Background Sex-specific predilection in neurological diseases caused by mutations in autosomal genes is a phenomenon whose molecular basis is poorly understood. We studied females of consanguineous Bedouin kindred presenting with severe global developmental delay and epilepsy.

Methods Linkage analysis, whole exome sequencing, generation of CRISPR/cas9 knock-in mice, mouse behaviour and molecular studies

Results Linkage analysis and whole exome sequencing studies of the affected kindred delineated a ~5 Mbp disease-associated chromosome 2q35 locus, containing a novel homozygous frameshift truncating mutation in ZNF142, in line with recent studies depicting similar ZNF142 putative loss-of-function human phenotypes with female preponderance. We generated knock-in mice with a truncating mutation adjacent to the human mutation in the mouse ortholog. Behaviour studies of homozygous Zfp142^R1508* mice showed significant phenotype only in mutant females, with learning and memory deficits, hyperactivity and aberrant loss of fear of open spaces. Bone marrow and spleen of homozygous Zfp142^R1508* mice showed depletion of lymphoid and haematopoietic cells, mostly in females. RT-PCR showed lower expression of Zpf142 in brain compartments of female versus male wild-type mice. RNA-seq studies of hippocampus, hypothalamus, cortex and cerebellum of female wild-type versus homozygous Zfp142^R1508* mice demonstrated differentially expressed genes. Notably, expression of Taok1 in the cortex and of Mllt6 in the hippocampus was downregulated in homozygous Zfp142^R1508* mice. Taok1 mutations have been associated with aberrant neurodevelopment and behaviour. Mllt6 expression is regulated by sex hormones and Mllt6 null-mutant mice present with haematopoietic, immune system and female-specific behaviour phenotypes.

Conclusion ZNF142 mutation downregulates Mllt6 and Taok1, causing a neurodevelopmental phenotype in humans and mice with female preponderance.