Submission Details

CYP7B1, CYP7B1-related disorder of oxysterol accumulation (http://purl.obolibrary.org/obo/MONDO_1060107), autosomal recessive

CYP7B1 was first described as a congenital bile acid synthesis disorder-causing gene in 1998 (Setchell et al. 1998, PMID: 9802883). The specific disease entity, congenital bile acid synthesis disorder (http://purl.obolibrary.org/obo/MONDO_1060107, OMIM:603711), is one of at least 6 forms of congenital bile acid synthesis defects. Some of the most common patient phenotypes are: Elevated circulating alanine aminotransferase concentration, Jaundice and one case of Prolonged neonatal jaundice, Elevated circulating aspartate aminotransferase concentration, Hepatosplenomegaly and Elevated Oxysterol Levels.

CYP7B1 was first described as a spastic paraplegia-causing gene in 2008 (Tsaousidou et al. 2008, PMID: 18252231). The specific disease entity, CYP7B1-related disorder of oxysterol accumulation (http://purl.obolibrary.org/obo/MONDO_1060107, OMIM:603711), is one of at least 100 spastic paraplegia disorders. Some of the most common patient phenotypes are: Affected/abnormal white brain matter, Lower limb spasticity, Lower limb hyperreflexia, Babinski sign, Increased total bilirubin, Impaired vibratory sensation, Upper limb hyperreflexia, Lower limb muscle weakness, Prolonged prothrombin time, and Elevated Oxysterol Levels.

Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (CYP7B1 loss-of-function) were found to be consistent between the congenital bile acid synthesis defect 3 cases and the spastic paraplegia 5A cases. In addition, the shared feature of elevated oxysterol levels observed in both groups of patients appeared to represent a single spectrum of disease. Therefore, cases caused by inherited CYP7B1 variants have been lumped for the purposes of gene curation into a single disease entity referred to as "CYP7B1-related disorder of oxysterol accumulation".

Thirteen variants: (4 types of genetic mutations: Nonsense (3), Missense (6), Splice Site (1) & Frameshift (3)) that have been reported in 14 probands in 13 publications (PMIDs: 9802883, 18252231, 12874406, 19187859, 19439420, 21214876, 24658845, 33849447, 24509641, 30546280, 35387662, 30333426, 21567895) are included in this curation.

The age of onset and diagnosis was highly variable among the probands. Probands with symptoms of bile acid synthesis tended to have congenital onset and require treatment whereas probands with spastic paraplegia tended to have milder, adult onset. A few probands appeared to display a combination of bile acid synthesis and spastic paraplegia phenotypes. Siblings of the probands were also found to be affected to varying degrees of severity. Some siblings were found to have symptoms of spastic paraplegia while the affected proband displayed bile acid synthesis phenotypes. There were also instances where siblings were found to have symptoms of bile acid synthesis while the affected proband displayed spastic paraplegia phenotypes.

Overall, the mechanism of pathogenicity appears to be loss of function as shown in the types of variants harbored by the probands.

This gene-disease relationship is also supported by multiple forms of experimental evidence such as BioChem B (Quantity: 1), Model System: Mouse (Mus musculus) (Quantity: 2) (PMIDs: 19687010, 10748048 and 31013940). First, Stiles et al. 2009 (PMID: 19687010), the affected oxysterol 7-alpha-hydroxylase activity recapitulates what is seen in the human probands. Next, Li-Hawkins et al. 2000 had a knockout mouse that showed affected oxysterol activity which recapitulates what is seen in the human probands. Meljon et al. 2019 also had a knockout mouse that showed the same phenotype (PMID: 31013940).

In conclusion, CYP7B1 is definitively associated with CYP7B1-related disorder of oxysterol accumulation. This classification has been clearly demonstrated and confirmed through both experimental and genetic evidence and has been upheld over time.

This classification was approved by the General IEM GCEP on February 28th, 2025 (SOP Version 11).