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NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases
  1. Joyce El Hokayem1,
  2. Céline Huber1,
  3. Adeline Couvé1,
  4. Jacqueline Aziza2,
  5. Geneviève Baujat1,
  6. Raymonde Bouvier3,
  7. Denise P Cavalcanti4,
  8. Felicity A Collins5,
  9. Marie-Pierre Cordier6,
  10. Anne-Lise Delezoide7,
  11. Marie Gonzales8,
  12. Diana Johnson9,
  13. Martine Le Merrer1,
  14. Annie Levy-Mozziconacci10,
  15. Philippe Loget11,
  16. Dominique Martin-Coignard12,
  17. Jelena Martinovic13,
  18. Geert R Mortier14,
  19. Marie-José Perez15,
  20. Joëlle Roume16,
  21. Gioacchino Scarano17,
  22. Arnold Munnich1,
  23. Valérie Cormier-Daire1
  1. 1Department of Genetics, INSERM U781, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker, AP-HP, Paris, France
  2. 2Laboratoire d'anatomie et cytologie pathologiques, Hôpital Purpan, Toulouse, France
  3. 3Centre de pathologie EST, Hôpital Louis Pradel, Hôpital Pierre Wertheimer, Hôpital Femme Mère enfant, Lyon, France
  4. 4Programa de Genética Perinatal, Departamento de Genética Médica, FCM, UNICAMP, Campinas, São Paulo, Brazil
  5. 5Western Sydney Genetics Program, Department of Clinical Genetics, Children's, Hospital at Westmead, Sydney, Australia
  6. 6Service de Génétique, Groupement Hospitalier Est, HFME, Bron, France
  7. 7Service de Biologie de Développement, Université Paris Diderot, Hôpital Robert Debré, AP-HP, Paris, France
  8. 8Service de Génétique et d'Embryologie Médicales, Hôpital Armand Trousseau, (AP-HP), Université Pierre et Marie Curie - Paris 6, France
  9. 9Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundations Trust, Western Bank, England
  10. 10Laboratoire de Biochimie et Biologie Moléculaire, Hôpital Nord, Marseille, France
  11. 11Centre hospitalier universitaire de Rennes, Service d'anatomie et cytologie pathologiques, Rennes, France
  12. 12Pôle de biopathologie, UF 3162, Centre hospitalier, Le Mans, France
  13. 13Unit of Fetal Pathology, Cerba Laboratory, Cergy Pontoise
  14. 14Department of Medical Genetics, Antwerp University Hospital and University of Antwerp, Antwerp, Belgium
  15. 15Département Génétique Médicale, Arnaud de Villeneuve Hospital, Montpellier, France
  16. 16Service de génétique médicale, centre hospitalier Poissy-Saint-Germain, France
  17. 17Department of Medical Genetics, Sannio University, Benevento, Italy
  1. Correspondence to Professor Valérie Cormier-Daire, Department of Genetics, INSERM U781, Hôpital Necker, Université Paris Descartes, Sorbonne Paris Cité, Paris 75015, France; valerie.cormier-daire{at}


Background The lethal short rib polydactyly syndromes (SRP type I–IV) are characterised by notably short ribs, short limbs, polydactyly, multiple anomalies of major organs, and autosomal recessive mode of inheritance. Among them, SRP type II (Majewski; MIM 263520) is characterised by short ovoid tibiae or tibial agenesis and is radiographically closely related to SRP type IV (Beemer-Langer; MIM 269860) which is distinguished by bowed radii and ulnae and relatively well tubulated tibiae. NEK1 mutations have been recently identified in SRP type II. Double heterozygosity for mutations in both NEK1 and DYNC2H1 in one SRP type II case supported possible digenic diallelic inheritance.

Methods The aim of this study was to screen DYNC2H1 and NEK1 in 13 SRP type II cases and seven SRP type IV cases. It was not possible to screen DYNC2H1 in two patients due to insufficient amount of DNA.

Results The study identified homozygous NEK1 mutations in 5/13 SRP type II and compound heterozygous DYNC2H1 mutations in 4/12 cases. Finally, NEK1 and DYNC2H1 were excluded in 3/12 SRP type II and in all SRP type IV cases. The main difference between the mutation positive SRP type II group and the mutation negative SRP type II group was the presence of holoprosencephaly and polymycrogyria in the mutation negative group.

Conclusion This study confirms that NEK1 is one gene causing SRP type II but also reports mutations in DYNC2H1, expanding the phenotypic spectrum of DYNC2H1 mutations. The exclusion of NEK1 and DYNC2H1 in 3/12 SRP type II and in all SRP type IV cases further support genetic heterogeneity.

  • SRP II
  • SRP IV
  • NEK1
  • DYNC2H1
  • ciliopathy group
  • genetic heterogeneity
  • genetics
  • aneuploidy
  • cytogenetics
  • clinical genetics
  • calcium and bone
  • chromosomal
  • molecular genetics
  • diagnosis
  • congenital heart disease
  • congenital heart disease

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  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Respective participating institutions.

  • Provenance and peer review Not commissioned; externally peer reviewed.