Abstract
Autosomal recessive microcephaly is a rare clinical condition, which is characterized by reduced brain size that can be associated with delayed intellectual ability, developmental delay, and seizure. In this study, we describe two siblings with microcephaly: a 12-year-old girl with primary microcephaly, and a 7-year-old boy with secondary microcephaly, whose episodes of seizure and neurodevelopmental regression started at 6 years and 6 months of age, respectively. The interesting finding in these siblings was two different presentations of the same variant: one case with primary and one case with secondary microcephaly. Whole-exome sequencing was performed in order to identify causative variants in one family having two affected siblings with microcephaly. Confirmation of the identified variant in the ZNF335 gene in the proband and her affected brother and segregation analysis in the family were performed using the Sanger sequencing method. In both patients, a novel homozygous missense variant, [NM_022095.4: c.3346G>A; p.(Gly1116Arg)], in the ZNF335 gene was identified. The p.(Gly1116Arg) variant causes a defect in the last zinc finger domain of the protein. Conservation analysis by ConSurf server and UCSC genome browser revealed that Gly1116 is a highly conserved amino acid among different species. Different in-silico prediction tools and bioinformatics analysis predicted this variant as damaging.
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The data that support the findings of this study are openly available in Sequence Read Archive (SRA), (Submission ID: SUB10725571 at https://submit.ncbi.nlm.nih.gov/subs/sra/SUB10725571/overview, (SRA number: SRR17053705), (BioProject ID: PRJNA783183), (BioSample ID: SAMN23421294). Human variant and pertinent phenotypes have been reported to ClinVar (Submission ID: SUB10485891; Accession ID: SCV001976525). https://submit.ncbi.nlm.nih.gov/subs/clinvar_wizard/ SUB10485891/overview
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Acknowledgements
We thank all the participants in this research. The authors are especially thankful to the patients and their parents who took part in this study and also the personnel of the Children’s Medical Center for supporting us in this study. Also, we thank Iranian Genetic Foundation and Iranian Social Welfare.
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PM and MH conceived and designed the experiments. EHEM, PM, MRA, RH, ART, EP, and HGH conducted the experiments; PM, MH, ZR, RH, ART, and EHEM analyzed and interpreted the data. PM, EHEM, MH, RH, and MRA contributed reagents/materials/analysis tools. PM, RH, and MH wrote the paper. All the authors reviewed the manuscript.
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The written informed consent was obtained from the parents as legal guardians of the proband and her affected brother. The study protocol was approved by the local medical ethics committee of Children’s Medical Center, Tehran, Iran. The study was being performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
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Ali Reza Tavasoli and Elmira Haji Esmaeil Memar have equal contribution as the first authors.
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Tavasoli, A.R., Memar, E.H.E., Ashrafi, M.R. et al. Primary and Secondary Microcephaly, Global Developmental Delay, and Seizure in Two Siblings Caused by a Novel Missense Variant in the ZNF335 Gene. J Mol Neurosci 72, 719–729 (2022). https://doi.org/10.1007/s12031-021-01955-y
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DOI: https://doi.org/10.1007/s12031-021-01955-y