Dataset Information

Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement.

ABSTRACT:

Background

Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis.

Aims and methods

To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing.

Results and conclusions

We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.

SUBMITTER: Schmidts M

PROVIDER: S-EPMC3627132 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Jeune syndrome, or asphyxiating thoracic dystrophy (JATD), is a rare autosomal recessive skeletal dysplasia with heterogeneous genetic and clinical phenotypes, which primarily affects cartilage and bone development. Herein, we report a patient with a lethal form of SRTD3 without polydactyly (JATD), which led to severe restrictive lung disease and fatal respiratory failure. A full-term boy was born to a 30-year-old mother who was known to have hypothyroidism and was on thyroxine. The parents were first-degree cousins and had one healthy older son. Fetal ultrasound showed a cephalic fetus, normal amniotic fluid and a fundal placenta. All long bones and ribs were below the 1% percentile. The femur was bowed with no fractures or signs of significant demineralization at time of imaging. Head and abdominal circumference were within normal range. An echocardiogram on the 2nd day of life showed severe pulmonary hypertension (PHTN). Nitric oxide was started due to the presence of persistent hypoxia and severe PHTN. The patient continued to require high cardiorespiratory support, but the medical condition worsened, and respiratory failure persisted. The patient died of severe respiratory failure at 16 days of life due to respiratory insufficiency secondary to a severely restricted thoracic cage. Whole-exome sequencing (WES) revealed a homozygous mutation in the DYNC2H1 (NM_001377.3) gene, namely, the c.9041G>T NP_001368.2: p.(Arg3014Ile) missense variant, which results in the substitution of the arginine codon at amino acid position 3014 with an isoleucine codon. The phenotyping of the patient's JATD and the detection of a homozygous variant in the DYNC2H1 gene confirmed the diagnosis of short-rib thoracic dysplasia-3 without polydactyly. In summary, the patient had isolated skeletal anomalies without polydactyly or other organ involvement. Additionally, the infant had severe PHTN on top of the respiratory failure, which eventually caused death. Considerably more work will need to be done to determine the clinical spectrum of JATD and understand its genetic heterogeneity.