Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: A screen of known genes in 200 families
Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: A screen of known genes in 200 families
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DOI：
10.1167/iovs.05-1443
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发表时间：
2006-07-01
影响因子：
4.4
通讯作者：
Daiger, Stephen P.
中科院分区：
文献类型：
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作者：
Sullivan, Lori S.;Bowne, Sara J.;Daiger, Stephen P.
目的。目的：调查具有常染色体显性视网膜色素变性（adRP）临床证据的家族中已知引起adRP的基因突变。通过家谱分析，研究人员从400多个潜在家族中选出了200个adRP家族。纳入adRP队列的最低标准包括至少三代受影响个体的证据或两代有男性间传播的证据。从每个家族中筛选13个已知导致adRP的基因突变的先证：CA4、CRX、FSCN2、IMPDH1、NRL、PRPF3 （RP18）、PRPF8 （RP13）、PRPF31 （RP11）、RDS、RHO、ROM1、RP1和RP9。对常染色体基因无突变且不能排除x连锁遗传模式的家庭进行了x连锁RPGR的orf15突变检测。根据各种遗传和计算标准评估潜在致病性变异，以确认或排除致病性。在测试的基因中共检测到82种不同的、罕见的（非多态性）变异。其中，57例根据多种标准明确为致病性，10例可能为致病性，15例可能为良性。在200个家庭的队列中，94个（47%）有一种明显致病变异，10个（5%）有一种可能致病变异。一个家族（0.5%）有遗传性RDS-ROM1突变。两个家族（1%）有致病性RPGR突变，表明RP明显常染色体遗传的家族实际上可能患有x连锁遗传病。因此，107个家庭（53.5%）存在已知基因突变，其余93个家庭的根本原因尚不清楚。总的来说，在这项调查中，已知的adRP基因在大约一半的家庭中解释了视网膜疾病，大多数是欧洲血统的美国人。在adRP基因中，IMPDH1、PRPF8、PRPF31、RDS、RHO、RP1各占总数的2%以上；CRX、PRPF3和RPGR各占大约1%。在CA4、FSCN2、NRL或RP9中未发现致病突变。由于一些突变是频繁的，一些区域比其他区域更容易发生突变，因此通过筛选不到总基因序列的10%，可以发现超过三分之二的检测到的突变。在剩余的家族中，突变可能位于未检测的已知基因区域，突变可能无法通过基于pcr的测序检测到，或者可能涉及其他位点。
PURPOSE. To survey families with clinical evidence of autosomal dominant retinitis pigmentosa (adRP) for mutations in genes known to cause adRP.METHODS. Two hundred adRP families, drawn from a cohort of more than 400 potential families, were selected by analysis of pedigrees. Minimum criteria for inclusion in the adRP cohort included either evidence of at least three generations of affected individuals or two generations with evidence of male-to-male transmission. Probands from each family were screened for mutations in 13 genes known to cause adRP: CA4, CRX, FSCN2, IMPDH1, NRL, PRPF3 (RP18), PRPF8 (RP13), PRPF31 (RP11), RDS, RHO, ROM1, RP1, and RP9. Families without mutations in autosomal genes and in which an X-linked mode of inheritance could not be excluded were tested for mutations in ORF 15 of X-linked RPGR. Potentially pathogenic variants were evaluated based on a variety of genetic and computational criteria, to confirm or exclude pathogenicity.RESULTS. A total of 82 distinct, rare (nonpolymorphic) variants were detected among the genes tested. Of these, 57 are clearly pathogenic based on multiple criteria, 10 are probably pathogenic, and 15 are probably benign. In the cohort of 200 families, 94 (47%) have one of the clearly pathogenic variants and 10 (5%) have one of the probably pathogenic variants. One family (0.5%) has digenic RDS-ROM1 mutations. Two families (1%) have a pathogenic RPGR mutation, indicating that families with apparent autosomal transmission of RP may actually have X-linked genetic disease. Thus, 107 families (53.5%) have mutations in known genes, leaving 93 whose underlying cause is still unknown.CONCLUSIONS. Together, the known adRP genes account for retinal disease in approximately half of the families in this survey, mostly Americans of European origin. Among the adRP genes, IMPDH1, PRPF8, PRPF31, RDS, RHO, and RP1 each accounts for more than 2% of the total; CRX, PRPF3, and RPGR each accounts for roughly 1%. Disease-causing mutations were not found in CA4, FSCN2, NRL, or RP9. Because some mutations are frequent and some regions are more likely to harbor mutations than others, more than two thirds of the detected mutations can be found by screening less than 10% of the total gene sequences. Among the remaining families, mutations may lie in regions of known genes that were not tested, mutations may not be detectable by PCR-based sequencing, or other loci may be involved.