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This summary integrates multiple lines of evidence demonstrating that loss‐of‐function variants in FERMT3 are strongly associated with leukocyte adhesion deficiency 3. The disorder, inherited in an autosomal recessive manner, is characterized by defective integrin activation leading to impaired leukocyte adhesion and platelet aggregation, which underlies clinical manifestations including recurrent infections, bleeding diathesis, and other hematologic abnormalities (PMID:20216991, PMID:22139635). In several independent case reports and multi‐patient studies, affected individuals from unrelated families have been reported; segregation analyses in these families along with detailed clinical evaluations support the pathogenicity of FERMT3 mutations.
Genetic evidence is robust and includes a spectrum of variants such as splice site changes, deletions, and nonsense mutations. A representative pathogenic variant is c.1717C>T (p.Arg357Ter) which causes a premature stop codon and has been recurrently observed in multiple studies (PMID:20216991, PMID:32092470). Segregation data further strengthen the association as additional affected relatives in diverse families demonstrate concordant inheritance patterns.
Functional and experimental assessments have shown that FERMT3 mutations disrupt integrin-mediated signaling. In vitro assays, animal models, and post-hematopoietic stem cell transplant (HSCT) observations confirm that loss of kindlin-3 impairs both leukocyte adhesion and platelet aggregation. These findings elucidate the mechanistic basis for the clinical phenotype of immunodeficiency and bleeding, and they demonstrate that restoration of normal FERMT3 function results in improvement of integrin activity (PMID:25086068, PMID:25854317).
The overall evidence meets a ClinGen classification of Strong. Approximately 23 probands across multiple independent studies (PMID:20216991, PMID:22139635) have been documented with segregating variants and complementary experimental data that support the causality of FERMT3 variants in leukocyte adhesion deficiency 3. In addition, extensive functional studies further corroborate the role of kindlin-3 deficiency in dysregulation of integrin activation.
Additionally, multi-patient cohorts and case series have consistently reported a broad phenotypic spectrum ranging from recurrent infections (e.g., HP:0002719) and neonatal sepsis to thrombocytopenia and leukocytosis (HP:0001873, HP:0001974), emphasizing the diagnostic importance and clinical utility of genetic testing for FERMT3 in suspected cases. These integrated findings guide optimal diagnostic decision-making and support the use of genetic screening in commercial and clinical laboratory settings.
Key Take‑home: Recognizing FERMT3 loss-of‑function variants, such as c.1717C>T (p.Arg357Ter), in patients with suggestive clinical findings is critical for timely diagnosis and management of leukocyte adhesion deficiency 3.
Gene–Disease AssociationStrongApproximately 23 probands across independent studies with segregation evidence and consistent functional data establish a strong association between FERMT3 mutations and leukocyte adhesion deficiency 3 (PMID:20216991, PMID:22139635). Genetic EvidenceStrongMultiple studies report a spectrum of pathogenic variants, notably the recurrent c.1717C>T (p.Arg357Ter) mutation, observed in several unrelated families with clear autosomal recessive segregation and confirmed by molecular genetic testing (PMID:20216991, PMID:32092470). Functional EvidenceModerateRobust functional assays, including integrin activation studies and HSCT rescue experiments, confirm that loss of kindlin-3 disrupts leukocyte and platelet functions, aligning with the clinical phenotype observed in LAD‑III patients (PMID:25086068, PMID:25854317). |