1+/APOE4- (family 1) and one unaffected individual is SORL1-/APOE4+ (family 2). To be clear, I have absolutely no doubt of a major role of the SORL1 variant here, but I feel that this is very much consistent with a more complex inheritance and not purely autosomal-dominant, as shown in our penetrance paper (Schramm et al., 2022). Interestingly, we have the same variant in three independent families from France (one of them is mentioned in this preprint). Although there is an obvious aggregation of AD cases in the families, there is a huge diversity of ages of onset and younger cases have a positive family history in both branches, suggesting the contribution of additional factors. Some of them are APOE4+ but not the two youngest probands. This may suggest the contribution of undetected contributing variants along with SORL1.
Overall, our penetrance paper (Schramm et al., 2022) and many pedigrees suggest a contribution of additional factors with SORL1 variants and that SORL1 alone may not be sufficient/fully penetrant. We have clear evidence for APOE4, as this is a common allele, but we know that there are many other other AD-associated variants, especially rare variants, among known variants (such as families with SORL1+ABCA7 as we previously reported in Campion et al., 2019), and in other papers and, obviously, not yet known variants.
I thus recommend to use such results with great caution for genetic counseling, as we still don't exactly know how variants in other genes may drastically change an age of onset from 50 to 75-80 for example, or to absence of AD (as also shown for some truncating variants, as in Campion et al., 2019 where a mother transmitted a truncating a truncating variant and was unaffected with AD at age 95 years).
References:
Schramm C, Charbonnier C, Zaréa A, Lacour M, Wallon D, CNRMAJ collaborators, Boland A, Deleuze JF, Olaso R, ADES consortium, Alarcon F, Campion D, Nuel G, Nicolas G. Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes. Genome Med. 2022 Jun 28;14(1):69. PubMed. Correction.
Campion D, Charbonnier C, Nicolas G. SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data. Acta Neuropathol. 2019 Aug;138(2):173-186. Epub 2019 Mar 25 PubMed.
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