BPTF was first reported in relation to autosomal dominant syndromic intellectual disability in 2017 (Stankiewicz et al., PMID: 28942966). BPTF encodes the largest subunit of the nucleosome remodeling complex (NURF), a highly conserved chromatin remodeling complex involved in regulation of transcription. Individuals with variants in BPTF are reported to present with a phenotypic spectrum including developmental delay/intellectual disability, speech/language delay, motor delay, hypotonia, microcephaly, dysmorphic features, and variable distal limb anomalies including fifth digit clinodactyly and sandal gap.
BPTF has been noted to be associated with the following disease entities: neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (OMIM:617755), and non-specific syndromic intellectual disability (ORPHA:528084). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the above disease entities have been lumped into one disease entity, syndromic intellectual disability (MONDO:0000508), given that this term captures the neurodevelopmental and syndromic findings reported in the literature to date.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. Seven variants (e.g., frameshift, nonsense, missense) reported in 8 probands (PMIDs: 28942966, 33522091) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by both non-mammalian and mammalian model systems (PMIDs: 28942966, 35604347).
In summary, there is definitive evidence to support the relationship between BPTF and autosomal dominant syndromic intellectual disability. 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 Intellectual Disability and Autism Gene Curation Expert Panel on 7/6/2022 (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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