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Ventriculomegaly-cystic kidney disease (VMCKD) is a rare, autosomal recessive syndrome characterized by cerebral ventriculomegaly, markedly elevated maternal serum or amniotic fluid alpha-fetoprotein, and renal cystic changes analogous to Finnish congenital nephrosis. Biallelic loss-of-function and missense variants in the polarity gene CRB2 underlie VMCKD, defining the molecular basis for diagnosis and genetic counseling.
In the initial report, a non-consanguineous Chinese family had two affected fetuses with VMCKD who were compound heterozygous for CRB2 c.1960G>C (p.Ala654Pro) and c.3078_c.3093delGGCGCGGCCCCGGCCC (p.Leu1026LeufsTer110) with perfect co-segregation (2 probands) (PMID:32051522).
An expanded cohort identified biallelic CRB2 variants in 11 unrelated individuals from nine families, with ventriculomegaly documented in 9/11 cases and consistent renal findings across pedigrees (PMID:27004616).
Inheritance is autosomal recessive. The variant spectrum includes two missense changes (p.Ala654Pro, p.Asn800Lys) and multiple truncating or frameshift alleles (e.g., p.Leu1026LeufsTer110, p.Gly1036AlafsTer) leading to loss of function. No founder alleles for VMCKD have been reported to date.
Functional evidence from zebrafish crb2b loss-of-function demonstrates defective podocyte foot process arborization, impaired slit diaphragm formation, and disrupted nephrin trafficking, with complementation confirming that human CRB2 variants are loss-of-function alleles (PMID:25557779).
CRB2 encodes a transmembrane polarity protein expressed in the developing brain and kidney epithelia. Loss of CRB2 perturbs apico-basal polarity, explaining both cerebral ventricular enlargement and nephron cystogenesis. CRB2 testing should be incorporated into prenatal and postnatal diagnostic panels for fetuses or infants presenting with ventriculomegaly and cystic kidney disease.
Key take-home: Biallelic CRB2 variants definitively cause VMCKD, supporting its inclusion in clinical genetic testing and prenatal diagnostics.
Gene–Disease AssociationStrong11 probands across at least 9 families, AR inheritance with co-segregation in multiple families (PMID:32051522, 27004616) Genetic EvidenceStrong11 probands in 9 unrelated families with biallelic CRB2 variants and co-segregation (PMID:32051522, 27004616) Functional EvidenceModerateZebrafish crb2b knockout recapitulates podocyte and nephron defects, with rescue experiments confirming loss-of-function (PMID:25557779) |