DYNC2H1 – Asphyxiating Thoracic Dystrophy 3

Short rib-polydactyly syndrome type III (SRTD3), also known as asphyxiating thoracic dystrophy 3, is a perinatal lethal autosomal recessive skeletal ciliopathy characterized by a narrow thorax, shortened long bones, and post-axial polydactyly. Next-generation sequencing studies have identified biallelic DYNC2H1 variants as the molecular cause of SRTD3.

Genetic analyses across 12 unrelated probands from eight families revealed compound heterozygous or homozygous variants in DYNC2H1, including missense, frameshift, and splice-site changes. Representative variants include c.10711_10714del (p.Phe3571ArgfsTer5) (PMID:27323140). Parental segregation confirmed recessive inheritance in each case.

Phenotypic presentations consistently feature a constricted thoracic cage (HP:0000774) and polydactyly (HP:0010442) with variable skeletal and visceral anomalies. Prenatal ultrasound often detects thoracic hypoplasia and limb shortening, supporting early diagnosis.

Functional characterization through RNA sequencing and minigene splicing assays demonstrated aberrant splicing, intron retention, and significantly reduced DYNC2H1 transcript levels, consistent with loss-of-function pathogenicity (PMID:37489014)(PMID:36442996).

No significant conflicting evidence has been reported. The collective genetic and experimental data support a haploinsufficiency mechanism underlying DYNC2H1-associated SRTD3.

The definitive association of biallelic DYNC2H1 variants with asphyxiating thoracic dystrophy 3 underpins the use of targeted sequencing and RNA-based assays for accurate prenatal diagnosis and informed genetic counseling.

References

• Genetics and molecular research : GMR • 2016 • Identification of novel DYNC2H1 mutations associated with short rib-polydactyly syndrome type III using next-generation panel sequencing. PMID:27323140
• Molecular genetics & genomic medicine • 2023 • RNA sequencing resolves novel DYNC2H1 variants causing short-rib thoracic dysplasia type 3: Case report. PMID:37489014
• Cold Spring Harbor molecular case studies • 2022 • Characterization of a novel deep-intronic variant in DYNC2H1 identified by whole-exome sequencing in a patient with a lethal form of a short-rib thoracic dysplasia type III. PMID:36442996
• Frontiers in genetics • 2023 • Genetic analysis and prenatal diagnosis of short-rib thoracic dysplasia 3 with or without polydactyly caused by compound heterozygous variants of DYNC2H1 gene in four Chinese families. PMID:37007936

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