neurogenetics

, Volume 19, Issue 2, pp 93–103 | Cite as

MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype

  • T. Smol
  • F. Petit
  • A. Piton
  • B. Keren
  • D. Sanlaville
  • A. Afenjar
  • S. Baker
  • E. C. Bedoukian
  • E. J. Bhoj
  • D. Bonneau
  • E. Boudry-Labis
  • S. Bouquillon
  • O. Boute-Benejean
  • R. Caumes
  • N. Chatron
  • C. Colson
  • C. Coubes
  • C. Coutton
  • F. Devillard
  • A. Dieux-Coeslier
  • M. Doco-Fenzy
  • L. J. Ewans
  • L. Faivre
  • E. Fassi
  • M. Field
  • C. Fournier
  • C. Francannet
  • D. Genevieve
  • I. Giurgea
  • A. Goldenberg
  • A. K. Green
  • A. M. Guerrot
  • D. Heron
  • B. Isidor
  • B. A. Keena
  • B. L. Krock
  • P. Kuentz
  • E. Lapi
  • N. Le Meur
  • G. Lesca
  • D. Li
  • I. Marey
  • C. Mignot
  • C. Nava
  • A. Nesbitt
  • G. Nicolas
  • C. Roche-Lestienne
  • T. Roscioli
  • V. Satre
  • A. Santani
  • M. Stefanova
  • S. Steinwall Larsen
  • P. Saugier-Veber
  • S. Picker-Minh
  • C. Thuillier
  • A. Verloes
  • G. Vieville
  • M. Wenzel
  • M. Willems
  • S. Whalen
  • Y. A. Zarate
  • A. Ziegler
  • S. Manouvrier-Hanu
  • V. M. Kalscheuer
  • B. Gerard
  • Jamal Ghoumid
Original Article

Abstract

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to “MED13L haploinsufficiency syndrome.” Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15–17 and 25–31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.

