Targeted next-generation sequencing in a large series of fetuses with severe renal diseases
Targeted next-generation sequencing in a large series of fetuses with severe renal diseases
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DOI：
10.1002/humu.24324
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发表时间：
2022-01-10
期刊：
影响因子：
3.9
通讯作者：
Heidet, Laurence
中科院分区：
文献类型：
--
作者：
Jordan, Penelope;Dorval, Guillaume;Heidet, Laurence
我们报道了在一系列的100个胎儿（98个家庭）中筛选了大量的基因，这些胎儿患有严重的肾脏缺陷。22%的病例中发现了致病变异，这大大改善了遗传咨询。解释表型的变异百分比根据表型类型不同而不同。诊断率最高的是纤毛病样表型（11/15个家族，此外，在3例不相关的常染色体隐性多囊肾病患者中，PKHD1单杂合或纯合3类变异）。在肾脏和尿路先天性异常的病例中，诊断率最低（9/78家族，此外，在3例不相关的双侧肾发育不全病例中，GREB1L的3类变异）。9个基因（PKHD1、NPHP3、CEP290、TMEM67、DNAJB11、FRAS1、ACE、AGT、AGTR1）为常染色体隐性遗传，6个基因（PKD1、PKD2、PAX2、EYA1、BICC1、心肌）为常染色体显性遗传。最后，我们开发了一种新一代测序靶向RNA测序的原始方法，使用用于DNA测序的定制捕获面板来验证在两个患有兆天阶的男性兄弟姐妹中发现的一种心肌杂合剪接变异，该变异遗传自他们的健康母亲。
We report the screening of a large panel of genes in a series of 100 fetuses (98 families) affected with severe renal defects. Causative variants were identified in 22% of cases, greatly improving genetic counseling. The percentage of variants explaining the phenotype was different according to the type of phenotype. The highest diagnostic yield was found in cases affected with the ciliopathy-like phenotype (11/15 families and, in addition, a single heterozygous or a homozygous Class 3 variant in PKHD1 in three unrelated cases with autosomal recessive polycystic kidney disease). The lowest diagnostic yield was observed in cases with congenital anomalies of the kidney and urinary tract (9/78 families and, in addition, Class 3 variants in GREB1L in three unrelated cases with bilateral renal agenesis). Inheritance was autosomal recessive in nine genes (PKHD1, NPHP3, CEP290, TMEM67, DNAJB11, FRAS1, ACE, AGT, and AGTR1), and autosomal dominant in six genes (PKD1, PKD2, PAX2, EYA1, BICC1, and MYOCD). Finally, we developed an original approach of next-generation sequencing targeted RNA sequencing using the custom capture panel used for the sequencing of DNA, to validate one MYOCD heterozygous splicing variant identified in two male siblings with megabladder and inherited from their healthy mother.