Compound dominant-null heterozygosity in a family with RP1-related retinal dystrophy.
Compound dominant-null heterozygosity in a family with RP1-related retinal dystrophy.
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DOI：
10.1016/j.ajoc.2022.101698
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发表时间：
2022-12
影响因子：
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通讯作者：
MacLaren, Robert E
中科院分区：
文献类型：
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作者：
Buckley, Thomas M W;Cehajic-Kapetanovic, Jasmina;Shanks, Morag;Clouston, Penny;MacLaren, Robert E
报告在同一个非血缘家族中存在的常染色体显性和复合显性无效RP 1相关的视网膜色素变性。父亲症状轻微，由38岁的验光师转诊。他被诊断出患有视杆-视锥营养不良，证实是由之前报道的RP 1 c.2613dupA突变引起的。他确信，他11岁的女儿有50%的机会遗传到相同的突变，如果她有这种情况，很可能是相似的。然而，他女儿的临床表型显示早发性视锥-视杆细胞营养不良。母亲完全无症状，临床表现正常。女儿的RP 1基因的桑格测序证实了双等位基因突变的存在-来自她父亲的显性c.2613dupA变体和来自她母亲的c.3843dupT截短变体，两者都位于RP 1基因的外显子4。母亲c.3843dupT先前已报告。已知RP 1外显子4中的致病性变体引起不同的显性和隐性疾病。在一个家族中同时存在这两种表型的情况尚未报道。父亲，是最低限度的症状，是由一个已知的显性变异，截断RP 1蛋白更近端的影响。然而，在女儿的复合杂合子状态下的两种变体的遗传导致了更严重的，早发性锥杆表型类似于隐性疾病的模式。这对遗传咨询和开发针对RP 1突变的基因疗法提出了挑战。
To report on the presence of autosomal dominant and compound dominant-null RP1-related retinitis pigmentosa in the same non-consanguineous family. The father was minimally symptomatic and referred by his optometrist aged 38. He was diagnosed with rod-cone dystrophy, confirmed to be caused by the previously reported RP1 c.2613dupA mutation. He was reassured that his 11-year-old daughter had a 50% chance of inheriting the same mutation and that the condition, if she had it, would most likely be similar. Clinical phenotyping of his daughter however revealed an early onset cone-rod dystrophy. The mother was entirely asymptomatic and clinically normal. Sanger sequencing of the RP1 gene in the daughter confirmed the presence of biallelic mutations – the dominant c.2613dupA variant from her father and a c.3843dupT truncating variant inherited from her mother, both located in exon 4 of the RP1 gene. The maternal c.3843dupT has previously been reported. Pathogenic variants in exon 4 of RP1 are known to cause differential dominant and recessive disease. The presence of both phenotypes in a single family has not yet been reported. The father, being minimally symptomatic, is affected by a known dominant variant which truncates the RP1 protein more proximally. However, inheritance of both variants in a compound heterozygous state in the daughter resulted in a much more severe, early onset cone-rod phenotype in a pattern akin to recessive disease. This raises challenges for genetic counselling and development of gene-based therapies for RP1 mutations.