Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity

Abstract

Chronically increased echogenicity on renal ultrasound is a sensitive early finding of chronic kidney disease that can be detected before manifestation of other symptoms. Increased echogenicity, however, is not specific for a certain etiology of chronic kidney disease. Here, we performed whole exome sequencing in 79 consanguineous or familial cases of suspected nephronophthisis in order to determine the underlying molecular disease cause. In 50 cases, there was a causative mutation in a known monogenic disease gene. In 32 of these cases whole exome sequencing confirmed the diagnosis of a nephronophthisis-related ciliopathy. In 8 cases it revealed the diagnosis of a renal tubulopathy. The remaining 10 cases were identified as Alport syndrome (4), autosomal-recessive polycystic kidney disease (2), congenital anomalies of the kidney and urinary tract (3), and APECED syndrome (1). In 5 families, in whom mutations in known monogenic genes were excluded, we applied homozygosity mapping for variant filtering and identified 5 novel candidate genes (RBM48, FAM186B, PIAS1, INCENP, and RCOR1) for renal ciliopathies. Thus, whole exome sequencing allows the detection of the causative mutation in 2/3 of affected individuals, thereby presenting the etiologic diagnosis, and allows identification of novel candidate genes.

Figure 1. Relative number of cases molecularly diagnosed by WES in 79 families with child-hood onset chronically increased echogenicity or ≥2 cysts on renal ultrasound

A) We performed whole exome sequencing in 79 consanguineous or sibling cases with increased echogenicity and/or ≥2 cysts on renal ultrasound. In 50 families (63.3%) we identified a mutation in a known monogenic disease gene as causative. In 5 families (6.3%) we identified a mutation in a novel candidate gene for NPHP-RC, and 24 families (30.4%) remained without a molecular diagnosis after WES. B) Fractional contribution of different disease entities to the molecular diagnosis of 50 families in whom a causative mutation in a known monogenic disease gene was detected. (See Table 1 for the underlying monogenic causes in each disease group.)

Figure 2. Algorithm for molecular diagnostics in consanguineous or familial cases of suspected nephronophthisis based on renal ultrasound presentation

Of 79 families with childhood-onset increased renal echogenicity and/or ≥ 2 cysts on RUS, 60 individuals were born of consanguineous unions, and 19 families were non-consanguineous with two or more affected children. In 63.3% of consanguineous families, we identified a mutation in a known monogenic disease gene as causative. The majority of these mutations were, as postulated, present in the homozygous state. In 63.2% of familial cases, we identified a causative mutation in a recessive, monogenic disease gene. 3/4 of these mutations were compound heterozygous. ^a In one consanguineous family a single heterozygous mutation in the dominant gene HNF1ß was identified as the molecular disease cause.