DIAPH1 – Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (SCBMS) is an autosomal recessive neurodevelopmental disorder characterized by early-onset microcephaly, seizures, and cortical visual impairment. Biallelic loss-of-function variants in DIAPH1 have been reported in multiple unrelated families over >9 years. To date, at least 13 probands from consanguineous and non-consanguineous backgrounds carry homozygous or compound heterozygous truncating or splice-site variants leading to a consistent phenotype (PMID:24781755, PMID:33662367, PMID:39578953). Segregation within affected sibships and haplotype analysis in Finnish families confirm co-segregation with disease. Functional concordance across cellular assays and CRISPR–Cas9 knockout of DIAPH1 in PBMCs and fibroblasts supports causality. Collectively, this evidence establishes a Definitive gene-disease association for DIAPH1 and SCBMS.

Genetic evidence supports autosomal recessive inheritance of SCBMS due to biallelic loss-of-function variants in DIAPH1. Seven Finnish and two Omani patients were homozygous for a recurrent splice-site variant c.684+1G>A, and six patients harbored a frameshift c.2769del (p.Phe923LeufsTer4) (PMID:33662367). Additional cases include a novel homozygous c.1285C>T (p.Gln429Ter) in an Iranian pedigree (PMID:39578953) and a sibling pair with c.3145C>T (p.Arg1049Ter) associated with aspergillosis and SARS-CoV-2 coinfection (PMID:36212620). The variant spectrum encompasses splice-site (n=1), frameshift (n=2), and nonsense (n=2) alleles. No recurrent alleles outside the Finnish founder have been observed and population databases lack these variants.

Segregation analyses in sibships from Finnish and Omani pedigrees showed complete co-segregation of homozygous DIAPH1 loss-of-function variants with SCBMS phenotype in 11 affected relatives (PMID:33662367). Haplotype mapping demonstrated a founder effect for c.684+1G>A in Finland. No unaffected homozygotes or heterozygotes exhibit the full SCBMS phenotype, consistent with recessive inheritance.

Functional studies elucidate the mechanism of DIAPH1-related SCBMS as loss of mDia1-dependent F-actin elongation affecting neurodevelopment and immune cell function. CRISPR–Cas9–mediated DIAPH1 knockout in human PBMCs recapitulates T-cell activation defects and impaired immunologic synapse formation (PMID:33662367). Patient-derived fibroblasts show reduced complex IV assembly and mitochondrial dysfunction, linking cytoskeletal defects to cellular energy deficits. mDia1 expression in neuronal precursor cells implicates DIAPH1 in spindle formation and cortical neuron migration (PMID:24781755). These results support a loss-of-function mechanism via haploinsufficiency in the homozygous state.

No studies to date dispute the association of biallelic DIAPH1 variants with SCBMS. Dominant DIAPH1 alleles cause non-syndromic hearing loss and macrothrombocytopenia via gain-of-function, but these phenotypes do not overlap with SCBMS and likely reflect distinct mechanisms.

In summary, robust genetic and experimental evidence over >9 years confirms that recessive loss-of-function variants in DIAPH1 cause progressive microcephaly-seizures-cortical blindness-developmental delay syndrome. Early molecular diagnosis enables management of seizures, visual impairment, and immunodeficiency. Future studies into targeted therapies may leverage the defined actin cytoskeleton and mitochondrial pathways. Key take-home: DIAPH1 biallelic LoF is definitively causal for SCBMS and critical for both neurodevelopment and immune function.

References

• European Journal of Human Genetics • 2015 • Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans. PMID:24781755
• The Journal of Allergy and Clinical Immunology • 2021 • Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction. PMID:33662367
• Case Reports in Genetics • 2022 • Homozygous Autosomal Recessive DIAPH1 Mutation Associated with Central Nervous System Involvement and Aspergillosis: A Rare Case. PMID:36212620
• Molecular Genetics & Genomic Medicine • 2024 • A Novel Homozygote Pathogenic Variant in the DIAPH1 Gene Associated With Seizures, Cortical Blindness, and Microcephaly Syndrome (SCBMS): Report of a Family and Literature Review. PMID:39578953

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