GLE1 – lethal arthrogryposis-anterior horn cell disease syndrome

GLE1 encodes a conserved mRNA export mediator essential for nucleocytoplasmic transport and motor neuron development. Recessive mutations in GLE1 have been implicated in severe fetal motor neuron diseases, including lethal arthrogryposis-anterior horn cell disease syndrome (PMID:28657126).

This syndrome follows an autosomal recessive inheritance pattern with five probands reported across four unrelated families (PMID:28657126). Affected individuals harbor either compound heterozygous or homozygous GLE1 variants, confirming AR segregation.

The variant spectrum includes the founder insertion p.Thr144_Glu145insProPheGln in compound heterozygosity with missense changes p.Arg569His, p.Val617Met or homozygous c.2051T>C (p.Ile684Thr) (PMID:28657126).

Clinical features uniformly include fetal akinesia, arthrogryposis multiplex congenita (HP:0002804), neonatal seizures (HP:0001250), and progressive respiratory failure (HP:0002878). Autopsy reveals anterior horn cell loss consistent with motor neuron degeneration (PMID:28657126).

Patient-derived fibroblast assays demonstrate that p.Ile684Thr impairs GLE1 nuclear envelope localization, supporting a loss-of-function mechanism via disrupted mRNA export at the nuclear pore (PMID:28657126).

Combined genetic and functional evidence yields a Moderate clinical validity classification. GLE1 sequencing should be included in diagnostic panels for neonatal arthrogryposis with anterior horn cell disease to enable early molecular diagnosis, prognosis estimation, and genetic counseling.

References

• Clinical genetics • 2018 • A homozygous I684T in GLE1 as a novel cause of arthrogryposis and motor neuron loss PMID:28657126

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