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Human Genetics

, Volume 137, Issue 9, pp 753–768 | Cite as

Genetic variants in components of the NALCN–UNC80–UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies)

  • Nuria C. BramswigEmail author
  • Aida M. Bertoli-Avella
  • Beate Albrecht
  • Aida I. Al Aqeel
  • Amal Alhashem
  • Nouriya Al-Sannaa
  • Maissa Bah
  • Katharina Bröhl
  • Christel Depienne
  • Nathalie Dorison
  • Diane Doummar
  • Nadja Ehmke
  • Hasnaa M. Elbendary
  • Svetlana Gorokhova
  • Delphine Héron
  • Denise Horn
  • Kiely James
  • Boris Keren
  • Alma Kuechler
  • Samira Ismail
  • Mahmoud Y. Issa
  • Isabelle Marey
  • Michèle Mayer
  • Jennifer McEvoy-Venneri
  • Andre Megarbane
  • Cyril Mignot
  • Sarar Mohamed
  • Caroline Nava
  • Nicole Philip
  • Cecile Ravix
  • Arndt Rolfs
  • Abdelrahim Abdrabou Sadek
  • Lara Segebrecht
  • Valentina Stanley
  • Camille Trautman
  • Stephanie Valence
  • Laurent Villard
  • Thomas Wieland
  • Hartmut Engels
  • Tim M. Strom
  • Maha S. Zaki
  • Joseph G. Gleeson
  • Hermann-Josef Lüdecke
  • Peter Bauer
  • Dagmar Wieczorek
Original Investigation

Abstract

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the “NALCN channelosome”, consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.

Notes

Acknowledgements

We are grateful to the families for participating in this study and giving their consent for publication. We thank Sabine Kaya for excellent technical assistance. NE is participant in the Clinician Scientist Program, funded by the Berlin Institute of Health (BIH) and the Charité. LS received a Medical Student Research Grant from the BIH. This work was in part supported by the German Ministry of Research and Education [grant numbers 01GS08164 (HE), 01GS08167 (DW), 01GS08163 (TMS), German Mental Retardation Network] as part of the National Genome Research Network, the Broad Institute (U54HG003067 to E. Lander and UM1HG008900 to D. MacArthur), the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton and M. Gunel), NIH grants R01NS048453, R01NS052455, the Simons Foundation for Autism Research Initiative and Howard Hughes Medical Institute (to JGG). We would like to thank Prince Abdullah Ben Khalid Celiac Disease Research Chair, Vice Deanship of Research Chairs, King Saud University, Riyadh, Kingdom of Saudi Arabia for their support.

Compliance with ethical standards

Conflict of interest

Arndt Rolfs is founder and shareholder of CENTOGENE AG, a commercial company offering genetic testing service. Aida Bertoli-Avella and Peter Bauer are employees of CENTOGENE AG.

Supplementary material

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Supplementary material 1 (XLSX 26 KB)
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Supplementary material 2 (XLSX 16 KB)

Supplementary material 3 (MOV 31022 KB)

