The SPEN gene is located on chromosome 1 at 1p36.21-p36.13 and appears to function as a nuclear matrix platform that organizes and integrates transcriptional responses, and is thought to be involved in chromatin remodeling. SPEN was first reported in relation to autosomal dominant SPEN-related neurodevelopmental disorder in 2021 by Radio et al. (PMID: 33596411). The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, behavioral abnormalities, hypotonia, brain and spine anomalies, congenital heart defects, gait imbalance, variable facial dysmorphisms, and obesity/increased BMI, especially in females. This curation included 7 unique truncating variants (4 nonsense and 3 frameshift) in 7 probands from 1 publication (PMID: 33596411). The majority of cases showed de novo inheritance, but familial inheritance in one family was scored. Note there are additional unpublished cases. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence including expression in the developing human neocortex and several animal models (Drosophila and conditional knockout mouse) in which inactivation of SPEN was associated with a neuronal phenotype (PMIDs: 10704397, 17457934). In summary, there is definitive evidence supporting the relationship between SPEN and autosomal dominant SPEN-related neurodevelopmental disorder. 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 Syndromic Disorders Gene Curation Expert Panel on the meeting date 11/01/2023.
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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