Novel somatic mosaicism likely masking syndromic CAKUT in an adult with bilateral kidney hypoplasia.

Background: 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.

Methods: 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).

Results: 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.

Conclusions: -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.