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Original research
Biallelic variants in ZNF526 cause a severe neurodevelopmental disorder with microcephaly, bilateral cataract, epilepsy and simplified gyration
  1. Maria Lisa Dentici1,2,
  2. Viola Alesi3,
  3. Mathieu Quinodoz4,5,
  4. Barbara Robens6,7,
  5. Andrea Guerin8,
  6. Sébastien Lebon9,
  7. Annapurna Poduri6,7,
  8. Lorena Travaglini10,
  9. Federica Graziola11,12,
  10. Alexandra Afenjar13,
  11. Boris Keren14,
  12. Valerio Licursi15,
  13. Alessandro Capuano11,
  14. Bruno Dallapiccola16,
  15. Andrea Superti-Furga4,
  16. Antonio Novelli3
  1. 1Medical Genetics Unit, Academic Department of Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
  2. 2Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Rome, Italy
  3. 3Medical Genetics Laboratory, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
  4. 4Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland
  5. 5Department of Ophthalmology, University of Basel, Basel, Switzerland
  6. 6Department of Neurology, F.M. Kirby Neurobiology Center, Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Boston Children’s Hospital, Boston, Massachusetts, USA
  7. 7Division of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital, Boston, Massachusetts, USA
  8. 8Division of Medical Genetics, Department of Pediatrics, Kingston Health Sciences Centre, Queen's University, Kingston, Ontario, Canada
  9. 9Unit of Pediatric Neurology and Neurorehabilitation Unit, Division of Pediatrics, Department Woman-Mother-Child, Lausanne University Hospital (CHUV), Lausanne, Switzerland
  10. 10Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
  11. 11Neurology Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
  12. 12Neuroscience department, Tor Vergata University, Rome, Italy
  13. 13CRMR Déficiences Intellectuelles de Causes Rares, Département de Génétique, Sorbonne Université, APHP, Hôpital Trousseau, Paris, France
  14. 14APHP, Département de Génétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France
  15. 15Dept. of Biology and Biotechnology, "Charles Darwin", Sapienza University of Rome, Rome, Italy
  16. 16Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
  1. Correspondence to Dr Maria Lisa Dentici, Medical Genetics Unit, Academic Department of Pediatrics, Bambino Gesù Pediatric Hospital, Roma, Italy; marialisa.dentici{at}


Background Next-generation sequencing, combined with international pooling of cases, has impressively enhanced the discovery of genes responsible for Mendelian neurodevelopmental disorders, particularly in individuals affected by clinically undiagnosed diseases. To date, biallelic missense variants in ZNF526 gene, encoding a Krüppel-type zinc-finger protein, have been reported in three families with non-syndromic intellectual disability.

Methods Here, we describe five individuals from four unrelated families with an undiagnosed neurodevelopmental disorder in which we performed exome sequencing, on a combination of trio-based (4 subjects) or single probands (1 subject).

Results We identified five patients from four unrelated families with homozygous ZNF526 variants by whole exome sequencing. Four had variants resulting in truncation of ZNF526; they were affected by severe prenatal and postnatal microcephaly (ranging from −4 SD to −8 SD), profound psychomotor delay, hypertonic–dystonic movements, epilepsy and simplified gyral pattern on MRI. All of them also displayed bilateral progressive cataracts. A fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (−2 SD), progressive bilateral cataracts, severe intellectual disability and unremarkable brain MRI.

Mutant znf526 zebrafish larvae had notable malformations of the eye and central nervous system, resembling findings seen in the human holoprosencephaly spectrum.

Conclusion Our findings support the role of ZNF526 biallelic variants in a complex neurodevelopmental disorder, primarily affecting brain and eyes, resulting in severe microcephaly, simplified gyral pattern, epileptic encephalopathy and bilateral cataracts.

  • Microcephaly
  • simplified gyration
  • epileptic encephalopathy
  • bilateral cataract
  • holoprosencephaly
  • ZNF526

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  • Correction notice The article has been corrected since it was published Online First. The list of authors and their affiliations have been corrected.

  • Contributors All the authors approved the final content of the manuscript. MLD, VA and AC monitored the cohort gathering, conceived and designed the work. MLD, AG, AA, SL, AC, FG, BD and AS-F contributed to the clinical information. VA, MQ, BK, LT and LC contributed to the molecular information, analysis and interpretation of the data. BR and AP participated on the zebrafish studies. BD, AS-F and AN supervised the writing of the manuscript.

  • Funding This work was supported by Ministero della Salute [RC2020, to MLD], and OPBG Project “Vite Coraggiose”.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval The study was approved by the ethics committee of the Bambino Gesù Pediatric Hospital, Rome. All participants provided informed consent.

  • Data availability statement All data relevant to the study are included in the article or uploaded as online supplemental information. For further information, contact the corresponding author (, ORCID number

  • 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.

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