MYD88 – Pyogenic bacterial infections due to MyD88 deficiency

MyD88 deficiency is a rare autosomal recessive inborn error of immunity (IEI) characterized by life-threatening pyogenic bacterial infections in early infancy without typical inflammatory signs. Patients typically present with severe or recurrent infections such as pneumococcal sepsis and skin abscesses, often leading to significant morbidity and mortality if unrecognized.

Clinical Validity: The association between biallelic MYD88 loss-of-function variants and susceptibility to pyogenic infections is classified as Moderate in the ClinGen framework based on 3 unrelated probands harboring the same homozygous in-frame deletion c.157_159del (p.Glu53del) suggesting a founder effect in Roma descent populations ([PMID:39859960]). Functional data are concordant with the human phenotype.

Genetic Evidence: Inheritance is autosomal recessive. To date, 3 unrelated patients have been described with homozygous c.157_159del (p.Glu53del) variants in MYD88, all belonging to Roma families, consistent with a founder allele ([PMID:39859960]). No additional segregating affected relatives were reported in these families. Variant spectrum for this disease is currently limited to this recurrent in–frame deletion.

Functional Evidence: The c.157_159del (p.Glu53del) variant abolishes MyD88 interaction with IRAK4 and disrupts Myddosome assembly in vitro, as shown by analytical gel filtration and NMR titration assays, leading to loss of NF-κB activation ([PMID:24316379]). These findings confirm a loss-of-function mechanism consistent with the clinical phenotype.

No conflicting reports to date dispute the causal role of MYD88 deficiency in pyogenic bacterial susceptibility. Future studies may explore additional alleles and genotype–phenotype correlations.

Key Take-home: Screening for the recurrent c.157_159del (p.Glu53del) variant in MYD88 is recommended in Roma patients with early severe pyogenic infections to enable prompt diagnosis and management.

References

• MyD88 deficiency is a rare inborn error of immunity characterized by susceptibility to pyogenic infections without overt signs of inflammation. PMID:39859960
• Molecular immunology • 2014 • Functional assessment of the mutational effects of human IRAK4 and MyD88 genes. PMID:24316379

Evidence Based Scoring (AI generated)