Alternative titles; symbols
HGNC Approved Gene Symbol: DEAF1
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38) : 11:644,220-707,083 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.5 | Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures | 617171 | Autosomal recessive | 3 |
| Vulto-van Silfout-de Vries syndrome | 615828 | Autosomal dominant | 3 |
The DEAF1 gene encodes the Drosophila deformed epidermal autoregulatory factor-1 homolog, which regulates the expression of various genes as both a transcriptional activator and repressor. It has high expression in the brain and central nervous system, suggesting a role in early neurodevelopment (summary by Vulto-van Silfhout et al., 2014; Nabais Sa et al., 2019; Andoni et al., 2020).
Suppressin is a 63-kD inhibitor of cell proliferation. LeBoeuf et al. (1998) cloned the cDNA encoding rat suppressin. The deduced amino acid sequence contains 2 domains with significant homology to a transcription factor in Drosophila called 'deformed epidermal autoregulatory factor-1' (DEAF1). By RT-PCR, LeBoeuf et al. (1998) found that suppressin was expressed in all rat tissues tested.
LeBoeuf et al. (1998) also cloned the human suppressin cDNA sequence (GenBank AF007165), which encodes a predicted 497-amino acid polypeptide.
Jensik et al. (2004) determined that the full-length 565-amino acid DEAF1 protein contains a central SAND DNA-binding domain, followed by a zinc-binding motif, a monopartite nuclear localization signal, a leucine-rich nuclear export signal, and a C-terminal MYND domain. The region encompassing the SAND domain and nuclear localization signal also constitutes a dimerization domain.
Vulto-van Silfhout et al. (2014) found the highest expression of the DEAF1 gene in human and murine fetal and adult brain compared to other tissues. In the developing zebrafish, deaf1 homologs were expressed in the brain and spinal cord, with the highest level of expression at 24 days postfertilization and low to absent expression at all embryonic stages.
Using deletion constructs, Jensik et al. (2004) determined that the zinc-binding motif and nuclear localization signal of DEAF1, which together constitute a dimerization domain, were required for DNA binding by the DEAF1 SAND domain. The results suggested that dimerization is a prerequisite for DNA binding by DEAF1.
The DNA-dependent protein kinase (DNAPK) complex, which is made up of Ku70 (XRCC6; 152690), Ku80 (XRCC5; 194364), and a catalytic subunit (PRKDC; 600899), has a role in repairing double-stranded DNA breaks. Using human GST-DEAF1 to pull-down proteins from PC-3 human prostate cells, followed by mass spectrometry, Jensik et al. (2012) found that DEAF1 interacted with the DNAPK complex. The DNA-binding SAND domain of DEAF1 interacted directly with the C terminus of Ku70, a region also required for interaction of Ku70 with proapoptotic BAX (600040). DEAF1 was phosphorylated by DNAPK in vitro in a manner that was independent of double-stranded DNA. Both DEAF1 and Ku70/Ku80 bound double-stranded DNA, but not simultaneously. A synthetic nucleotide containing 2 DEAF1-binding TTCG motifs inhibited interaction of DEAF1 with DNAPK.
By yeast 2-hybrid analysis of a human fetal brain cDNA library, Ordureau et al. (2013) found that DEAF1 interacted with pellino-1 (PELI1; 614797), an intermediate component of the innate immune response. Protein pull-down assays confirmed the interaction, which required the C-terminal nuclear export signal and MYND domain of DEAF1. Phosphorylation of PELI1 weakened the interaction. Peli1 is required for production of interferon-beta (IFNB; see 147640) in mouse embryonic fibroblasts (MEFs) infected with Sendai virus. Deaf1 increased secretion of Ifnb from MEFs in response to Sendai virus or poly(I:C), and this effect was mediated by binding of Deaf1 to Irf3 (603734) and Irf7 (605047) at the Ifnb promoter, which induced Ifnb transcription. DEAF1 was also needed for Toll-like receptor-3 (TLR3; 603029)-dependent IFNB production. Deaf1 -/- MEFs showed defective recruitment of Irf3 to the Ifnb promoter following Sendai virus infection, and transfection of wildtype mouse Deaf1 fully restored Sendai virus-induced Ifnb secretion in Deaf1 -/- MEFs.
Vulto-van Silfhout-de Vries syndrome
In a boy with Vulto-van Silfhout-de Vries syndrome (VSVS; 615828), Vissers et al. (2010) identified a de novo heterozygous missense mutation in the DEAF1 gene (I228S; 602635.0001). The mutation was found by exome sequencing of a cohort of 10 patients with impaired intellectual development. In a girl with VSVS, Rauch et al. (2012) identified a de novo heterozygous missense mutation in the DEAF1 gene (Q264P; 602635.0002). The patient was ascertained from a large cohort of 51 patients with intellectual disability who underwent exome sequencing.
