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ZFTRAF1 encodes a ubiquitously expressed nucleocytoplasmic protein of previously unknown function. Biallelic variants in ZFTRAF1 have been recently implicated in a severe autosomal recessive neurodevelopmental disorder characterized by global developmental delay, postnatal microcephaly, and hypotonia. These findings establish ZFTRAF1 as a novel disease gene and provide a rationale for diagnostic sequencing in patients with similar presentations.
Genetic evidence derives from 5 affected individuals across 3 unrelated families (PMID:38641995). Four individuals from two families harbored homozygous frameshift variants, and one individual from a third family carried a homozygous intronic splice‐site variant, all leading to predicted loss of function. Segregation analysis demonstrated co-segregation of these variants with disease in each family without unaffected homozygotes observed, supporting an autosomal recessive inheritance mode.
The variant spectrum is limited to loss-of-function alleles, including the recurrent c.1085_1086del (p.Phe362CysfsTer18) (PMID:38641995). No missense, deep intronic, or structural variants have yet been reported. Carrier frequency and founder effects remain to be defined in broader populations.
Functional characterization in patient-derived fibroblasts revealed complete absence of ZFTRAF1 protein by immunoblotting and immunofluorescence, confirming loss of protein expression. Pulldown assays identified 110 interacting proteins enriched in mRNA processing and autophagy pathways, linking ZFTRAF1 to cellular protein homeostasis.
Autophagy marker profiling demonstrated irregularities in protein degradation in patient cells, suggesting that defective autophagy contributes to neuronal dysfunction. RNA sequencing further highlighted dysregulated transcripts involved in neurodevelopmental pathways, demonstrating concordance between cellular phenotypes and clinical features.
No conflicting studies have been reported. Taken together, the genetic and experimental data provide strong evidence that loss of ZFTRAF1 function underlies this neurodevelopmental syndrome. Future studies on variant spectrum and mechanistic rescue will further inform therapeutic strategies.
Key Take-home: Biallelic loss-of-function variants in ZFTRAF1 cause a severe autosomal recessive neurodevelopmental disorder with microcephaly and hypotonia, supporting inclusion of ZFTRAF1 in diagnostic gene panels.
Gene–Disease AssociationStrong5 probands from 3 unrelated families, homozygous variants segregating in 2 families, and concordant functional data (PMID:38641995) Genetic EvidenceModerate5 probands with biallelic loss-of-function variants in 3 unrelated families, segregation confirmed Functional EvidenceModerateCellular assays show absent ZFTRAF1 protein in patient fibroblasts and disrupted autophagy pathways |