DYNC2I1 – Jeune Syndrome

Jeune syndrome, or Jeune asphyxiating thoracic dystrophy, is a rare autosomal recessive skeletal ciliopathy characterized by a narrow chest, short ribs, polydactyly, and variable extraskeletal involvement. Pathogenic variants in DYNC2I1 have been implicated in disrupted retrograde intraflagellar transport within the primary cilium, leading to pleiotropic phenotypes. The inheritance mode is autosomal recessive, consistent with bi-allelic variants identified in consanguineous and outbred families.

In a consanguineous Pakistani pedigree, two adolescent sisters presented with retinal degeneration and postaxial polydactyly but lacked thoracic or chondrodysplasia features. Targeted sequencing revealed a novel homozygous N-terminal truncating variant, c.44delC (p.Ala15GlufsTer90), which co-segregated with disease in both sisters (1 family; 2 affected relatives) (PMID:29271569).

A Chinese patient with mild skeletal involvement and renal insufficiency was found to harbor a homozygous missense variant, c.2789C>T (p.Ser930Leu), expanding the phenotypic spectrum to include renal disease (PMID:36381051).

In a multi-patient cohort, compound heterozygous DYNC2I1 variants were detected in an Australian individual with SRPS type III and a Spanish patient with mild Jeune syndrome; both probands carried truncating and missense alleles, demonstrating locus heterogeneity (2 probands; 2 families) (PMID:23910462).

Functional studies show that DYNC2I1 localizes to the base of the primary cilium in human chondrocytes and that patient fibroblasts exhibit defective ciliogenesis with aberrant GLI2 accumulation, confirming a role in retrograde IFT (PMID:23910462). Neuronal migration assays further demonstrated that Wdr60 knockdown disrupts cortical neuron polarity and migration, rescuable by acetylation-mimicking α-tubulin, indicating non-ciliary roles in microtubule organization (PMID:33436552).

Integrating genetic and experimental data, the evidence supports a strong autosomal recessive association between DYNC2I1 variants and Jeune syndrome via loss of intraflagellar transport function. No conflicting reports have been identified. This association is clinically actionable for diagnostic gene panels and informs prognosis and genetic counseling.

Key Take-home: Bi-allelic DYNC2I1 variants cause Jeune syndrome through defective ciliary retrograde transport, supporting its inclusion in diagnostic ciliopathy panels.

References

• American journal of medical genetics. Part A • 2018 • Expanding the phenotype associated with biallelic WDR60 mutations: Siblings with retinal degeneration and polydactyly lacking other features of short rib thoracic dystrophies. PMID:29271569
• Clinical case reports • 2022 • A novel WDR60 variant contributes to a late diagnosis of Jeune asphyxiating thoracic dystrophy in a Chinese patient: A case report. PMID:36381051
• American journal of human genetics • 2013 • Short-rib polydactyly and Jeune syndromes are caused by mutations in WDR60. PMID:23910462
• Cell death & disease • 2021 • SRPS associated protein WDR60 regulates the multipolar-to-bipolar transition of migrating neurons during cortical development. PMID:33436552

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