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Autosomal dominant polycystic kidney disease (ADPKD) is a common ciliopathy characterized by progressive bilateral renal cyst formation and eventual renal insufficiency. While PKD1 and PKD2 account for ~90% of cases, heterozygous variants in ALG9 have emerged as a novel cause of ADPKD spectrum disorders.
In genetic studies of 122 unresolved ADPKD or polycystic liver disease cases, two unrelated probands with rare ALG9 loss-of-function variants were identified by whole-exome sequencing (PMID:31395617). In a population-based cohort of eight ALG9 carriers aged >50 years, seven (88%) had ≥4 renal cysts compared with none of matched noncarriers (PMID:31395617). In a separate multicenter screening of >3,900 families, 23 ALG9 families (0.6%) were ascertained, including five multiplex pedigrees, confirming autosomal dominant inheritance and familial segregation.
ALG9 variants identified include truncating and missense alleles across the gene, with recurrent stop-gain c.1780C>T (p.Gln594Ter) reported in multiple carriers (PMID:31395617). The variant spectrum comprises nonsense, frameshift, and deleterious missense changes, consistent with a loss of α-1,2-mannosyltransferase activity.
Functional assays demonstrated that ALG9 inactivation impairs N-glycosylation and maturation of polycystin-1 in vitro, leading to defective PC1 trafficking and cystogenesis (PMID:31395617). These data establish a loss-of-function mechanism for ALG9 in ADPKD pathogenesis.
No conflicting reports have challenged the link between heterozygous ALG9 variants and kidney cysts in adults. The consistency of genetic segregation, population enrichment, and concordant functional defects supports a definitive association.
Key Take-home: Heterozygous loss-of-function variants in ALG9 cause an autosomal dominant polycystic kidney phenotype via impaired polycystin-1 glycosylation, warranting inclusion of ALG9 in genetic testing panels for ADPKD.
Gene–Disease AssociationStrongApproximately 33 probands across independent cohorts, five multiplex families, and concordant functional data Genetic EvidenceStrongMultiple rare ALG9 loss-of-function and missense variants in 23 families and population carriers with ADPKD phenotypes Functional EvidenceModerateIn vitro assays demonstrate that ALG9 loss impairs polycystin-1 glycosylation and maturation |