Expansion of phenotype and genotypic data in CRB2-related syndrome

Abstract

Sequence variants in CRB2 cause a syndrome with greatly elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein levels, cerebral ventriculomegaly and renal findings similar to Finnish congenital nephrosis. All reported patients have been homozygotes or compound heterozygotes for sequence variants in the Crumbs, Drosophila, Homolog of, 2 (CRB2) genes. Variants affecting CRB2 function have also been identified in four families with steroid resistant nephrotic syndrome, but without any other known systemic findings. We ascertained five, previously unreported individuals with biallelic variants in CRB2 that were predicted to affect function. We compiled the clinical features of reported cases and reviewed available literature for cases with features suggestive of CRB2-related syndrome in order to better understand the phenotypic and genotypic manifestations. Phenotypic analyses showed that ventriculomegaly was a common clinical manifestation (9/11 confirmed cases), in contrast to the original reports, in which patients were ascertained due to renal disease. Two children had minor eye findings and one was diagnosed with a B-cell lymphoma. Further genetic analysis identified one family with two affected siblings who were both heterozygous for a variant in NPHS2 predicted to affect function and separate families with sequence variants in NPHS4 and BBS7 in addition to the CRB2 variants. Our report expands the clinical phenotype of CRB2-related syndrome and establishes ventriculomegaly and hydrocephalus as frequent manifestations. We found additional sequence variants in genes involved in kidney development and ciliopathies in patients with CRB2-related syndrome, suggesting that these variants may modify the phenotype.

Figure 1

MRI scan of the brain and optical coherence tomography (OCT) in the first patient, demonstrating hydrocephalus and a retinal defect. (a) Axial T2-weighted sequences (i,ii) and sagittal T1-weighted sequence (iii). Imaging demonstrates asymmetric lateral (i,ii) and third ventriculomegaly (ii). There is volume loss of the cerebral cortex and white matter, particularly parietal and occipital lobes (i–iii). Heterotopic gray matter is present at the margins of the ventricles (arrows). The posterior fossa is displaced downwards (iii). (b) An OCT image of the left macula shows an identifiable pit (arrow) and a hole (short arrow) in the outer retinal laminae at the foveal site.

Figure 2

Position of ‘Cys' and ‘Charge' Mutations in CRB2. Representation of residues 439-1284 in CRB2, showing variants that affected a cysteine residue (‘Cys' variants) in yellow and variants that were predicted to alter charge (‘charge' mutations) at a residue in red. The two variants that have both properties are colored in orange. The N-terminus of the protein has not been included as there were no mutations affecting this portion of the protein.