Submission Details

LIFR is located on chromosome 5 at 5p13.1 and encodes leukemia inhibitory factor receptor protein. LIFR was first reported in relation to autosomal recessive Stüve-Wiedemann syndrome in 2004 (Dagoneau et al., PMID 14740318). At least 28 unique variants (nonsense, frameshift, splicing, missense, gross deletions) have been reported in affected individuals, 22 of which are predicted to cause a loss of function of the protein, suggesting biallelic loss of function is the mechanism of disease for this gene. Variants in this gene have been reported in at least 22 probands in four publications (Dagoneau et al., 2004, PMID 14740318; Jung et al., 2010, PMID 20447141; Yeşil et al., 2014, PMID 24988918; Maddirevula et al., 2018, PMID 29620724). Additional genetic evidence is available in the literature; however, the maximum score for genetic evidence (12 pts) was reached. Further evidence supporting this gene-disease relationship includes functional alteration experiments and a LIFR-deficient mouse model, which recapitulates several features of the disease phenotype, including feeding difficulties, skeletal abnormalities, decreased bone volume and nervous system dysfunction (Dagoneau et al., 2004 PMID 14740318; Bellais et al., 2010 PMID 19603067; Ware et al., 1995 PMID 7789261). In summary, LIFR is definitively associated with autosomal recessive Stüve-Wiedemann syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 2Sept2020 (SOP Version 7).