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Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy characterized by rod-cone dystrophy, postaxial polydactyly, truncal obesity, renal anomalies, and variable neurodevelopmental involvement. IFT74 (HGNC:21424) encodes a core intraflagellar transport protein essential for ciliary assembly and maintenance, implicating it in the pathogenesis of BBS when disrupted.
Compound heterozygous loss-of-function variants in IFT74 were reported in a second BBS patient, who presented with postaxial polydactyly, retinal dystrophy, and childhood obesity. This individual harbored c.371_372del (p.Gln124ArgfsTer9) and c.1685-1G>T in trans, alongside one previously published case ([PMID:32144365]).
A third unrelated patient with classical BBS features—postaxial polydactyly, retinal dystrophy, truncal obesity, and motor delays—was identified with a homozygous splice-site variant c.1685-1G>T ([PMID:33748949]).
In a cohort of 92 unrelated BBS patients assessed by array comparative genomic hybridization, one individual was found to carry an exon-disruptive deletion and a splice-site mutation in IFT74 under a recessive model, further supporting its role in disease causation ([PMID:27486776]).
All reported IFT74 variants in BBS are predicted to result in loss of function (frameshift or splice disruption), consistent with an autosomal recessive inheritance pattern. No additional segregation data beyond proband descriptions have been reported. The core phenotypic spectrum includes HP:0000556 (Retinal dystrophy), HP:0100259 (Postaxial polydactyly), and HP:0001956 (Truncal obesity).
Overall, four unrelated probands with biallelic IFT74 loss-of-function variants present a consistent BBS phenotype, supporting a Moderate clinical validity classification. Functional studies specifically modeling IFT74 deficiency in BBS are currently lacking. Key Take-home: Biallelic IFT74 variants cause Bardet-Biedl syndrome and IFT74 should be included in diagnostic gene panels for BBS.
Gene–Disease AssociationModerate4 unrelated probands with biallelic loss-of-function IFT74 variants; consistent BBS phenotype Genetic EvidenceModerateTotal of four probands with compound heterozygous or homozygous frameshift or splice-site variants in IFT74 Functional EvidenceLimitedNo functional studies directly assessing IFT74 deficiency in Bardet-Biedl syndrome models |