DYNC2H1 – Jeune syndrome

Jeune syndrome (asphyxiating thoracic dystrophy) is a rare autosomal recessive skeletal ciliopathy characterized by a narrow thorax, shortened ribs, and tubular bones, with variable polydactyly and extraskeletal manifestations. The heavy chain dynein motor protein encoded by DYNC2H1 drives retrograde intraflagellar transport essential for primary cilia function in chondrocytes and respiratory epithelia, and its disruption underlies Jeune syndrome (Jeune syndrome).

Biallelic DYNC2H1 variants have been reported in over 40 unrelated families worldwide, including homozygous missense and truncating alleles in a consanguineous family and compound heterozygous changes in nonconsanguineous cases ([PMID:19442771], [PMID:35893076], [PMID:38550721]). Variant classes span 13 early protein-truncating alleles (nonsense/frameshift), canonical splice-site disruptions, and clustered missense substitutions within the ATPase motor domains.

A representative pathogenic change is c.5960C>T (p.Thr1987Met), identified by homozygosity mapping in three affected siblings from a Moroccan pedigree presenting with thoracic dystrophy and skeletal abnormalities ([PMID:19442771]). Prenatal and neonatal case reports further describe compound heterozygous missense variants c.12716T>G (p.Leu4239Arg) and homozygous c.9041G>T (p.Arg3014Ile) in lethal short-rib thoracic dysplasia without extra-skeletal involvement ([PMID:35893076], [PMID:38550721]).

Segregation analysis in multiple families confirms autosomal recessive inheritance, with at least two additional affected siblings segregating DYNC2H1 variants in trans in the Moroccan family and consistent trans inheritance in nonconsanguineous kindreds.

Functional high-speed video microscopy of respiratory cilia from affected individuals demonstrated impaired dynein-2 motor activity, abnormal ciliary beating, and accumulation of intraflagellar cargo at ciliary tips, supporting a hypomorphic loss-of-function mechanism ([PMID:28257607]).

Together, comprehensive genetic and experimental evidence justify a Strong clinical validity rating for DYNC2H1 in Jeune syndrome, endorsing DYNC2H1 molecular testing in diagnostic workflows and facilitating genetic counseling.

Key Take-home: Biallelic DYNC2H1 loss-of-function and hypomorphic variants reliably cause autosomal recessive Jeune syndrome by disrupting retrograde ciliary transport, underpinning molecular diagnosis and family risk assessment.

References

• American journal of human genetics • 2009 • DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. PMID:19442771
• The clinical respiratory journal • 2018 • DYNC2H1 mutation causes Jeune syndrome and recurrent lung infections associated with ciliopathy. PMID:28257607
• Genes • 2022 • Prenatal Diagnosis of Jeune Syndrome Caused by Compound Heterozygous Variants in DYNC2H1 Gene-Case Report with Rapid WES Procedure and Differential Diagnosis of Lethal Skeletal Dysplasias. PMID:35893076
• International medical case reports journal • 2024 • Whole-Exome Sequencing Identifies DYNC2H1 Mutations as a Cause of Jeune Asphyxiating Thoracic Dystrophy Without Extra-Skeletal Organ Involvement. PMID:38550721

Evidence Based Scoring (AI generated)