KIFBP – Goldberg‑Shprintzen syndrome

This summary consolidates evidence from case reports, multi‑patient studies, and functional analyses to support a strong association between KIFBP and Goldberg‑Shprintzen syndrome. The clinical validity is rated as strong, based on findings in over 37 patients across independent studies, with multiple unrelated probands showing homozygous loss‑of‑function variants, robust segregation data, and concordant experimental findings (PMID:25846562, PMID:28277559).

The genetic evidence indicates an autosomal recessive inheritance pattern. Affected individuals typically present with a spectrum of features including intellectual disability, microcephaly, iris coloboma, motor delay, hypotonia, ptosis, and other congenital anomalies. Reported case series and family studies document recurrent pathogenic variants, notably nonsense and frameshift mutations, which result in loss‑of‑function of the KIFBP protein. For example, the variant c.976C>T (p.Gln326Ter) has been reported in a multi‑patient study, underscoring its relevance (PMID:28277559).

Segregation analysis across families further supports pathogenicity as additional affected relatives consistently inherit these variants. In several studies, affected siblings and extended family members have been found to segregate with the causative alleles, reinforcing the gene‑disease relationship.

Functional studies have provided critical insights into the molecular mechanisms underlying this condition. Experimental evidence from cellular assays and animal models has demonstrated that loss of KIFBP function disrupts neuronal migration, axonal outgrowth, and microtubule dynamics. These findings recapitulate key clinical features of Goldberg‑Shprintzen syndrome, such as central nervous system malformations and peripheral neuropathy (PMID:23427148, PMID:18192286).

The integration of robust genetic data with experimental validation offers a coherent narrative that fortifies the clinical utility of genetic testing for KIFBP in patients suspected of having Goldberg‑Shprintzen syndrome. While additional cases and functional data continue to emerge and exceed the ClinGen scoring maximum, the present evidence is sufficient to support diagnostic decision‑making and clinical management.

Key take‑home sentence: The strong association between homozygous loss‑of‑function mutations in KIFBP and Goldberg‑Shprintzen syndrome underscores the relevance of molecular diagnostics in establishing precision medicine strategies for affected individuals.

References

• American journal of medical genetics. Part A • 2015 • Goldberg‑Shprintzen megacolon syndrome with associated sensory motor axonal neuropathy PMID:25846562
• Iranian journal of child neurology • 2017 • Association of a Novel Nonsense Mutation in KIAA1279 with Goldberg‑Shprintzen Syndrome PMID:28277559
• Frontiers in molecular neuroscience • 2019 • Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg‑Shprintzen Syndrome PMID:31736709
• Human molecular genetics • 2013 • KBP‑cytoskeleton interactions underlie developmental anomalies in Goldberg‑Shprintzen syndrome PMID:23427148
• Human mutation • 2020 • Goldberg‑Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP PMID:32939943
• Molecular syndromology • 2021 • Goldberg‑Shprintzen Syndrome Associated with a Novel Variant in the KIFBP Gene PMID:34421502
• Development (Cambridge, England) • 2008 • KBP is essential for axonal structure, outgrowth and maintenance in zebrafish, providing insight into the cellular basis of Goldberg‑Shprintzen syndrome PMID:18192286

Evidence Based Scoring (AI generated)