IFT140 – Leber congenital amaurosis

IFT140, encoding the intraflagellar transport protein 140, is implicated in autosomal recessive Leber congenital amaurosis (LCA). The clinical validity of this association is supported by multiple unrelated probands across independent cohorts. At least six patients (PMID:24698627; PMID:26216056) harbor biallelic variants and present early-onset severe retinal dystrophy consistent with LCA. Based on ClinGen criteria, the association meets a Moderate level of evidence. The evidence includes case-level data, segregation in families, and functional concordance in cellular assays. This summary details genetic and functional findings to inform diagnostic and therapeutic decision-making.

Two unrelated children presented with early-onset severe retinal dystrophy, hypotonia, and developmental delay. Both carried compound heterozygous variants in IFT140, including one missense variant, c.1990G>A (p.Glu664Lys), confirmed by Sanger sequencing (PMID:24698627). These cases illustrate that LCA can be the initial manifestation of IFT140-related ciliopathy. Systemic features underscore the importance of screening for extra-ocular involvement in children with early LCA. However, the retinal phenotype dominated the clinical presentation, fulfilling diagnostic criteria for LCA. No additional affected relatives were reported in these families.

Exome and panel sequencing in cohorts of LCA and retinitis pigmentosa patients identified IFT140 variants in multiple unrelated non-syndromic LCA cases. Candidate variants passed Sanger validation and segregation where DNA was available, indicating germline biallelic inheritance (PMID:26216056). Variants included splice site, frameshift, and nonsense changes, highlighting loss-of-function as a key mechanism in non-syndromic LCA. Segregation analyses supported autosomal recessive inheritance in families. These findings expanded the phenotype spectrum of IFT140 to include isolated retinal dystrophy without systemic features.

The spectrum of reported IFT140 variants in LCA includes at least one missense (c.1990G>A (p.Glu664Lys)), multiple splice-site alterations (e.g., c.1653-2A>G), frameshift indels (e.g., c.167del (p.Thr56fs)), and premature termination codons (e.g., c.2980C>T (p.Gln994Ter)) across different cohorts (PMID:26216056). All variants are extremely rare in control databases and predicted to disrupt protein function. A founder allele has not been established in LCA cases. Variant distribution suggests that LoF alleles in IFT140 consistently lead to a retinal dystrophy phenotype.

In vitro studies in hTERT-RPE1 cells demonstrated that certain missense mutations reduce basal body localization of IFT140, with quantitative reduction in ciliated cells compared to wild type constructs (PMID:26968735). These assays confirmed that both syndromic and non-syndromic LCA-associated variants impair retrograde intraflagellar transport. Cellular localization defects correlated with severity of the retinal phenotype, supporting a loss-of-function mechanism. Rescue experiments in knockout cells further underscored the requirement of IFT140 for normal ciliary trafficking. Together, functional data meet a Moderate level of experimental evidence.

IFT140 is a core component of the IFT-A complex responsible for retrograde ciliary transport. Biallelic loss-of-function variants lead to dysfunctional ciliary trafficking in photoreceptor cells, resulting in early-onset retinal degeneration. Although systemic involvement can occur in IFT140-related ciliopathies, isolated retinal disease suggests tissue-specific vulnerability. The data support haploinsufficiency and loss-of-function as the primary pathogenic mechanism in LCA. Additional in vivo models, such as zebrafish knockdowns, recapitulate retinal degeneration but remain under the ClinGen scoring cap.

In summary, autosomal recessive IFT140 variants cause Leber congenital amaurosis based on multiple probands, segregation, and concordant functional assays. Genetic testing for IFT140 is recommended in AR LCA panels, particularly in patients with early-onset severe retinal dystrophy. Identification of IFT140 mutations enables precise diagnosis, prognostic counseling, and potential eligibility for emerging gene-based therapies. Key take-home: IFT140 should be considered in the differential diagnosis of AR LCA, with functional assays guiding variant interpretation.

References

• Journal of AAPOS | 2014 | Early-onset severe retinal dystrophy as the initial presentation of IFT140-related skeletal ciliopathy. PMID:24698627
• Human Genetics | 2015 | Mutations in human IFT140 cause non-syndromic retinal degeneration. PMID:26216056
• Investigative ophthalmology & visual science | 2016 | Nonsyndromic Retinal Dystrophy due to Bi-Allelic Mutations in the Ciliary Transport Gene IFT140. PMID:26968735

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