Sullivan Lori S, Bowne Sara J, Birch David G, Hughbanks-Wheaton Dianna, Heckenlively John R, Lewis Richard Alan, Garcia Charles A, Ruiz Richard S, Blanton Susan H, Northrup Hope, Gire Anisa I, Seaman Robyn, Duzkale Hatice, Spellicy Catherine J, Zhu Jingya, Shankar Suma P, Daiger Stephen P
Human Genetics Center, School of Public Health, Department of Ophthalmology and Visual Science, the University of Texas Health Science Center, Houston 77030, USA.
Invest Ophthalmol Vis Sci. 2006 Jul;47(7):3052-64. doi: 10.1167/iovs.05-1443.
To survey families with clinical evidence of autosomal dominant retinitis pigmentosa (adRP) for mutations in genes known to cause adRP.
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.
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.
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.
对有常染色体显性遗传性视网膜色素变性（adRP）临床证据的家庭进行调查，以寻找已知可导致adRP的基因突变。
通过系谱分析，从400多个潜在家庭的队列中选取了200个adRP家庭。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对男性传递的证据。对每个家庭的先证者进行13个已知可导致adRP的基因突变筛查：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X连锁RPGR的ORF 15基因突变检测。根据多种遗传和计算标准对潜在的致病变异进行评估，以确认或排除致病性。
在所检测的基因中总共检测到82个不同的罕见（非多态性）变异。其中，根据多种标准，57个变异明确致病，10个可能致病，15个可能良性。在200个家庭的队列中，94个（47%）有一个明确的致病变异，10个（5%）有一个可能的致病变异。一个家庭（0.5%）有双基因RDS-ROM1突变。两个家庭（1%）有致病性RPGR突变，表明具有明显常染色体遗传的RP家庭实际上可能患有X连锁遗传病。因此，107个家庭（53.5%）在已知基因中有突变，仍有93个家庭的潜在病因未知。
在本次调查中，已知的adRP基因约占一半家庭视网膜疾病的病因，这些家庭大多是欧洲裔美国人。在adRP基因中，IMPDH1、PRPF8、PRPF31、RDS、RHO和RP1各自占总数的2%以上；CRX、PRPF3和RPGR各自约占1%。在CA4、FSCN2、NRL或RP9中未发现致病突变。由于一些突变很常见，且某些区域比其他区域更易发生突变，因此通过筛查不到10%的总基因序列就能发现超过三分之二的检测到的突变。在其余家庭中，突变可能存在于未检测的已知基因区域，基于PCR的测序可能无法检测到突变，或者可能涉及其他基因座。
