Submission Details

IGBP1 was first reported in relation to X-linked corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome in 2003 (Graham et al., PMID: 14556245). Two brothers with intellectual disability, macrocephaly, short stature, scoliosis, retrognathia, coloboma, and agenesis of corpus callosum were found to share a maternally inherited 5’ UTR variant in IGBP1 (c.-57_-55delTATinsAA) (PMID: 14556245). Analysis of IGBP1 expression in skin fibroblasts of an affected individual showed normal localization, with 20% increase in protein levels. Because there was no evidence of a deleterious effect of the variant and investigation into additional potential etiologies was limited, this variant was not scored. In 2017, a large exome sequencing study in individuals with developmental disorders reported a de novo missense variant in IGBP1, without phenotype information (DDD Study, PMID: 28135719). This variant is absent from gnomAD v2.1.1, but since there is no functional evidence of pathogenicity, it was not scored. In terms of experimental evidence, the IGBP1 protein binds to MID1 (PMID: 11371618), which is associated with syndromic X-linked intellectual disability (Opitz G/BBB syndrome). In the context of extremely limited genetic evidence, we opted not to score this experimental evidence. In summary, the evidence supporting the relationship between IGBP1 and X-linked corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome is disputed. More evidence is needed to either support or entirely refute the role IGBP1 plays in this disease. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 2/2/2021 (SOP Version 8).