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Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly
  1. José-Mario Capo-Chichi1,
  2. Joseph Tcherkezian2,
  3. Fadi F Hamdan1,
  4. Jean Claude Décarie3,
  5. Sylvia Dobrzeniecka4,
  6. Lysanne Patry1,
  7. Marc-Antoine Nadon1,
  8. Bettina E Mucha1,
  9. Philippe Major1,
  10. Michael Shevell5,
  11. Bouchra Ouled Amar Bencheikh4,6,
  12. Ridha Joober7,
  13. Mark E Samuels1,
  14. Guy A Rouleau6,
  15. Philippe P Roux2,8,
  16. Jacques L Michaud1
  1. 1CHU Sainte-Justine Research Center, Montreal, Quebec, Canada
  2. 2Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec, Canada
  3. 3Department of Medical Imaging, CHU Sainte-Justine, Montreal, Quebec, Canada
  4. 4CHUM Research Center, Montreal, Quebec, Canada
  5. 5Department of Neurology and Neurosurgery, McGill University, and Montreal Children's Hospital, Montreal, Quebec, Canada
  6. 6Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
  7. 7Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada
  8. 8Department of Pathology and Cell Biology, Université de Montreal, Montreal, Quebec, Canada
  1. Correspondence to Dr Jacques L Michaud, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, 3175 Côte Sainte-Catherine, Montreal, Quebec, Canada H3T 1C5; jacques.michaud{at}


Background Mutations in TSC1 or TSC2 cause the tuberous sclerosis complex (TSC), a disorder characterised by the development of hamartomas or benign tumours in various organs as well as the variable presence of epilepsy, intellectual disability (ID) and autism. TSC1, TSC2 and the recently described protein TBC1D7 form a complex that inhibits mTORC1 signalling and limits cell growth. Although it has been proposed that mutations in TBC1D7 might also cause TSC, loss of its function has not yet been documented in humans.

Methods and Results We used homozygosity mapping and exome sequencing to study a consanguineous family with ID and megalencephaly but without any specific features of TSC. We identified only one rare coding variant, c.538delT:p.Y180fsX1 in TBC1D7, in the regions of homozygosity shared by the affected siblings. We show that this mutation abolishes TBC1D7 expression and is associated with increased mTORC1 signalling in cells of the affected individuals.

Conclusions Our study suggests that disruption of TBC1D7 causes ID but without the other typical features found in TSC. Although megalencephaly is not commonly observed in TSC, it has been associated with mTORC1 activation. Our observation thus reinforces the relationship between this pathway and the development of megalencephaly.

  • Clinical genetics
  • Molecular genetics

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