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Intragenic KANSL1 mutations and chromosome 17q21.31 deletions: broadening the clinical spectrum and genotype–phenotype correlations in a large cohort of patients
  1. Marcella Zollino1,
  2. Giuseppe Marangi1,
  3. Emanuela Ponzi1,
  4. Daniela Orteschi1,
  5. Stefania Ricciardi1,
  6. Serena Lattante1,
  7. Marina Murdolo1,
  8. Domenica Battaglia2,
  9. Ilaria Contaldo2,
  10. Eugenio Mercuri2,
  11. Maria Chiara Stefanini2,
  12. Roseline Caumes3,
  13. Patrick Edery4,
  14. Massimiliano Rossi4,
  15. Maria Piccione5,
  16. Giovanni Corsello5,
  17. Matteo Della Monica6,
  18. Francesca Scarano6,
  19. Manuela Priolo7,
  20. Mattia Gentile8,
  21. Giuseppe Zampino9,
  22. Raymon Vijzelaar10,
  23. Omar Abdulrahman11,
  24. Anita Rauch12,
  25. Beatrice Oneda12,
  26. Matthew A Deardorff13,
  27. Sulagna C Saitta13,
  28. Marni J Falk13,
  29. Holly Dubbs13,
  30. Elaine Zackai13
  1. 1Istituto di Genetica Medica, Università Cattolica Sacro Cuore, Roma, Italy
  2. 2Istituto di Neuropsichiatria Infantile, Università Cattolica Sacro Cuore, Roma, Italy
  3. 3CCA Génétique, Hôpital Necker Enfants Malades, Paris, France
  4. 4Centre de référence des anomalies du développement Hôpital Femme-Mère-Enfant Hospices Civils de Lyon, Lyon, France
  5. 5Dipartimento Materno-Infantile, Università di Palermo, Palermo, Italy
  6. 6Dipartimento di Genetica Medica, Azienda Ospedaliera G.Rummo, Benevento, Italy
  7. 7Genetica Medica, AO Bianchi-Melacrino-Morelli, Reggio Calabria, Italy
  8. 8Genetica Medica, Dipartimento Materno-Infantile, Ospedale di Venere, Bari, Italy
  9. 9Istituto di Pediatria, Università Cattolica Sacro Cuore, Roma, Italy
  10. 10MRC-Holland, Amsterdam, The Netherlands
  11. 11Department of Pediatrics, University of Mississippi Medical Center, Jackson, USA
  12. 12Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland
  13. 13Division of Clinical Genetics, Children's Hospital of Philadelphia, Philadelphia, USA
  1. Correspondence to Professor Marcella Zollino, MD, Istituto di Genetica Medica, Università Cattolica Sacro Cuore, Largo F. Vito, 1 00168 Roma, Italy; mzollino{at}


Background The 17q21.31 deletion syndrome phenotype can be caused by either chromosome deletions or point mutations in the KANSL1 gene. To date, about 60 subjects with chromosome deletion and 4 subjects with point mutation in KANSL1 have been reported. Prevalence of chromosome deletions compared with point mutations, genotype–phenotype correlations and phenotypic variability have yet to be fully clarified.

Methods We report genotype–phenotype correlations in 27 novel subjects with 17q21.31 deletion and in 5 subjects with KANSL1 point mutation, 3 of whom were not previously reported.

Results The prevalence of chromosome deletion and KANSL1 mutation was 83% and 17%, respectively. All patients had similar clinical features, with the exception of macrocephaly, which was detected in 24% of patients with the deletion and 60% of those with the point mutation, and congenital heart disease, which was limited to 35% of patients with the deletion. A remarkable phenotypic variability was observed in both categories, mainly with respect to the severity of ID. Cognitive function was within normal parameters in one patient in each group. Craniosynostosis, subependymal heterotopia and optic nerve hypoplasia represent new component manifestations.

Conclusions In KANSL1 haploinsufficiency syndrome, chromosome deletions are greatly prevalent compared with KANSL1 mutations. The latter are sufficient in causing the full clinical phenotype. The degree of intellectual disability (ID) appears to be milder than expected in a considerable number of subjects with either chromosome deletion or KANSL1 mutation. Striking clinical criteria for enrolling patients into KANSL1 analysis include speech delay, distinctive facial dysmorphism, macrocephaly and friendly behaviour.

  • 17q21.31 deletion
  • KANSL1 mutation
  • genotype-phenotype correlations
  • clinical heterogeneity

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