The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant PMID: 26306646

Target-related Cytokines

2026-09-23

The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant

Eur J Hum Genet. 2016 May;24(5):652-9. doi: 10.1038/ejhg.2015.178.

David A Koolen ¹ , Rolph Pfundt ¹ , Katrin Linda ¹ , Gea Beunders ² , Hermine E Veenstra-Knol ³ , Jessie H Conta ⁴ , Ana Maria Fortuna ⁵ , Gabriele Gillessen-Kaesbach ⁶ , Sarah Dugan ⁷ , Sara Halbach ⁸ , Omar A Abdul-Rahman ⁹ , Heather M Winesett ¹⁰ , Wendy K Chung ¹¹ , Marguerite Dalton ¹² , Petia S Dimova ¹³ , Teresa Mattina ¹⁴ , Katrina Prescott ¹⁵ , Hui Z Zhang ¹⁶ , Howard M Saal ¹⁷ , Jayne Y Hehir-Kwa ¹ , Marjolein H Willemsen ¹ , Charlotte W Ockeloen ¹ , Marjolijn C Jongmans ¹ , Nathalie Van der Aa ¹⁸ , Pinella Failla ¹⁹ , Concetta Barone ¹⁹ , Emanuela Avola ¹⁹ , Alice S Brooks ²⁰ , Sarina G Kant ²¹ , Erica H Gerkes ³ , Helen V Firth ²² , Katrin Õunap ²³ , Lynne M Bird ²⁴ , Diane Masser-Frye ²⁴ , Jennifer R Friedman ²⁴ , Modupe A Sokunbi ²⁵ , Abhijit Dixit ²⁶ , Miranda Splitt ²⁷ , DDD Study , Mary K Kukolich ²⁸ , Julie McGaughran ²⁹ , Bradley P Coe ³⁰ , Jesús Flórez ³¹ , Nael Nadif Kasri ¹ , Han G Brunner ¹ ³² , Elizabeth M Thompson ³³ , Jozef Gecz ³⁴ , Corrado Romano ¹⁹ , Evan E Eichler ³⁰ ³⁵ , Bert B A de Vries ¹

Affiliations

1. Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
2. Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
3. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
4. Department of Laboratories, Seattle Children's Hospital, Seattle, WA, USA.
5. Unidade de Genética Médica, Centro de Genética Médica Dr Jacinto Magalhães, Centro Hospitalar do Porto, Porto, Portugal.
6. Institut für Humangenetik, University of Luebeck, Luebeck, Germany.
7. Genetics Department, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
8. Department of Human Genetics, University of Chicago, Chicago, IL, USA.
9. Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, USA.
10. St Luke's Pediatric Associates, Duluth, MN, USA.
11. Department of Pediatrics and Medicine, Columbia University, New York, NY, USA.
12. Counties Manukau District Health Board, South Auckland, New Zealand.
13. Epilepsy Center, St Ivan Rilski University Hospital, Sofia, Bulgaria.
14. Department of Pediatrics, Medical Genetics University of Catania, Catania, Italy.
15. Clinical Genetics, Yorkshire Regional Genetics Service, Leeds, UK.
16. Department of genetics, Yale University School of Medicine, New Haven, CT, USA.
17. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
18. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
19. Pediatrics and Medical Genetics, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy.
20. Department of Clinical Genetics, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
21. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
22. Department of Medical Genetics, Cambridge University Addenbrooke's Hospital, Cambridge, UK.
23. Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
24. Departments of Neurosciences and Pediatrics, University of California San Diego, and Divisions of Neurology and Genetics, Rady Children's Hospital San Diego, San Diego, CA, USA.
25. Nacogdoches Pediatrics, Nacogdoches, TX, USA.
26. Clinical Genetics, Nottingham City Hospital, Nottingham, UK.
27. Northern Genetic Service, Institute of Genetic Medicine, Newcastle upon Tyne, UK.
28. Clinical Genetics, Cook Children's Hospital, Fort Worth, TX, USA.
29. Genetic Health Queensland, Royal Brisbane and Women's Hospital and School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
30. Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
31. Department of Physiology and Pharmacology, University of Cantabria, Cantabria, Spain.
32. Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
33. South Australian Clinical Genetics Service, Women's and Children's Hospital; and Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia.
34. School of Paediatrics and Reproductive Health and Robinson Research Institute, The University of Adelaide at the Women's and Children's Hospital, North Adelaide, South Australia, Australia.
35. Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.

Abstract

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, Epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.