Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France.
Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France.
J Alzheimers Dis. 2018;62(2):821-831. doi: 10.3233/JAD-170981.
Heterozygous SORL1 protein truncating variants (PTV) are a strong risk factor for early-onset Alzheimer's disease (EOAD). In case control studies performed at the genome-wide level, PTV definition is usually straightforward. Regarding splice site variants, only those affecting canonical sites are typically included. Some other variants, not annotated as PTV, could, however, affect splicing and hence result in a loss of SORL1 function. We took advantage of the whole exome sequencing data from the 9/484 patients with a previously reported SORL1 PTV in the French EOAD series and searched for a second variant which may affect splicing and eventually result in more than 50% loss of function overall. We found that one patient, known to carry a variant predicted to disrupt the canonical 5' splice site of exon 8, also carried a second novel intronic variant predicted to affect SORL1 splicing of exon 29. Segregation analysis showed that the second variant was located in trans from the known PTV. We performed ex vivo minigene splicing assays and showed that both variants led to the generation of transcripts containing a premature stop codon. This is therefore the first evidence of a human carrying biallelic SORL1 PTV. This patient had a family history of dementia in both maternal and paternal lineages with later ages of onset than the proband himself. However, his 55 years age at onset was in the same ranges as previously published SORL1 heterozygous PTV carriers. This suggests that biallelic loss of SORL1 function is an extremely rare event that was not associated with a dramatically earlier age at onset than heterozygous SORL1 loss-of-function variant carriers, in this single patient.
杂合性 SORL1 蛋白截断变异（PTV）是早发性阿尔茨海默病（EOAD）的一个强烈危险因素。在全基因组水平进行的病例对照研究中，PTV 的定义通常很直接。关于剪接位点变异，通常只包括那些影响规范位点的变异。然而，其他一些未被注释为 PTV 的变异可能会影响剪接，从而导致 SORL1 功能丧失。我们利用来自法国 EOAD 系列中先前报道的 SORL1 PTV 的 9/484 名患者的全外显子组测序数据，寻找第二个可能影响剪接并最终导致整体功能丧失超过 50%的变异。我们发现，一名已知携带变异的患者，该变异预计会破坏外显子 8 的规范 5'剪接位点，还携带第二个新的内含子变异，预计会影响外显子 29 的 SORL1 剪接。连锁分析表明，第二个变异与已知的 PTV 位于反式。我们进行了体外迷你基因剪接分析，结果表明这两个变异都导致了产生含有提前终止密码子的转录本。这是第一个携带 SORL1 双等位 PTV 的人类的证据。该患者的母系和父系家族中均有痴呆病史，发病年龄晚于先证者。然而，他的发病年龄为 55 岁，与先前报道的 SORL1 杂合 PTV 携带者相似。这表明双等位 SORL1 功能丧失是一种极其罕见的事件，与杂合 SORL1 功能丧失变异携带者相比，不会导致发病年龄明显提前，在这名患者中就是如此。
