The TRRAP gene is located on chromosome 7 at 7q22.1 and encodes the transformation/transcription domain associated protein, which functions as a cofactor to mediate histone acetylation and also plays a role in DNA damage repair. The TRRAP gene was first reported in relation to autosomal dominant complex neurodevelopmental disorder with or without congenital anomalies in 2012 (Xu et al. 2012, PMID: 23042115). This variable disorder can include developmental delay, intellectual disability, seizures, other psychiatric disorders, characteristic dysmorphism, and in some cases, malformations or anomalies of other body systems. More than 30 cases have been described, almost exclusively with missense variants, the majority of which were shown to have occurred de novo (PMIDs: 23042115, 28628100, 28392909, 30424743, 30827496). At least one case of parental mosaicism has been reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Twenty-four unique missense variants reported in 24 individuals from three publications were included in this curation (PMIDs: 23042115, 30424743, 30827496). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease has not yet been clearly delineated, although a gain of function or dominant-negative mechanism has been proposed. (PMID: 24792116). In a mouse model, Nestin-cre driven neural-cell-specific conditional knock out results in microcephaly, premature differentiation of neural progenitors, depletion of progenitor pools, and reduced cortical thickness (PMID: 24792116); traditional gene knockout is embryonic lethal (PMID: 11544477). CRISPR-mediated disruption of TRRAP in zebrafish also results in developmental abnormalities that cannot be easily related to the human phenotype (PMIDs: 31231791, 34934055). In summary, TRRAP is definitively associated with autosomal dominant complex neurodevelopmental disorder with or without congenital anomalies. This relationship 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 Intellectual Disability and Autism Gene Curation Expert Panel on July 19, 2022.
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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