CRB2 Mutations Produce a Phenotype Resembling Congenital Nephrosis, Finnish Type, with Cerebral Ventriculomegaly and Raised Alpha-Fetoprotein

Abstract

We report five fetuses and a child from three families who shared a phenotype comprising cerebral ventriculomegaly and echogenic kidneys with histopathological findings of congenital nephrosis. The presenting features were greatly elevated maternal serum alpha-fetoprotein (MSAFP) or amniotic fluid alpha-fetoprotein (AFAFP) levels or abnormalities visualized on ultrasound scan during the second trimester of pregnancy. Exome sequencing revealed deleterious sequence variants in Crumbs, Drosophila, Homolog of, 2 (CRB2) consistent with autosomal-recessive inheritance. Two fetuses with cerebral ventriculomegaly and renal microcysts were compound heterozygotes for p.Asn800Lys and p.Trp759Ter, one fetus with renal microcysts was a compound heterozygote for p.Glu643Ala and p.Asn800Lys, and one child with cerebral ventriculomegaly, periventricular heterotopias, echogenic kidneys, and renal failure was homozygous for p.Arg633Trp in CRB2. Examination of the kidneys in one fetus showed tubular cysts at the corticomedullary junction and diffuse effacement of the epithelial foot processes and microvillous transformation of the renal podocytes, findings that were similar to those reported in congenital nephrotic syndrome, Finnish type, that is caused by mutations in nephrin (NPHS1). Loss of function for crb2b and nphs1 in Danio rerio were previously shown to result in loss of the slit diaphragms of the podocytes, leading to the hypothesis that nephrosis develops from an inability to develop a functional glomerular barrier. We conclude that the phenotype associated with CRB2 mutations is pleiotropic and that the condition is an important consideration in the evaluation of high MSAFP/AFAFP where a renal cause is suspected.

Clinical application of whole-exome sequencing across clinical indications

“…Utilizing the power of our large data set, we were able to identify novel candidate genes in which multiple patients with similar phenotypes had rare variants predicted to result in loss of function, many of which were de novo. Access to this large number of cases has proven extremely valu- [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] As a result of our experience, we believe that candidate genes should be reported from WES analysis and shared in databases, such as GeneMatcher, so that clinicians, researchers, and clinical laboratories can be connected to facilitate more rapid dissemination of information and validation of novel disease genes. Our series is larger than previously reported clinical diagnostic series and has the power to begin to address the yield of WES for a large number of clinical indications.…”

The Family of Crumbs Genes and Human Disease

“…The prognosis in CRB2-related syndrome was initially thought to be poor, with no survival reported beyond 7 months of age from the first report of 6 affected individuals [Slavotinek et al, 2015]. However, the outcome has since been recognized as more variable and normal cognition and health have subsequently been reported in 2 individuals of 6 and 7 years of age, with both having ventriculo-peritoneal shunts inserted for treatment of a hydrocephalus at an early age [Jaron et al, 2016;Lamont et al, 2016].…”

“…Several recurrent mutations have been described, including p.Asn800Lys (p.N800K), a missense mutation that has been reported with Ashkenazi Jewish ethnicity [Slavotinek et al, 2015;Jaron et al, 2016]. This sequence variation was found in 2/128 Ashkenazi Jewish control genomes from a recent study [Carmi et al, 2014], resulting in a carrier frequency of 1 in 64 [Jaron et al, 2016].…”

“…Clinical Phenotype Biallelic mutations in CRB2 cause CRB2-related syndrome that is characterized by the phenotypic triad of greatly elevated maternal serum alpha-fetoprotein (MSAFP) and amniotic fluid alpha-fetoprotein levels, cerebral ventriculomegaly and cystic renal disease with histopathological findings resembling congenital Finnish nephrosis [Slavotinek et al, 2015;Jaron et al, 2016;Lamont et al, 2016] [Slavotinek et al, 2015;Jaron et al, 2016;Lamont et al, 2016]. Although initially ascertained due to raised MSAFP and renal disease, hydrocephalus or ventriculomegaly has been present in 11/13 (85%) individuals.…”

“…In all cases of CRB2-related syndrome, compound heterozygosity or homozygosity for sequence variants predicted to affect the function of CRB2 were demonstrated ( table 2 ) [Slavotinek et al, 2015;Jaron et al, 2016;Lamont et al, 2016]. The sequence variants were hypothesized to act by loss of function based on nonsense and frameshift mutations and biallelic inheritance.…”