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FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta
  1. Mathilde Doyard1,
  2. Séverine Bacrot1,
  3. Céline Huber1,
  4. Maja Di Rocco2,
  5. Alice Goldenberg3,
  6. Mona S Aglan4,
  7. Perrine Brunelle1,
  8. Samia Temtamy4,
  9. Caroline Michot1,
  10. Ghada A Otaify4,
  11. Coralie Haudry1,
  12. Mireille Castanet5,
  13. Julien Leroux6,
  14. Jean-Paul Bonnefont1,
  15. Arnold Munnich1,
  16. Geneviève Baujat1,
  17. Pablo Lapunzina7,8,
  18. Sophie Monnot1,
  19. Victor L Ruiz-Perez8,9,
  20. Valérie Cormier-Daire1
  1. 1 Department of Medical Genetics, INSERM U1163, Université Paris-Descartes, Institut Imagine, Hôpital Necker-Enfants Malades, Paris, France
  2. 2 Unit of Rare Diseases, Department of Pediatrics, Giannina Gaslini Institute, Genova, Italy
  3. 3 Department of Genetics, Centre Normand de Génomique Médicale et Médecine Personnalisée, CHU de Rouen, Rouen, France
  4. 4 Department of Clinical Genetics. Human Genetics and Genome Research Division, Centre of Excellence of Human Genetics, National Research Centre, Cairo, Egypt
  5. 5 Department of Pediatric, CHU de Rouen, Rouen, France
  6. 6 Department of Pediatric Surgery, CHU de Rouen, Rouen, France
  7. 7 Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain
  8. 8 CIBER de enfermedades Raras (CIBERER), Insitituto de Salud Carlos III, Madrid, Spain
  9. 9 Instituto de Investigaciones Biomédicas de Madrid, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain
  1. Correspondence to Dr Victor L Ruiz-Perez, CIBER de enfermedades Raras (CIBERER), Insitituto de Salud Carlos III, Madrid, Spain; vlruiz{at} and Professor Valérie Cormier-Daire, Département of Genetics, INSERM U1193, Paris Descartes University, Instititut Imagine, Hôpital Necker-Enfants Malades, Paris 75015, France; valerie.cormier-daire{at}


Background Stüve-Wiedemann syndrome (SWS) is characterised by bowing of the lower limbs, respiratory distress and hyperthermia that are often responsible for early death. Survivors develop progressive scoliosis and spontaneous fractures. We previously identified LIFR mutations in most SWS cases, but absence of LIFR pathogenic changes in five patients led us to perform exome sequencing and to identify homozygosity for a FAM46A mutation in one case [p.Ser205Tyrfs*13]. The follow-up of this case supported a final diagnosis of osteogenesis imperfecta (OI), based on vertebral collapses and blue sclerae.

Methods and results This prompted us to screen FAM46A in 25 OI patients with no known mutations.

We identified a homozygous deleterious variant in FAM46A in two affected sibs with typical OI [p.His127Arg]. Another homozygous variant, [p.Asp231Gly], also classed as deleterious, was detected in a patient with type III OI of consanguineous parents using homozygosity mapping and exome sequencing.

FAM46A is a member of the superfamily of nucleotidyltransferase fold proteins but its exact function is presently unknown. Nevertheless, there are lines of evidence pointing to a relevant role of FAM46A in bone development. By RT-PCR analysis, we detected specific expression of FAM46A in human osteoblasts andinterestingly, a nonsense mutation in Fam46a has been recently identified in an ENU-derived (N-ethyl-N-nitrosourea) mouse model characterised by decreased body length, limb, rib, pelvis, and skull deformities and reduced cortical thickness in long bones.

Conclusion We conclude that FAM46A mutations are responsible for a severe form of OI with congenital bowing of the lower limbs and suggest screening this gene in unexplained OI forms.

  • calcium and bone
  • clinical genetics
  • developmental

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  • MD and SB contributed equally.

  • Contributors All authors of this manuscript fulfil the criteria of authorship. Families 1-2: MD, SB, CH, PB, CH, J-PB and SM contributed to the molecular studies. Clinical studies are from MDR, AG, CM, MC, JL, GB and VC-D. Family 3: PL and VLR-P conducted molecular studies and clinical assessment was carried out by MSA, ST and GAO. VC-D designed the study and MD, AM, VLR-P and VC-D wrote the manuscript.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The study was approved by corresponding ethics board committees from The Necker Hospital, France, the National Research Centre in Cairo and Hospital La Paz.

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