Type of mutations
Most of the variants reported in LIFR are either nonsense or frameshift null variants, affecting its extracellular domain and resulting in lack of LIFR signalling.
The p.(Glu219Glyfs*3) pathogenic frameshift variant is described as a founder mutation in patients from the United Arab and the p.(Lys253*) nonsense variant could have a founder effect in the Romanian/gypsy population.
In addition, there are two reports in the literature of individuals that harbour missense variants in both alleles of LIFR, showing a partial SWS phenotype lacking the typical long bone skeletal dysplasia.
Suspected pathophysiologic mechanism
Functional experiments in affected individual cells have demonstrated a failure to express high-affinity LIFRs affecting JAK/STAT signalling and resulting in lack of STAT3 phosphorylation but the exact mechanisms resulting in the different manifestations of the disorder remain unclear and as yet unidentified.
Genotype-phenotype correlation
There is no clear genotype–phenotype correlation. There are patients habouring the same null variant resulting in both surviving and nonsurviving phenotypes.
The two patients reported with missense variants in both alleles lack the typical long bone dysplasia. It remains to be seen if an overlapping but different and mild phenotype from the typical SWS is the result of residual protein activity due to missense variants.
Genetic testing
Possible molecular diagnostic approaches to confirm the diagnosis in a proband include:
-Next generation sequencing of a multi-gene panel, which includes LIFR, or performing whole exome sequencing (WES).
- LIFR Sanger sequencing (single-gene testing), if the clinical suspicion of Stuve Wiedemann syndrome is high.
Parents’ targeted genetic testing of identified variants in the LIFR gene is recommended.
LIFR