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Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia

ABSTRACT: Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia

PROVIDER: PRJNA951710 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24058368_1.fastq.gz	Fastqsanger.gz
	SRR24058368_2.fastq.gz	Fastqsanger.gz
	SRR24058369_1.fastq.gz	Fastqsanger.gz
	SRR24058369_2.fastq.gz	Fastqsanger.gz
	SRR24058370_1.fastq.gz	Fastqsanger.gz

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Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia by impairing autophagy

Project description:Neurodevelopmental disorders have great clinical and genetic heterogeneity and are known to arise from dysfunction in components of diverse cellular pathways, the precise pathomechanism for the majority however remains elusive. We studied five patients from three unrelated families originating from Yemen, Germany and Spain. The affected individuals manifested global developmental delay, variable degrees of microcephaly and hypotonia. Whole exome sequencing identified biallelic variants in the ZFTRAF1, encoding a protein of unknown function. The four patients from two unrelated families segregated two homozygous frameshift variants, NM_001330618.2:c.1085_1086delTT;p.(Phe362Cysfs*18), NM_001330618.2:c.1162_1163delCT;p.(Leu388Glyfs*49) whereas the third family carried an intronic variant NM_001330618.2:c.612-2A>C;p.(?). We studied this protein at the cellular level and show that endogenous ZFTRAF1 is a nucleocytoplasmic protein with predominant nuclear expression in different human cell lines. We also investigated ZFTRAF1 interactome by pulldown assay and identified 110 interacting proteins that are the crucial components of mRNA processing and autophagy-related pathways. ZFTRAF1 was completely absent in primary fibroblasts derived from two independent patients. Posthoc, profiling of autophagy markers, whole-transcriptome, and whole-proteome analyses discovered dysfunctional autophagy in patient-derived fibroblasts. The same, when attempted to be reprogrammed, could only achieve the pre-iPSCs phase, another indication of impaired autophagy. Briefly, discovered ZFTRAF1 as an indispensable novel component of neurodevelopment, and through multiple lines of evidence implicate its role in autophagy. Our findings suggest that biallelic variants of ZFTRAF1 cause severe neurodevelopmental disability syndrome and the loss-of-function leads to deficient autophagy and mRNA processing, both of which have crucial roles in normal human brain development.

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Biallelic UNC5C variants cause a recessive neurodevelopmental disorder with brain anomalies

Project description:Precise axon guidance is fundamental to neural circuit formation, yet the full spectrum of neurodevelopmental disorders arising from disruptions in this process remains undefined. Here, we describe a multi-ethnic cohort of eight patients from five independent families presenting with a neurodevelopmental disorder characterized by structural brain anomalies, distal limb contractures, developmental delay, intellectual disability, and additional variable features. All affected individuals carry biallelic deleterious variants in UNC5C, a gene encoding a conserved netrin receptor essential for axon guidance and neuronal migration. To investigate the functional consequences of these variants, we performed structural analyses, which indicated that the identified variants disrupt key functional domains, including the immunoglobulin-like (Ig), thrombospondin-1 type repeats (TSP), ZU5, UPA, and death domains. We then introduced disease-associated mutations into conserved residues of the Caenorhabditis elegans unc-5 orthologue using CRISPR/Cas9 genome editing and assessed phenotypic outcomes in vivo. Cell-type-specific rescue experiments revealed the observed motor defects are primarily neurogenic in origin. Consistent with the clinical features observed in patients, C. elegans carrying the corresponding human mutations exhibited defects in axon guidance, locomotion, and behaviour, supporting disruption of UNC-5–mediated signalling pathways. Together, our findings establish biallelic pathogenic variants in UNC5C as the cause of a previously unrecognized autosomal recessive neurodevelopmental disorder with structural brain anomalies and distal limb contractures. Our combined approach of human genetics and in vivo modelling defines a critical role for UNC5C in human neurodevelopment and expands the spectrum of disorders arising from disrupted axon guidance machinery.

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