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Copyright information

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

Authors and Affiliations

  • Nuria C. Bramswig
    • 1
    Email author
  • Aida M. Bertoli-Avella
    • 2
  • Beate Albrecht
    • 1
  • Aida I. Al Aqeel
    • 3
    • 4
    • 5
  • Amal Alhashem
    • 3
    • 6
  • Nouriya Al-Sannaa
    • 7
  • Maissa Bah
    • 8
  • Katharina Bröhl
    • 9
  • Christel Depienne
    • 1
    • 10
  • Nathalie Dorison
    • 11
  • Diane Doummar
    • 12
  • Nadja Ehmke
    • 13
    • 14
  • Hasnaa M. Elbendary
    • 15
  • Svetlana Gorokhova
    • 16
    • 17
  • Delphine Héron
    • 8
  • Denise Horn
    • 13
  • Kiely James
    • 18
  • Boris Keren
    • 8
  • Alma Kuechler
    • 1
  • Samira Ismail
    • 15
  • Mahmoud Y. Issa
    • 15
  • Isabelle Marey
    • 8
  • Michèle Mayer
    • 12
  • Jennifer McEvoy-Venneri
    • 18
  • Andre Megarbane
    • 19
    • 20
  • Cyril Mignot
    • 8
  • Sarar Mohamed
    • 3
    • 21
  • Caroline Nava
    • 8
    • 10
  • Nicole Philip
    • 16
    • 17
  • Cecile Ravix
    • 17
  • Arndt Rolfs
    • 2
    • 22
  • Abdelrahim Abdrabou Sadek
    • 23
  • Lara Segebrecht
    • 13
    • 14
  • Valentina Stanley
    • 18
  • Camille Trautman
    • 18
  • Stephanie Valence
    • 12
  • Laurent Villard
    • 16
    • 17
  • Thomas Wieland
    • 24
  • Hartmut Engels
    • 25
  • Tim M. Strom
    • 24
    • 26
  • Maha S. Zaki
    • 15
  • Joseph G. Gleeson
    • 18
  • Hermann-Josef Lüdecke
    • 1
    • 27
  • Peter Bauer
    • 2
  • Dagmar Wieczorek
    • 1
    • 27
  1. 1.Institut für HumangenetikUniversitätsklinikum Essen, Universität Duisburg-EssenEssenGermany
  2. 2.CENTOGENE AG, The Rare Disease CompanyRostockGermany
  3. 3.Department of PediatricsPrince Sultan Military Medical CityRiyadhSaudi Arabia
  4. 4.American University of BeirutBeirutLebanon
  5. 5.Alfaisal UniversityRiyadhSaudi Arabia
  6. 6.Department of Anatomy and Cell Biology, College of MedicineAlfaisal UniversityRiyadhSaudi Arabia
  7. 7.John Hopkins Aramco Health Care, Pediatric ServicesDhahranSaudi Arabia
  8. 8.Groupe de Recherche Clinique sorbonne Université “Déficiences Intellectuelles et Autisme”, Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes RaresAP-HP, Hôpital de la Pitié SalpêtrièreParisFrance
  9. 9.Internal Medicine DepartmentWaldkrankenhaus Evangelical HospitalBerlinGermany
  10. 10.Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, and Inserm U 1127, and CNRS UMR 7225, and ICMParisFrance
  11. 11.Service de Neurochirurgie PédiatriqueFondation Ophtalmologique Adolphe de RothschildParisFrance
  12. 12.AP-HP, Département de neuropédiatrieGHUEP, Hôpital Armand TrousseauParisFrance
  13. 13.Institute of Medical and Human GeneticsCharité-Universitätsmedizin BerlinBerlinGermany
  14. 14.Berlin Institute of HealthBerlinGermany
  15. 15.Human Genetics and Genome Research Division, Clinical Genetics DepartmentNational Research CentreCairoEgypt
  16. 16.Département de Génétique MédicaleAPHM, CHU Timone EnfantsMarseilleFrance
  17. 17.Aix Marseille Univ, MMG, INSERMMarseilleFrance
  18. 18.Departments of Neurosciences and Pediatrics, Howard Hughes Medical InstituteUniversity of California San Diego, Rady Children’s Institute for Genomic MedicineLa JollaUSA
  19. 19.CEMEDIPP-Centre Medico PsychopedagogiqueBeirutLebanon
  20. 20.Institut Jerome LejeuneParisFrance
  21. 21.Prince Abdullah bin Khaled Coeliac Disease Research Chair, College of MedicineKing Saud UniversityRiyadhSaudi Arabia
  22. 22.Albrecht Kossel InstituteUniversity of RostockRostockGermany
  23. 23.Pediatric Neurology Unit, Department of Pediatrics, Faculty of MedicineSohag UniversitySohâgEgypt
  24. 24.Institute of Human GeneticsHelmholtz Zentrum MünchenNeuherbergGermany
  25. 25.Institute of Human GeneticsUniversity of Bonn, School of Medicine and University Hospital BonnBonnGermany
  26. 26.Institute of Human GeneticsTechnische Universität MünchenMunichGermany
  27. 27.Institut für HumangenetikUniversitätsklinikum Düsseldorf, Heinrich-Heine-Universität DüsseldorfDüsseldorfGermany

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