DYNC2LI1 – Short-rib Thoracic Dysplasia 15 with Polydactyly

DYNC2LI1 encodes the light intermediate chain of the dynein-2 motor complex, essential for retrograde intraflagellar transport in primary cilia. Short-rib thoracic dysplasia 15 with polydactyly (SRTD15) is an autosomal recessive skeletal ciliopathy characterized by short horizontal ribs, short limbs, and postaxial polydactyly. Affected fetuses typically present with a perinatal lethal phenotype due to thoracic insufficiency and severe limb shortening.

Genetic evidence for DYNC2LI1 in SRTD15 includes compound heterozygous variants identified by whole-exome sequencing in multiple unrelated families. In one consanguineous Chinese pedigree, two fetuses harbored c.358C>T (p.Pro120Ser) of paternal origin and c.928A>T (p.Lys310Ter) of maternal origin, correlating with SRPS-like skeletal changes (PMID:33030252). Separately, three additional families exhibited segregating splice-site, nonsense, frameshift, and missense variants under an autosomal recessive model (PMID:26077881).

The DYNC2LI1 variant spectrum comprises at least 15 distinct alleles, including four canonical splice-site variants (c.900+1G>A, c.126+1G>C, c.900+1G>T, c.802+2T>A) and multiple truncating changes (e.g., c.420del (p.Lys140_Val141insTer), c.961G>T (p.Glu321Ter), c.372G>A (p.Trp124Ter)), as well as hypomorphic missense changes (e.g., c.349C>G (p.Leu117Val)) (PMID:26077881).

Functional studies in patient fibroblasts and engineered knockout models demonstrate that DYNC2LI1 mutations destabilize the dynein-2 complex, cause aberrant ciliary length (hyperelongated or truncated), impair Hedgehog pathway signalling, and lead to intraflagellar transport accumulations consistent with skeletal dysplasia phenotypes (PMID:26077881). Rescue assays confirm that wild-type DYNC2LI1 restores normal ciliary morphology, whereas pathogenic deletion variants fail to complement, especially in compound heterozygous contexts (PMID:34997029).

No conflicting reports have been described. The combined genetic and experimental data firmly establish DYNC2LI1 as a disease gene for SRTD15. Further identification of hypomorphic versus null alleles may refine genotype–phenotype correlations.

Key Take-home: DYNC2LI1 loss-of-function and hypomorphic variants underlie autosomal recessive SRTD15, supporting molecular diagnosis, prenatal counseling, and future therapeutic development.

References

• Molecular Genetics & Genomic Medicine • 2020 • Whole-exome sequencing identified two novel mutations of DYNC2LI1 in fetal skeletal ciliopathy. PMID:33030252
• Nature Communications • 2015 • Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome. PMID:26077881
• Scientific Reports • 2022 • Combinations of deletion and missense variations of the dynein-2 DYNC2LI1 subunit found in skeletal ciliopathies cause ciliary defects. PMID:34997029

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