The BAZ2B gene is a member of the BAZ gene family that encodes integral components of chromatin remodeling complexes that modulate transcription, DNA replication, and DNA repair. BAZ2B was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2020 (Scott et al., PMID:31999386). Clinical features in reported probands include neurodevelopmental disorders such as intellectual disability, developmental delay, and autism spectrum disorder. Other features are highly variable, reported only in one or few individuals.
At least 24 unique variants (7 nonsense, 3 frameshift, 12 missense, 2 large deletions) have been reported in the literature (PMIDs: 25363768, 28135719, 28554332, 28867142, 31398340, 31981491, 31999386, 33057194). In 26 unrelated probands reported, 19 (73%) variants were de novo, 1 inherited from an unaffected parent, and the rest of unknown inheritance. While BAZ2B is intolerant to truncating variants (pLI 0.98, gnomAD v2.1.1), it is not significantly constrained for missense variants (Z = 1.33). Thus, in the absence of functional evidence of pathogenicity, missense variants were not scored. Probands with other potential genetic explanations for their neurodevelopmental phenotypes, deletions of BAZ2B that encompass additional genes, mosaic variants at low allele frequencies, and truncating variants reported in gnomAD or inherited from reportedly unaffected parents were also not scored since the impact of BAZ2B on the phenotype is unclear. Six truncating de novo variants in 6 probands from 5 publications (PMIDs: 25363768, 28554332, 31981491, 31999386, 33057194) are included in this curation.
Although the total points contained within this curation meet the threshold for a “Moderate” classification, the expert panel elected to downgrade the overall classification to “Limited” while we await additional human genetic evidence. In summary, there is limited evidence at this time to support the relationship between BAZ2B and autosomal dominant complex neurodevelopmental disorder. Additional studies are required to verify this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 19, 2022 (SOP Version 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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