Abstract
Primrose syndrome is characterized by variable intellectual deficiency, behavior disorders, facial features with macrocephaly, and a progressive phenotype with hearing loss and ectopic calcifications, distal muscle wasting, and contractures. In 2014, ZBTB20 variants were identified as responsible for this syndrome. Indeed, ZBTB20 plays an important role in cognition, memory, learning processes, and has a transcription repressive effect on numerous genes. A more severe phenotype was discussed in patients with missense single nucleotide variants than in those with large deletions. Here, we report on the clinical and molecular results of 14 patients: 6 carrying ZBTB20 missense SNVs, 1 carrying an early truncating indel, and 7 carrying 3q13.31 deletions, recruited through the AnDDI-Rares network. We compared their phenotypes and reviewed the data of the literature, in order to establish more powerful phenotype–genotype correlations. All 57 patients presented mild-to-severe ID and/or a psychomotor delay. Facial features were similar with macrocephaly, prominent forehead, downslanting palpebral fissures, ptosis, and large ears. Hearing loss was far more frequent in patients with missense SNVs (p = 0.002), ectopic calcification, progressive muscular wasting, and contractures were observed only in patients with missense SNVs (p nonsignificant). Corpus callosum dysgenesis (p = 0.00004), hypothyroidism (p = 0.047), and diabetes were also more frequent in this group. However, the median age was 9.4 years in patients with deletions and truncating variant compared with 15.1 years in those with missense SNVs. Longer follow-up will be necessary to determine whether the phenotype of patients with deletions is also progressive.
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Acknowledgements
We wish to thank the patients and their families involved in the study, and the physicians who referred their patients to our center. We also thank the University of Burgundy Centre de Calcul (CCuB) for technical support and management of the informatics platform. This work was supported by grants from Dijon University Hospital, the Regional Council of Burgundy Franche-Comté through the Plan d’Actions Régional pour l’Innovation (PARI 2016), and the European Union through the PO FEDER-FSE Bourgogne 2014/2020 programs and the FEDER 2016. This work was also partially funded by the French Ministry of Health (PHRC national 2008/2008-A00515-50) and the Regional Council of Burgundy/Dijon University hospital (PARI 2012). URLs DGV: http://dgv.tcag.ca/dgv/app/home. ClinVAR: https://www.ncbi.nlm.nih.gov/clinvar/. Decipher: https://decipher.sanger.ac.uk/. ExAC Browser: https://exac.broadinstitute.org, GnomAD: https://gnomad.broadinstitute.org. OMIM: https://www.omim.org. RefSeq: https://www.ncbi.nlm.nih.gov/refseq/. UCSC: https://genome.ucsc.edu.
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Juven, A., Nambot, S., Piton, A. et al. Primrose syndrome: a phenotypic comparison of patients with a ZBTB20 missense variant versus a 3q13.31 microdeletion including ZBTB20. Eur J Hum Genet 28, 1044–1055 (2020). https://doi.org/10.1038/s41431-020-0582-3
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DOI: https://doi.org/10.1038/s41431-020-0582-3
