Sarah Beaussant-Cohen, MD, pediatric hematology-oncologist and clinical immunologist with a post doc in immunology, discusses gene testing and WHIM syndrome.
WHIM syndrome is a rare, autosomal dominant combined primary immunodeficiency predominantly caused by gain-of-function variants in the CXCR4 gene. With autosomal dominant transmission, the probability of inheriting the disease is 50% for a child of an affected parent and an unaffected parent. Genetic testing is available to aid in the molecular diagnosis of WHIM syndrome. Wider availability of genetic testing panels and genetic counseling may offer opportunities for earlier management.
If WHIM syndrome is suspected, a patient’s diagnosis can be confirmed through genetic testing to identify pathogenic variants in the CXCR4 gene. Detection of a pathogenic CXCR4 variant in an affected individual supports the diagnosis of WHIM syndrome but relies on an appropriate annotation of disease-causing variants.
Advances in genetic diagnostic techniques (such as Next-Generation-Sequencing) and increasing awareness about the disease may facilitate early recognition and diagnosis and guide management. In fact, the use of the latest sequencing tecniques has greatly expanded the number of identified disease-causing CXCR4 variants, 33 additional variants have been reported (as of 2023), belonging to one of 3 groups (frameshift, non-sense, missense). Of these 36, only 19 are reported in ClinVar with 15 have been classified as pathogenic or likely-pathogenic. As ClinVar has been outpaced by scientific reports, it is critical to remain up-to-date on the latest pathogenic findings in the published literature to accurately classify newly identified variants. Researchers believe it is likely that additional de novo variants will be reported in the future.
For more information on WHIM syndrome, visit the WHIM Syndrome Learning Center.