Background X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the COL4A5 gene. Genotype-phenotype correlation in male XLAS is relatively well established; relative to truncating mutations, nontruncating mutations exhibit milder phenotypes. However, transcript comparison between XLAS cases with splicing abnormalities that result in a premature stop codon and those with nontruncating splicing abnormalities has not been reported, mainly because transcript analysis is not routinely conducted in patients with XLAS.

Methods We examined transcript expression for all patients with suspected splicing abnormalities who were treated at one hospital between January of 2006 and July of 2017. Additionally, we recruited 46 males from 29 families with splicing abnormalities to examine genotype-phenotype correlation in patients with truncating (n=21, from 14 families) and nontruncating (n=25, from 15 families) mutations at the transcript level.

Results We detected 41 XLAS families with abnormal splicing patterns and described novel XLAS atypical splicing patterns (n=14) other than exon skipping caused by point mutations in the splice consensus sequence. The median age for developing ESRD was 20 years (95% confidence interval, 14 to 23 years) among patients with truncating mutations and 29 years (95% confidence interval, 25 to 40 years) among patients with nontruncating mutations (P=0.001).

Conclusions We report unpredictable atypical splicing in the COL4A5 gene in male patients with XLAS and reveal that renal prognosis differs significantly for patients with truncating versus nontruncating splicing abnormalities. Our results suggest that splicing modulation should be explored as a therapy for XLAS with truncating mutations.

背景X连锁Alport综合征（XLAS）是由COL4A5基因突变引起的进行性遗传性肾病。男性XLAS的基因型-表型相关性相对较好。相对于截短突变，非截短突变表现出较温和的表型。但是，尚未报告在剪接异常导致终止密码子过早的XLAS病例与非截断剪接异常的XLAS病例之间进行转录本比较的情况，主要是因为在XLAS患者中常规不进行转录本分析。

方法我们检查了2006年1月至2017年7月在一家医院接受治疗的所有疑似剪接异常患者的转录本表达。此外，我们从29个剪接异常家庭中招募了46名男性，以检查截短患者的基因型与表型的相关性。在转录本水平上，n = 21，来自14个家庭）和非截断（n = 25，来自15家庭）突变。

结果我们检测到41个具有异常剪接模式的XLAS家族，并描述了新颖的XLAS非典型剪接模式（n = 14），而不是由剪接共有序列中的点突变引起的外显子跳跃。截断突变患者中发展为ESRD的中位年龄为20岁（95％置信区间14至23岁），非截断突变患者中位年龄为29岁（95％置信区间25至40岁（P = 0.001）。

结论我们报道了男性XLAS患者COL4A5基因的非典型剪接无法预测，并揭示了截短和非截短剪接异常患者的肾脏预后显着不同。我们的结果表明，应将剪接调节作为具有突变突变的XLAS的治疗方法。