SPRED1 – Legius Syndrome

Legius syndrome is a rare autosomal dominant disorder characterized by multiple café-au-lait macules, intertriginous freckling, macrocephaly and variable learning difficulties, without neurofibromas or Lisch nodules. It is caused by heterozygous germline loss-of-function variants in the SPRED1 gene, a negative regulator of the RAS-MAPK pathway. The condition overlaps phenotypically with Neurofibromatosis type 1 but lacks tumour complications, making molecular diagnosis essential for appropriate management and surveillance.

ClinGen classifies the SPRED1–Legius syndrome association as Definitive, based on observations in over 146 unrelated probands (PMID:22753041), consistent segregation in 14 families (PMID:21089071), and concordant functional evidence demonstrating RAS-ERK hyperactivation in model systems (PMID:19118178).

Genetic evidence includes identification of at least 89 distinct loss-of-function (nonsense, frameshift, splicing, copy-number) and several inactivating missense variants across 146 probands (PMID:22753041). Inheritance is autosomal dominant, with segregation of pathogenic variants in multiple multi-generation pedigrees (14 families) (PMID:21089071). The recurrent variant c.70C>T (p.Arg24Ter) exemplifies the truncating variant spectrum and has been reported in unrelated families (PMID:21089071).

Functional studies support haploinsufficiency as the mechanism: Spred1–/– mice exhibit impaired hippocampal synaptic plasticity, reduced learning and memory performance, and elevated ERK phosphorylation, mirroring neurodevelopmental features of Legius syndrome (PMID:19118178). Structural and biophysical analyses of pathogenic EVH1 domain missense mutations (e.g., p.Thr102Arg) demonstrate disrupted binding to neurofibromin’s GAP-related domain, abolishing RAS suppression (PMID:31401120). Rescue experiments in knock-in mice further highlight the potential for targeting autophagic clearance of SPRED1 aggregates.

No significant conflicting evidence has been reported; SPRED1 variants consistently map to disease-relevant domains and functional assays uniformly support a loss-of-function mechanism.

Integrated genetic and experimental findings confirm SPRED1 as a key negative regulator of RAS-MAPK signalling whose haploinsufficiency causes Legius syndrome. Accurate molecular diagnosis enables differentiation from NF1 and guides genetic counselling and tailored surveillance, highlighting the clinical utility of SPRED1 testing.

Key Take-home: SPRED1 loss-of-function variants cause a definitive autosomal dominant Legius syndrome phenotype, distinguishable from NF1 by absence of tumours and supported by robust genetic and functional evidence.

References

• Human Mutation • 2011 • Legius syndrome in fourteen families. PMID:21089071
• Journal of Neuroscience • 2008 • Spred1 is required for synaptic plasticity and hippocampus-dependent learning. PMID:19118178
• Journal of Molecular Biology • 2019 • Pathogenic Mutations Associated with Legius Syndrome Modify the Spred1 Surface and Are Involved in Direct Binding to the Ras Inactivator Neurofibromin. PMID:31401120
• Human Mutation • 2012 • Review and update of SPRED1 mutations causing Legius syndrome. PMID:22753041

Evidence Based Scoring (AI generated)