IFT140 – Jeune syndrome

IFT140, encoding a retrograde intraflagellar transport complex A subunit, is associated with autosomal recessive Jeune asphyxiating thoracic dystrophy (MONDO:0018770). This association is classified as Strong by ClinGen based on multiple unrelated probands, segregation in families, and concordant functional data.

Biallelic IFT140 variants have been reported in at least 15 unrelated probands across ~14 families: six families in a cohort of Mainzer-Saldino syndrome (PMID:22503633), five Jeune families in a mixed JATD/MSS screening (PMID:23418020), one case unmasked by segmental isodisomy (PMID:28724397), and two patients with cranioectodermal dysplasia (PMID:32007091). Segregation of compound heterozygous or homozygous variants in multiple pedigrees confirms autosomal recessive inheritance.

The variant spectrum is dominated by loss-of-function alleles (>30 unique frameshift, nonsense, and splice-site changes) alongside pathogenic missense variants. A representative recurrent splice-site LoF variant is c.2980C>T (p.Gln994Ter) (PMID:22503633).

Functional studies demonstrate impaired retrograde intraflagellar transport: patient urine-derived renal epithelial cells show IFT88 accumulation at ciliary tips in 41% of cilia, absent in controls, and mutant IFT140 constructs fail to rescue this phenotype (PMID:30479745). Zebrafish complementation assays of the p.Gly212Arg allele validate a loss-of-function mechanism with recapitulation of ciliopathy features (PMID:28724397).

No studies to date have refuted the IFT140–Jeune syndrome relationship or identified alternative causal loci in these cohorts. Modifier effects have been suggested but do not undermine the primary autosomal recessive association.

In conclusion, robust genetic and experimental evidence supports IFT140 as a definitive gene for autosomal recessive Jeune syndrome. Clinical sequencing of IFT140 should be integrated into diagnostic panels for thoracic dystrophy, enabling accurate diagnosis and genetic counseling.

References

• American Journal of Human Genetics • 2012 • Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations. PMID:22503633
• Cilia • 2018 • Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer-Saldino syndrome diagnosis. PMID:30479745
• Human Genomics • 2017 • Partial uniparental isodisomy of chromosome 16 unmasks a deleterious biallelic mutation in IFT140 that causes Mainzer-Saldino syndrome. PMID:28724397
• Orphanet Journal of Rare Diseases • 2020 • Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease. PMID:32007091

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