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Original research
Xq28 copy number gain causing moyamoya disease and a novel moyamoya syndrome
  1. Chaker Aloui1,
  2. Stéphanie Guey1,
  3. Eva Pipiras1,2,
  4. Manoelle Kossorotoff3,
  5. Sophie Guéden4,
  6. Michaelle Corpechot5,
  7. Pierre Bessou6,
  8. Jean-Michel Pedespan7,
  9. Marie Husson7,
  10. Dominique Hervé1,8,
  11. Florence Riant5,
  12. Markus Kraemer9,10,
  13. Julie Steffann11,
  14. Olivier Quenez12,
  15. Elisabeth Tournier-Lasserve1,5
  1. 1 Université de Paris, NeuroDiderot, Inserm UMR1141, Paris, France
  2. 2 Department of Cytogenetics, Embryology and Histology, AP-HP Hôpital Jean-Verdier, Bondy, France
  3. 3 French Center for Pediatric Stroke, Department of Pediatric Neurology, APHP, University Hospital Necker-Enfants Malades, Paris, France
  4. 4 Department of Pediatric Neurology, CHU Angers, Angers, France
  5. 5 Service de Génétique Moléculaire Neurovasculaire, AP-HP Hôpital Lariboisière, Paris, France
  6. 6 Service d’imagerie anténatale, de l’enfant et de la femme, Groupe Hospitalier Pellegrin-Hôpital des enfants, Bordeaux, France
  7. 7 Service de neuropédiatrie, Groupe Hospitalier Pellegrin-Hôpital des enfants, Bordeaux, France
  8. 8 Service de Neurologie, AP-HP Hôpital Lariboisière, Paris, France
  9. 9 Department of Neurology, Alfried Krupp Hospital, Essen, Germany
  10. 10 Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  11. 11 Université Paris Descartes, Imagine INSERM UMR1163, Service de Génétique Moléculaire, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
  12. 12 Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics, Normandy Center for Genomic and Personalized Medicine, Rouen, France
  1. Correspondence to Professor Elisabeth Tournier-Lasserve, Université de Paris, NeuroDiderot, Inserm, Paris 75010, France; tournier-lasserve{at}


Background The molecular anomalies causing moyamoya disease (MMD) and moyamoya syndromes (MMS) are unknown in most patients.

Objective This study aimed to identify de novo candidate copy number variants (CNVs) in patients with moyamoya.

Methods Rare de novo CNVs screening was performed in 13 moyamoya angiopathy trios using whole exome sequencing (WES) reads depth data and whole genome high density SNP array data. WES and SNP array data from an additional cohort of 115 unrelated moyamoya probands were used to search for recurrence of these rare de novo CNVs.

Results Two de novo CNVs were identified in two unrelated probands by both methods and confirmed by qPCR. One of these CNVs, located on Xq28, was detected in two additional families. This interstitial Xq28 CNV gain is absent from curated gold standard database of control genomic variants and gnomAD databases. The critical region contains five genes, including MAMLD1, a major NOTCH coactivator. Typical MMD was observed in the two families with a duplication, whereas in the triplicated patients of the third family, a novel MMS associating moyamoya and various systemic venous anomalies was evidenced.

Conclusion The recurrence of this novel Xq28 CNV, its de novo occurrence in one patient and its familial segregation with the affected phenotype in two additional families strongly suggest that it is pathogenic. In addition to genetic counselling application, its association with pulmonary hypertension is of major importance for clinical care. These data also provide new insights into the genomic architecture of this emblematic, non-atherosclerotic, large vessel disease.

  • genetics
  • neurology
  • copy-number
  • cytogenetics

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  • SG and EP contributed equally.

  • Contributors CA, StG, ETL: study design. MKo, StG, PB, JMP, MH, SoG, DH, MKr: clinical and neuroimaging investigation and sample collection. MC, JS, EP, FR: experimental work and data interpretation. CA, EP, StG, OQ, ETL: exome and SNP array data analysis and interpretation. CA, StG, MKo, SoG, ETL: first draft of the manuscript. All authors read and approved the final manuscript. StG and EP are cosecond authors.

  • Funding This work was supported by Inserm. SG was a Fondation pour la Recherche Médicale fellowship recipient (FDM40678).

  • Competing interests None declared.

  • Patient consent for publication Not required.

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

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.