B4GALNT1 gene was first reported in relation to autosomal recessive hereditary spastic paraplegia (HSP) in 2005 (Wilkinson et al., PMID: 15635080). Unlike the autosomal dominant form of B4GALNT1-related HSP, the autosomal recessive form shows a broad phenotypic spectrum within and between families observed in the recorded subjects. Phenotypes reported with B4GALNT-related AR HSP include lower limb spasticity and weakness, mild to moderate intellectual impairment, amyotrophy, gait disturbance, and Babinski signs. Therefore, AR variants in B4GALNT have been lumped into one disease entity, complex hereditary spastic paraplegia. Fourteen different biallelic, loss-of-function variants (missense, nonsense, frameshift, deletion, duplication, splice-site) that have been reported in 13 families in 6 different publications (PMIDs: 15635080, 24103911, 24283893, 23746551, 30521973, 35775650) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached.
Haploinsufficiency is known to be the mechanism of disease (PMID: 35775650).This gene-disease relationship is not currently supported by experimental evidence.
In summary, there is definitive evidence supporting the relationship between B4GALNT1 and autosomal recessive complex hereditary spastic paraplegia. 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 Cerebral Palsy Gene Curation Expert Panel on June 1, 2023 (SOP 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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