Petzold Friederike, Jin Wenjun, Hantmann Elena, Korbach Katharina, Schönauer Ria, Halbritter Jan
Division of Nephrology, University of Leipzig Medical Center, Leipzig, Germany.
Bioscientia, Institute of Human Genetics, Ingelheim, Germany.
Clin Kidney J. 2022 Apr 6;15(7):1333-1339. doi: 10.1093/ckj/sfac092. eCollection 2022 Jul.
Congenital abnormalities of the kidney and urinary tract (CAKUT) are characterized by vast phenotypic heterogeneity and incomplete penetrance. Although CAKUT represent the main cause of pediatric chronic kidney disease, only ∼20% can be explained by single-gene disorders to date. While pathogenic alterations of were recently associated with a severe form of syndromic CAKUT, most CAKUT patients survive childhood and adolescence to reach end-stage kidney disease later in life. Although somatic mosaicism is known to attenuate severity in other kidney diseases, it has rarely been described or systematically been assessed in CAKUT.
We conducted an in-depth phenotypic characterization of the index patient and his family using targeted next-generation sequencing, segregation analysis and workup of mosaicism with DNA isolated from peripheral blood cells, oral mucosa and cultured urinary renal epithelial cells (URECs).
Somatic mosaicism was identified in a 20-year-old male with sporadic but mild syndromic renal hypoplasia. He was found to carry a novel truncating variant in [c.992C>A, p.(Ser331*)]. This variant was detected in 26% of sequencing reads from blood cells, 50% from oral mucosa and 20% from cultured URECs.
-associated CAKUT is characterized by a wealth of mutations. As in cases, mutations can occur intra- or post-zygotically and genetic mosaicism might represent a more common phenomenon in disease, accounting for variable expressivity on a general basis. Consequently we suggest ruling out somatic mosaicism in sporadic CAKUT, notably in attenuated and atypical clinical courses.
先天性肾脏和尿路异常（CAKUT）具有广泛的表型异质性和不完全外显率。尽管CAKUT是儿童慢性肾脏病的主要病因，但迄今为止，只有约20%可由单基因疾病解释。虽然最近发现[基因名称]的致病性改变与一种严重形式的综合征性CAKUT相关，但大多数CAKUT患者在儿童期和青春期存活下来，后期发展为终末期肾病。虽然已知体细胞镶嵌现象可减轻其他肾脏疾病的严重程度，但在CAKUT中很少被描述或系统评估。
我们使用靶向二代测序、分离分析以及对从外周血细胞、口腔黏膜和培养的尿路上皮细胞（URECs）中分离的DNA进行镶嵌现象检查，对先证者及其家族进行了深入的表型特征分析。
在一名患有散发性但轻度综合征性肾发育不全的20岁男性中发现了体细胞镶嵌现象。发现他携带一个新的[基因名称]截短变异[c.992C>A，p.(Ser331*)]。该变异在血细胞测序读数的26%、口腔黏膜的50%和培养的URECs的20%中被检测到。
与[基因名称]相关的CAKUT具有大量[基因名称]突变。与[基因名称]病例一样，突变可在合子内或合子后发生，遗传镶嵌现象可能是[疾病名称]中更常见的现象，总体上解释了可变表达性。因此，我们建议在散发性CAKUT中排除体细胞镶嵌现象，特别是在病情减轻和非典型临床病程中。
