Submission Details

DIAPH1 was first reported in relation to autosomal recessive progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (SCBMS) in 2015 (Ercan-Sencicek et al., PMID: 24781755). DIAPH1-related SCBMS is characterized by microcephaly, intellectual disability and developmental delay, seizures, and cortical blindness. Some individuals present with failure to thrive, hypoplasia of the corpus callosum, recurrent infections, bronchiectasis, and lymphoma.

DIAPH1 has also been reported in relation to autosomal dominant sensorineural hearing loss-thrombocytopenia syndrome (AD SNHL +/- thrombocytopenia) with gain of function mechanism of disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the phenotypic variability and inheritance pattern. Therefore, the following disease entities have been split into multiple disease entities, deafness, autosomal dominant 1, with or without thrombocytopenia (OMIM:124900) and seizures, cortical blindness, microcephaly syndrome (OMIM:616632). The split curation for autosomal dominant sensorineural hearing loss-thrombocytopenia syndrome has been curated separately.

A total of 7 variants (four nonsense, two frameshift, and one canonical splice site) have been reported in fifteen probands in six publications (PMIDs: 24781755, 26463574, 33662367, 36212620, 39076976, 39120629) are included in this curation. Several variants were recurrent within unrelated individuals from the same population, and all individuals were homozygous. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence (e.g. animal models, expression studies, in vitro functional assays, etc.) (PMIDs: 17595162, 24781755, 33662367, 39076976, 39120629). Loss of DIAPH1 protein has been demonstrated defective T cell, NK cell, and TCR signaling pathway in patient cells, mouse model, and DIAPH1 deficient Jurkat cells. Additionally, cytoskeleton regulation defects, consistent with the disruption to actin were observed. Interestingly, the mouse models were not reported to recapitulate the full phenotype, specifically the microcephaly, seizures, and cortical blindness, but did recapitulate the immune phenotype. Heterozygous carriers (parents of patients or siblings) were not reported to be clinically affected, this includes no reports of hearing impairment, suggesting the mechanism of disease between AR SCBMS and AD SNHL +/- thrombocytopenia may be different. The mechanism of disease for AR SCBMS is thought to be loss of function.

In summary, there is definitive evidence supporting the relationship between DIAPH1 autosomal recessive progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (SCBMS). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date [November, 21, 2024] (SOP Version 11)].