2. Academic Validation
  3. FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta

FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta

  • J Med Genet. 2018 Apr;55(4):278-284. doi: 10.1136/jmedgenet-2017-104999.
Mathilde Doyard # 1,  Séverine Bacrot # 1,  Céline Huber 1,  Maja Di Rocco 2,  Alice Goldenberg 3,  Mona S Aglan 4,  Perrine Brunelle 1,  Samia Temtamy 4,  Caroline Michot 1,  Ghada A Otaify 4,  Coralie Haudry 1,  Mireille Castanet 5,  Julien Leroux 6,  Jean-Paul Bonnefont 1,  Arnold Munnich 1,  Geneviève Baujat 1,  Pablo Lapunzina 7 8,  Sophie Monnot 1,  Victor L Ruiz-Perez 8 9,  Valérie Cormier-Daire 1
Affiliations

Affiliations

  • 1 Department of Medical Genetics, INSERM U1163, Université Paris-Descartes, Institut Imagine, Hôpital Necker-Enfants Malades, Paris, France.
  • 2 Unit of Rare Diseases, Department of Pediatrics, Giannina Gaslini Institute, Genova, Italy.
  • 3 Department of Genetics, Centre Normand de Génomique Médicale et Médecine Personnalisée, CHU de Rouen, Rouen, France.
  • 4 Department of Clinical Genetics. Human Genetics and Genome Research Division, Centre of Excellence of Human Genetics, National Research Centre, Cairo, Egypt.
  • 5 Department of Pediatric, CHU de Rouen, Rouen, France.
  • 6 Department of Pediatric Surgery, CHU de Rouen, Rouen, France.
  • 7 Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain.
  • 8 CIBER de enfermedades Raras (CIBERER), Insitituto de Salud Carlos III, Madrid, Spain.
  • 9 Instituto de Investigaciones Biomédicas de Madrid, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
  • # Contributed equally.
PMID: 29358272 DOI: 10.1136/jmedgenet-2017-104999
Abstract

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.

Keywords

calcium and bone; clinical genetics; developmental.

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