Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction

J Allergy Clin Immunol. 2021 Aug;148(2):599-611. doi: 10.1016/j.jaci.2020.12.656. Epub 2021 Mar 1.


Background: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency.

Objective: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1.

Methods: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used.

Results: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients' immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain.

Conclusions: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in SCBMS pathogenesis.

Keywords: DIAPH1; SCBMS; T cells; immunodeficiency; microcephaly; mitochondrial dysfunction.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blindness, Cortical* / genetics
  • Blindness, Cortical* / immunology
  • Blindness, Cortical* / pathology
  • Child
  • Child, Preschool
  • Female
  • Finland
  • Formins* / deficiency
  • Formins* / immunology
  • Humans
  • Male
  • Microcephaly* / genetics
  • Microcephaly* / immunology
  • Microcephaly* / pathology
  • Mitochondrial Diseases* / genetics
  • Mitochondrial Diseases* / immunology
  • Mitochondrial Diseases* / pathology
  • Oman
  • Seizures* / genetics
  • Seizures* / immunology
  • Seizures* / pathology
  • Severe Combined Immunodeficiency* / genetics
  • Severe Combined Immunodeficiency* / immunology
  • Severe Combined Immunodeficiency* / pathology
  • Syndrome


  • DIAPH1 protein, human
  • Formins