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Genotype-phenotype correlations
Original research
Further delineation of the rare GDACCF (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies syndrome): genotype and phenotype of 22 patients with ZNF148 mutations
  1. Katalin Szakszon1,2,
  2. Charles Marques Lourenco3,
  3. Bert Louis Callewaert4,5,
  4. David Geneviève6,7,
  5. Flavien Rouxel8,
  6. Denis Morin9,
  7. Anne-Sophie Denommé-Pichon10,11,
  8. Antonio Vitobello10,11,
  9. Wesley G Patterson12,
  10. Raymond Louie13,
  11. Filippo Pinto e Vairo14,
  12. Eric Klee14,
  13. Charu Kaiwar14,
  14. Ralitza H Gavrilova14,
  15. Katherine E Agre14,
  16. Sebastien Jacquemont15,16,
  17. Jizi Khadijé16,
  18. Jacques Giltay17,
  19. Koen van Gassen18,
  20. Gabriella Merő1,
  21. Erica Gerkes19,
  22. Bregje W Van Bon20,
  23. Tuula Rinne20,
  24. Rolph Pfundt20,
  25. Han G Brunner21,
  26. Oana Caluseriu22,
  27. Ute Grasshoff23,
  28. Martin Kehrer23,
  29. Tobias B Haack23,
  30. Melik Malek Khelifa24,
  31. Anke Katharina Bergmann25,
  32. Anna Maria Cueto-González26,27,
  33. Ariadna Campos Martorell28,29,
  34. Shwetha Ramachandrappa30,
  35. Lindsey B Sawyer31,
  36. Pascale Fasel32,
  37. Dominique Braun32,
  38. Atallah Isis33,
  39. Andrea Superti-Furga33,
  40. Vanda McNiven34,35,
  41. David Chitayat35,36,
  42. Syed Anas Ahmed34,
  43. Heiko Brennenstuhl37,
  44. Eva MC Schwaibolf37,
  45. Gladys Battisti38,
  46. Benoit Parmentier38,
  47. Servi J C Stevens39
  1. 1Faculty of Medicine Institute of Pediatrics, University of Debrecen, Debrecen, Hungary
  2. 2Rare Congenital Malformations and Rare intellectual Disability (ERN ITHACA), European Reference Networks, Debrecen, Hungary
  3. 3Neurogenetics Unit - Inborn Errors of Metabolism Clinics, National Reference Center for Rare Diseases, Medicine School of Sao Jose do Rio Preto, Sao Jose do Rio Preto, Brazil
  4. 4Center for Medical Genetics, University Hospital Ghent, Gent, Belgium
  5. 5Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
  6. 6Montpellier University, Inserm Unit U1183, Reference Center for Rare Disease: Developmental Anomalies. Clinical Genetic Unit, CHU Montpellier, Montpellier, France
  7. 7Rare Congenital Malformations and Rare Intellectual Disability (ERN ITHACA), European Reference Networks, Montpellier, France
  8. 8Génétique Clinique, Départment de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU Montpellier, Montpellier University, Centre de Référence Anomalies du Développement SOOR, Montpellier, France
  9. 9Rare Kidney Disease Center, Montpellier University Hospital, Montpellier, France
  10. 10Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
  11. 11Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
  12. 12Greenwood Genetic Center Foundation, Greenwood, South Carolina, USA
  13. 13Greenwood Genetic Center Inc, Greenwood, South Carolina, USA
  14. 14Department of Clinical Genomics, Center for Individualized Medicine, Mayo Clinic Research Rochester, Rochester, Minnesota, USA
  15. 15Sainte-Justine Research Center, Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, Canada
  16. 16Department of Medical Genetics, Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, Canada
  17. 17Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
  18. 18Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  19. 19University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
  20. 20Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
  21. 21Klinische Genetica, Maastricht University Medical Centre, Maastricht, The Netherlands
  22. 22Medical Genetics Clinic, University of Alberta, Edmonton, Alberta, Canada
  23. 23Institute of Medical Genetics and Applied Genomics, University Clinic, Tübingen University, Tübingen, Germany
  24. 24Department of Human Genetics, Medical College Hannover, Hannover, Germany
  25. 25Department of Human Genetics, Hannover Medical School, Hannover, Germany
  26. 26Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
  27. 27Rare Congenital Malformations and Rare intellectual Disability (ERN ITHACA), European Reference Networks, Barcelona, Spain
  28. 28Pediatric Endocrinology Department, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
  29. 29Endocrinology Group, Vall d'Hebron Barcelona Hospital Campus, Autonomous University of Barcelona, Vall d'Hebron Research Institute, Barcelona, Spain
  30. 30Clinical Genetics Department, Guy's & St Thomas' NHS Foundation Trust, London, UK
  31. 31Department of Medical Genetics, Children's Hospital of The King's Daughters, Norfolk, Virginia, USA
  32. 32Department of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland
  33. 33Division of Genetic Medicine, Lausanne University Hospital, Lausanne, Switzerland
  34. 34University Health Network and Mount Sinai Hospital, Fred A Litwin Family Centre in Genetic Medicine, Toronto, Ontario, Canada
  35. 35Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
  36. 36The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, Ontario, Canada
  37. 37Insittute of Human Genetics, Heidelberg University, Heidelberg, Germany
  38. 38Centre de Génétique Humaine, Institut de Pathologie et de Genetique asbl, Gosselies, Belgium
  39. 39Klinische Genetica, Maastricht University Medical Center, Maastricht, The Netherlands
  1. Correspondence to Dr Katalin Szakszon, Faculty of Medicine Institute of Pediatrics, University of Debrecen, Debrecen, 4032, Hungary; szakszon.katalin{at}med.unideb.hu

Abstract

Background Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far.

Methods As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals.

Results The core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the ZNF148 gene. Heterozygous deletion including the entire ZNF148 gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families.

Conclusion The GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term ‘GDACCF syndrome’ with ‘ZNF148-related neurodevelopmental disorder’.

  • Genetic Counselling
  • Paediatrics
  • Psychiatry
  • Behaviour and Behaviour Mechanisms
  • Epilepsy

Data availability statement

Data are available upon reasonable request. Not applicable.

https://doi.org/10.1136/jmg-2022-109030

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    Data availability statement

    Data are available upon reasonable request. Not applicable.

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    Footnotes

    • Correction notice This article has been corrected since it was published Online First. The name of one author has been amended to include the middle name's initial.

    • Contributors KS and SJCS designed and supervised the study and coordinated the international collaboration. KS analysed the data and wrote the manuscript with input from all authors, KS acting as guarantor. GM, CML, BC, DG, FR, DM, A-SD-P, WP, FPV, RHG, KEA, JK, JCG, EG, BWvB, HGB, OC, UG, MK. MMK, AKB, AMC-G, ACM, SR, LBS; PF, IA, AS-F, VMcN, SAA, HB, GB did the patient clinical work-up and provided phenotypic data. AV, RL, EWK, CK, SJ, KvG, TR, RP, TBH, DB, DC, EMCS and BP analysed the whole exome sequencing data and provided genotypic data. Authors’ contribution also included consultation, correction and proofreading the manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.