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Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families
  1. Geneviève Baujat1,
  2. Céline Huber1,
  3. Joyce El Hokayem1,
  4. Roseline Caumes1,
  5. Claire Do Ngoc Thanh2,
  6. Albert David3,
  7. Anne-Lise Delezoide4,
  8. Anne Dieux-Coeslier5,
  9. Brigitte Estournet2,
  10. Christine Francannet6,
  11. Honorine Kayirangwa1,
  12. Florence Lacaille7,
  13. Muriel Le Bourgeois8,
  14. Jelena Martinovic9,
  15. Rémi Salomon10,
  16. Sabine Sigaudy11,
  17. Valérie Malan1,
  18. Arnold Munnich1,
  19. Martine Le Merrer1,
  20. Kim Hanh Le Quan Sang1,
  21. Valérie Cormier-Daire1
  1. 1Département de Génétique et INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Fondation Imagine, Hôpital Necker-Enfants malades, AP-HP, Paris, France
  2. 2Médecine Physique et Réadaptation de l'Enfant, Hôpital Raymond Poincaré, Garches, France
  3. 3Service de Génétique Médicale, CHU de Nantes, Nantes, France
  4. 4Service de Biologie du Développement, Université Paris Diderot-Sorbonne Paris Cité, Hôpital Robert Debré, AP-HP, Paris, France
  5. 5Clinique de Génétique Guy Fontaine, CHRU, Hôpital Jeanne de Flandre, Lille, France
  6. 6Service de Génétique Médicale, CHU Estaing, Clermont Ferrand, France
  7. 7Service d'Hépatologie-Gastroenterologie-Nutrition, Université Paris Descartes, Hôpital Necker-Enfants malades, AP-HP, Paris, France
  8. 8Département of de Pneumologie et Allergologie, Université Paris Descartes, Hôpital Necker-Enfants malades, AP-HP, Paris, France
  9. 9Unité de Foetopathologie, Université Paris Sud, Hôpital Antoine Béclère, APHP, Paris, France
  10. 10Service de Néphrologie Pédiatrique et U574, Université Paris Descartes, Hôpital Necker-Enfants malades, AP-HP, Paris, France
  11. 11Département de Génétique Médicale, Hôpital d'Enfant de la Timone, Marseille, France
  1. Correspondence to Professor Valérie Cormier-Daire, Department of Genetics, Paris Descartes-Sorbonne Paris Cité, Fondation Imagine, Hopital Necker-Enfants malades, AP-HP, U781, Paris 75015, France; valerie.cormier-daire{at}inserm.fr

Abstract

Background Asphyxiating Thoracic Dysplasia (ATD) belongs to the short rib polydactyly group and is characterized by a narrow thorax, short long bones and trident acetabular roof. Other reported features include polydactyly, renal, liver and retinal involvement. To date, mutations in IFT80, DYNC2H1, TTC21B and WDR19 have been reported in ATD. The clinical and molecular heterogeneity leads to difficulties in the evaluation of the long-term prognosis.

Methods We investigated 53 ATD cases (23 living cases and 30 fetuses) from 39 families. They benefited from a combined approach of deep phenotyping and IFT80 and DYNC2H1 molecular screening.

Results Among the 23 postnatal cases, pulmonary insufficiency was noted in 60% of cases, with tracheotomy requirement in five cases. Renal and liver diseases occurred respectively in 17% and 22% of cases, whereas retinal alteration was present in 50% of cases aged more than 5 years. We identified DYNC2H1 mutations in 23 families (59%) and IFT80 mutations in two families (5%). However, in six families, only one heterozygote mutation in either IFT80 or DYNC2H1 was identified. Finally, the two genes were excluded in 14 families (36%).

Conclusions We conclude that DYNC2H1 is a major gene responsible for ATD, while IFT80 is rarely involved. The presence of only one mutation in six families and the exclusion of the two genes in 14 families support the involvement of other causal cilia genes. The long-term follow up emphasizes that the pulmonary prognosis is probably less pejorative and retinal involvement more frequent than previously thought.

  • Genetics
  • Clinical genetics
  • Molecular genetics

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