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Congenital anomalies of the kidney and urinary tract (CAKUT) affect approximately 1 in 500 live births and represent the most common cause of pediatric chronic kidney disease. Despite identification of ~40 CAKUT genes, only 20% of cases are molecularly solved. Recent exome sequencing in an international cohort of 1,265 families uncovered ARHGEF6 hemizygous variants in eight affected individuals from six unrelated families, implicating X-linked inheritance in CAKUT (6 families) ([PMID:36414417]).
Genetic analysis revealed six distinct hemizygous ARHGEF6 variants predicted to be deleterious, including missense and loss-of-function changes. Segregation of these variants was concordant with phenotype in available male relatives. No recurrent or founder alleles were observed, and carrier frequency remains unknown.
In vitro, overexpression of wild-type ARHGEF6—but not mutant proteins—enhanced active CDC42/RAC1 levels, induced lamellipodia, and stimulated PARVA-dependent spreading in kidney cells; mutant proteins failed to bind PARVA, and three-dimensional MDCK cultures exhibited lumen formation and polarity defects ([PMID:36414417]).
Arhgef6‐deficient mouse and Xenopus models recapitulated key CAKUT features, including renal hypodysplasia and ureteric branching defects, supporting a loss-of-function, haploinsufficiency mechanism of pathogenicity.
Collectively, genetic and experimental evidence support a Strong gene–disease association for ARHGEF6 and X-linked CAKUT. Incorporation of ARHGEF6 into diagnostic panels will improve molecular diagnosis and enable carrier testing in affected families.
Key Take-home: Hemizygous ARHGEF6 variants cause X-linked CAKUT via dysregulated integrin-parvin–RAC1/CDC42 signaling, warranting clinical screening in undiagnosed cases.
Gene–Disease AssociationStrongEight hemizygous individuals from six unrelated families; X-linked segregation; concordant functional and animal model data Genetic EvidenceStrongSix distinct ARHGEF6 variants in eight probands from six families support X-linked recessive inheritance and reach genetic evidence cap Functional EvidenceStrongIn vitro loss of PARVA interaction and RAC1/CDC42 dysregulation plus mouse and frog knockout models recapitulate CAKUT phenotype |