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.
- simplified gyration
- epileptic encephalopathy
- bilateral cataract
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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 (firstname.lastname@example.org, ORCID number https://orcid.org/0000-0002-9505-5906).
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