Relevance to Autism

De novo missense variants in the DEAF1 gene that resulted in impaired transcriptional regulation of the DEAF1 promoter were identified in four individuals from three reports (PMIDs 21076407, 23020937, 24726472). All four individuals presented with intellectual disability, mild motor delay, and severely affected speech development; three of these individuals also displayed severe behavioral problems consisting of autism/autistic behavior, hyperactive behavior, compulsive behavior, and aggressive behavior with striking mood swings and poor eye contact. Chen et al., 2017 identified potentially deleterious heterozygous DEAF1 variants in six novel individuals presenting with intellectual disability, motor delay, and autistic behavior. Rare de novo heterozygous missense variants that were predicted to be damaging have been observed in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014), as well as in ASD probands from the Autism Simplex Collection (TASC) and the Autism Clinical and Genetic Resources in China (ACGC) cohorts (Geisheker et al., 2017). Biallelic variants in the DEAF1 gene have also been observed in individuals presenting with an autosomal recessive neurodevelopmental disorder (dyskinesia, seizures, and intellectual developmental disorder; OMIM 617171); autistic features have been observed in a subset of these individuals (Rajab et al., 2015; Gund et al., 2016; Trujillano et al., 2017; Chen et al., 2017). Phentoypic characterization of a previously unreported cohort of 17 individuals with de novo DEAF1 variants and 5 individuals with biallelic DEAF1 variants in Nabais Sa et al., 2019 found that autism was present in 16 individuals with a de novo DEAF1 variant, as opposed to 1 individual with a biallelic DEAF1 variant. Furthermore, many of the de novo DEAF1 variants reported by Nabais Sa et al., 2019 were experimentally shown to impair transcriptional regulation of the DEAF1 promoter. Three additional de novo missense variants in the DEAF1 gene were identified in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified DEAF1 as a candidate gene with a false discovery rate (FDR) 0.01. A de novo loss-of-function variant and three rare and potentially damaging missense variants in the DEAF1 gene were reported in ASD probands from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified DEAF1 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

Transcription factor that binds to sequence with multiple copies of 5'-TTC[CG]G-3' present in its own promoter and that of the HNRPA2B1 gene and down-regulates transcription of these genes. Binds to the retinoic acid response element (RARE) 5'-AGGGTTCACCGAAAGTTCA-3'. Activates the proenkephalin gene independently of promoter binding, probably through protein-protein interaction. When secreted, behaves as an inhibitor of cell proliferation, by arresting cells in the G0 or G1 phase. Required for neural tube closure and skeletal patterning.

External Links

References

Model Summary

Maternal or zygotic DEAF-1 mutation results in early embryonic lethality prior to the expression of zygotic segmentation genes. Embryos that do no succumb to lethality develop into larvae with segmentation defects of variable severity. Embryonic overexpression of DEAF1 leads to defects in closure of the dorsal epidermis. Adult overexpression of DEAF1 leads to defects in eye and wing development.

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