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Targeted resequencing in a patient with a syndromic form of neurodevelopmental disorder

ABSTRACT: Targeted resequencing in a patient with a syndromic form of neurodevelopmental disorder

PROVIDER: PRJEB32673 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR3334776.fastq.gz	Fastqsanger.gz
	ERR3334777.fastq.gz	Fastqsanger.gz

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Project description:Katanins are microtubule-severing ATPases. Dysfunction of katanin subunits has been implicated in impaired neurogenesis, morphogenesis, and neuronal migration. Although heterozygous variants in KATNAL2 (katanin-like 2), a known autism-spectrum disorder (ASD) risk gene, have been reported in patients with ASD or other neurodevelopmental disorders (NDD), the underlying cellular mechanisms remain incompletely defined. Whole-exome sequencing (WES) identified a homozygous missense variant in KATNAL2 (NM_001387690.1: c.1390T>C; p.(Ser464Pro)) in a pediatric patient presenting with severe global developmental delay, intellectual disability, infantile-onset epilepsy, and autistic features, extending the phenotypic spectrum beyond prior autism-focused associations. To elucidate the cellular mechanisms underlying KATNAL2 dysfunction, we established induced pluripotent stem cells (iPSCs) from patient-derived fibroblasts and differentiated them into neural progenitor cells (NPCs) for quantitative immunofluorescence analyses of microtubule organization, KATNAL2-associated microtubule regulatory network, and transcriptome profiling. In parallel, we generated a zebrafish CRISPR/Cas9 katnal2 model and assessed body patterning and axonal projections using the transgenic nbt:dsRed line. Patient iPSC-derived NPCs showed impaired interphase microtubule network organization with increased angular standard deviation in directionality and mitotic/cytokinesis abnormalities, including abnormal positioning of the microtubule-rich cytokinetic midbody region. In vivo, CRISPR/Cas9 katnal2 zebrafish crispants showed abnormal body patterning together with disorganized motor neuron and posterior lateral line nerve axonal projections. Together, these findings support KATNAL2 as a regulator of microtubule network organization and mitotic progression in human NPCs. Our data from patient-derived NPCs and zebrafish model provide functional evidence linking the p.(Ser464Pro) variant to an extended syndromic neurodevelopmental phenotype.

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Targeted resequencing in a patient with a syndromic form of neurodevelopmental disorder

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