Submission Details

KIFBP (alternative titles KBP, KIAA1279) was first reported in relation to autosomal recessive Goldberg-Shprintzen syndrome (GOSHS; OMIM# 609460) in 2005 (Brooks et al., PMID: 15883926). GOSHS is characterized by intellectual disability and microcephaly, frequently seen with Hirschsprung disease and/or gyral abnormalities of the brain. Nine homozygous loss of function variants (nonsense, frameshift, intragenic deletion) that have been reported in ten probands in six publications (PMIDs: 15883926, 23427148, 24072599, 28277559, 32939943, 34421502) are included in this curation. All of these ten probands were homozygous variant carriers, eight of which were from families known to be consanguineous, many of which had more than one affected homozygote. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. While missense variants have been reported in cases with atypical presentations (PMID: 32939943), there is insufficient evidence to support a pathogenic role for missense variants in this disease at this time. This gene-disease relationship is also supported by a zebrafish kbp mutant model organism that displays disruption in axonal structure (PMID: 23427148) and a human cell culture model that shows abnormal neurite outgrowth (PMID: 18192286), mirroring the central and enteric neuronal developmental defects seen in GOSHS. In summary, there is definitive evidence supporting the relationship between KIFBP and autosomal recessive GOSHS. 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 Brain Malformations GCEP on the meeting date July 25, 2023 (SOP Version 9).