DYNC2I2 – Jeune syndrome

Jeune syndrome (asphyxiating thoracic dystrophy; MONDO:0018770) is a lethal autosomal recessive skeletal ciliopathy characterised by a constricted thorax, short ribs, and polydactyly. Biallelic mutations in DYNC2I2 (HGNC:28296) encoding the dynein-2 intermediate chain WDR34 disrupt retrograde intraflagellar transport and Hedgehog signalling critical for ciliogenesis.

Clinical Validity

A total of 10 unrelated probands from 10 families harbouring biallelic DYNC2I2 variants have been reported: 9 families in a multi-patient study ([PMID:24183451]) and one consanguineous case report ([PMID:29241935]). Functional assays in patient fibroblasts and WDR34-knockout cells demonstrate concordant ciliary defects and impaired signalling ([PMID:24183449], [PMID:36268591]).

Overall Classification: Strong

Genetic Evidence

Inheritance is autosomal recessive. 10 probands across 10 families carry 11 distinct DYNC2I2 alleles, including canonical splice (c.186+2T>C), frameshift (e.g., c.1284_1305dup (p.Lys436fs)), nonsense (e.g., c.361C>T (p.Arg121Ter)), and missense changes affecting WD40 repeats ([PMID:24183451]). Segregation in a consanguineous family confirmed homozygosity in the proband and obligate carrier status in parents; homozygosity mapping in three affected siblings provided additional segregation evidence ([PMID:24183449]).

Functional Evidence

WDR34 localises to centrioles and ciliary axonemes, co-immunoprecipitates with dynein-2 components, and is required for axoneme extension. Patient-derived fibroblasts and mutant cell lines display shortened, bulbous cilia with disrupted IFT-B protein localisation, reduced Hedgehog pathway activation, and NF-κB signalling alterations. Rescue experiments in zebrafish confirm partial phenotypic restoration by wild-type but not mutant WDR34 ([PMID:24183449], [PMID:36268591]).

Conflicting Evidence

No studies have refuted the DYNC2I2–Jeune syndrome association. Phenotypic variability underscores poor genotype–phenotype correlation but does not contradict pathogenicity.

Conclusion

Biallelic loss-of-function and deleterious missense variants in DYNC2I2 cause Jeune syndrome via defective retrograde ciliary transport and impaired signalling. Genetic testing for DYNC2I2 variants informs diagnosis, enables carrier screening in at-risk families, and guides management of pulmonary and skeletal complications.

Key Take-home: DYNC2I2 variants are a reliable molecular marker for Jeune syndrome, supporting early diagnosis and clinical decision-making.

References

• American journal of human genetics • 2013 • Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy. PMID:24183451
• American journal of human genetics • 2013 • WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-κB pathway in cilia PMID:24183449
• Taiwanese journal of obstetrics & gynecology • 2017 • Identification of a c.544C>T mutation in WDR34 as a deleterious recessive allele of short rib-polydactyly syndrome. PMID:29241935
• Journal of cell science • 2023 • Disease-associated mutations in WDR34 lead to diverse impacts on the assembly and function of dynein-2. PMID:36268591

Evidence Based Scoring (AI generated)