Keywords

MED13L Intellectual disability Mediator complex Cardiopathy 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10048_2018_541_MOESM1_ESM.xlsx (10 kb)
Supplemental Table 1 Comparison of clinical data of patients harboring MED13L protein-truncating variants and missense variants. (XLSX 9 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • T. Smol
    • 1
    • 2
  • F. Petit
    • 2
    • 3
  • A. Piton
    • 4
  • B. Keren
    • 5
  • D. Sanlaville
    • 6
  • A. Afenjar
    • 7
  • S. Baker
    • 8
  • E. C. Bedoukian
    • 9
  • E. J. Bhoj
    • 8
  • D. Bonneau
    • 10
  • E. Boudry-Labis
    • 1
  • S. Bouquillon
    • 1
  • O. Boute-Benejean
    • 2
    • 3
  • R. Caumes
    • 3
  • N. Chatron
    • 6
  • C. Colson
    • 2
    • 3
  • C. Coubes
    • 11
  • C. Coutton
    • 12
  • F. Devillard
    • 12
  • A. Dieux-Coeslier
    • 2
    • 3
  • M. Doco-Fenzy
    • 13
  • L. J. Ewans
    • 14
  • L. Faivre
    • 15
    • 16
  • E. Fassi
    • 17
  • M. Field
    • 18
  • C. Fournier
    • 4
  • C. Francannet
    • 19
  • D. Genevieve
    • 11
  • I. Giurgea
    • 20
  • A. Goldenberg
    • 21
  • A. K. Green
    • 22
  • A. M. Guerrot
    • 21
  • D. Heron
    • 5
  • B. Isidor
    • 23
  • B. A. Keena
    • 24
  • B. L. Krock
    • 8
  • P. Kuentz
    • 16
  • E. Lapi
    • 25
  • N. Le Meur
    • 21
  • G. Lesca
    • 6
  • D. Li
    • 8
  • I. Marey
    • 5
  • C. Mignot
    • 5
  • C. Nava
    • 5
  • A. Nesbitt
    • 8
  • G. Nicolas
    • 21
  • C. Roche-Lestienne
    • 1
  • T. Roscioli
    • 14
  • V. Satre
    • 12
  • A. Santani
    • 8
  • M. Stefanova
    • 22
  • S. Steinwall Larsen
    • 22
  • P. Saugier-Veber
    • 21
  • S. Picker-Minh
    • 26
  • C. Thuillier
    • 1
  • A. Verloes
    • 27
  • G. Vieville
    • 12
  • M. Wenzel
    • 24
  • M. Willems
    • 11
  • S. Whalen
    • 5
  • Y. A. Zarate
    • 28
  • A. Ziegler
    • 10
  • S. Manouvrier-Hanu
    • 2
    • 3
  • V. M. Kalscheuer
    • 29
  • B. Gerard
    • 4
  • Jamal Ghoumid
    • 2
    • 3
  1. 1.Institut de Génétique Médicale, Hôpital Jeanne de FlandreCHU LilleLilleFrance
  2. 2.University of Lille, EA 7364-RADEMELilleFrance
  3. 3.Service de Génétique Clinique, Hôpital Jeanne de FlandreCHU LilleLilleFrance
  4. 4.Laboratoire de diagnostic génétique, Institut de Génétique Médicale d’AlsaceHôpitaux Universitaires de StrasbourgStrasbourgFrance
  5. 5.Département de Génétique, Groupe Hospitalier Pitié-SalpêtrièreAP-HPParisFrance
  6. 6.Service de GénétiqueHospices Civils de LyonLyonFrance
  7. 7.Service de Génétique, Hôpital d’Enfants Armand-TrousseauAP-HPParisFrance
  8. 8.Department of Pathology Laboratory MedicineChildren’s Hospital of PhiladelphiaPhiladelphiaUSA
  9. 9.Roberts Individualized Medical Genetics CenterChildren’s Hospital of PhiladelphiaPhiladelphiaUSA
  10. 10.Service de GénétiqueCHU d’AngersAngersFrance
  11. 11.Département de Génétique MédicaleCHU MontpellierMontpellierFrance
  12. 12.Laboratoire de Génétique ChromosomiqueCHU Grenoble AlpesGrenobleFrance
  13. 13.Service de Génétique, EA3801, SFR-CAP SantéCHU de ReimsReimsFrance
  14. 14.St Vincent’s Clinical SchoolUniversity of New South WalesDarlinghurstAustralia
  15. 15.Centre de Génétique et Centre de Référence Maladies Rares ‘Anomalies du DéveloppementCHU DijonDijonFrance
  16. 16.Equipe GAD, UMR INSERM 1231, Université de BourgogneDijonFrance
  17. 17.Division of Genetics and Genomic Medicine, Department of PediatricsWashington University School of MedicineSt. LouisUSA
  18. 18.The Genetics of Learning Disability ServiceWaratahAustralia
  19. 19.Service de Génétique MédicaleCHU de Clermont-FerrandClermont-FerrandFrance
  20. 20.Service de Génétique, Hôpital TrousseauAP-HPParisFrance
  21. 21.Service de Génétique et Inserm U1079, Centre Normand de Génomique Médicale et Médecine PersonnaliséeCHU de Rouen, Inserm et Université de RouenRouenFrance
  22. 22.Department of Clinical GeneticsUniversity Hospital LinköpingLinköpingSweden
  23. 23.Service de Génétique Médicale, Unité de Génétique CliniqueCHU de NantesNantesFrance
  24. 24.Clinical GeneticsChildren’s Hospital of PhiladelphiaPhiladelphiaUSA
  25. 25.Medical Genetics UnitAnna Meyer Children’s University HospitalFlorenceItaly
  26. 26.Department of Pediatric NeurologyCharité-Universitätsmedizin BerlinBerlinGermany
  27. 27.Unité Fonctionnelle de Génétique Clinique, Hôpital Robert DebréAP-HPParisFrance
  28. 28.Section of Genetics and Metabolism, Department of PediatricsUniversity of Arkansas for Medical SciencesLittle RockUSA
  29. 29.Research Group Development and DiseaseMax Planck Institute for Molecular GeneticsBerlinGermany

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