In 2 unrelated patients with VSVS, Vulto-van Silfhout et al. (2014) identified different heterozygous missense mutations in the DEAF1 gene (R224W, 602635.0003 and R254S, 602635.0004). The patients were ascertained from a cohort of over 2,300 individuals with intellectual disability who underwent targeted resequencing of the DEAF1 gene. In vitro functional expression assays using a luciferase reporter indicated that all 4 mutations identified in the DEAF1 gene, including those reported by Vissers et al. (2010) and Rauch et al. (2012), resulted in a loss of the ability of DEAF1 to repress its own promoter, and all mutations produced proteins with loss of or significantly reduced DNA binding. Three of the mutations caused a loss of transcriptional activity. Compared to the other mutations, the R254S mutation resulted in less severe defects and enabled some residual DEAF1 activity. Vulto-van Silfhout et al. (2014) postulated a dominant-negative effect of the mutations.
In 5 unrelated patients with VSVS, Chen et al. (2017) identified 5 different de novo heterozygous mutations in the DEAF1 gene (see, e.g., 602635.0002; 602635.0007-602635.0009). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in several public databases, including ExAC. Four of the mutations occurred at conserved residues in the SAND domain and were demonstrated to result in significantly decreased transcriptional repression activity toward the DEAF1 promoter compared to wildtype, as well as decreased binding to dsDNA probes. Immunostaining in transfected cells showed normal nuclear localization of the mutant proteins. The fifth mutation (Lys305del; 602635.0009) occurred in the nuclear localization signal (NLS) and also resulted in decreased transcriptional repression activity, but the mutant protein predominantly localized to the cytoplasm.
In 17 unrelated patients with VSVS, Nabais Sa et al. (2019) identified de novo heterozygous mutations in the DEAF1 gene (see, e.g., 602635.0002; 602635.0007; 602635.0010-602635.0012). The mutations, which were found by exome sequencing, were not present in the gnomAD database. Most of the mutations occurred at highly conserved residues in the SAND domain. In vitro functional expression studies in HEK293 cells showed that the variants lost transcriptional repressive activity toward the DEAF1 promoter compared to wildtype, and also suppressed transcription of mouse Eif4g3 (603929) compared to wildtype. The authors postulated a dominant-negative effect of the variants.
In a 12-year-old Indian girl with VSVS, Sharma et al. (2019) identified a de novo heterozygous mutation in the DEAF1 gene, resulting in a stop codon and premature termination (Leu272Ter; 602635.0013). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in several public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to generate a truncated protein and result in decreased protein levels, rather than causing a dominant-negative effect. The authors postulated that the less severe phenotype in this patient may be due to the type of mutation.
Neurodevelopmental Disorder with Hypotonia and Impaired Expressive Language and with or without Seizures
In 3 sibs, born of consanguineous Omani parents, with neurodevelopmental disorder with hypotonia and impaired expressive language and with or without seizures (NEDHELS; 617171), Rajab et al. (2015) identified a homozygous splice site mutation in the DEAF1 gene (602635.0006). The mutation was found by a combination of linkage analysis and whole-exome sequencing and was confirmed by Sanger sequencing. It segregated with the disorder in the family. The mutation was verified to cause a splicing defect and about 80% mRNA decay, leaving only about 4 to 5% normal transcript in patient fibroblasts, consistent with a loss of function. The unaffected parents and an unaffected sib were heterozygous for the mutation, leading Rajab et al. (2015) to conclude that haploinsufficiency for DEAF1 does not cause symptoms.
In 2 boys from different branches of a consanguineous Saudi family with NEDHELS, Faqeih et al. (2014) identified a homozygous missense mutation in the DEAF1 gene (R226W; 602635.0005). The mutation, which was found by whole-exome sequencing combined with homozygosity mapping, segregated with the disorder in the family. All 4 unaffected parents were heterozygous for the mutation, which was not present in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases or in 650 ethnically matched controls. Functional studies of the variant were not performed. The authors noted that the R226W variant is located between previously identified heterozygous de novo mutations (Q264P, 602635.0002 and R224W, 602635.0003) and does not seem to interfere directly with the DNA-binding domain.
In a 14-year-old boy, born of consanguineous Pakistani parents, with NEDHELS, Gund et al. (2016) identified homozygosity for the R226W mutation in the DEAF1 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the unaffected parents. Functional studies of the variant and studies of patient cells were not performed.
In a 2-year-old boy (patient 615391) with NEDHELS, Chen et al. (2017) identified homozygosity for the R226W mutation in the DEAF1 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in each unaffected parent. In vitro functional expression studies showed that the mutation had no effect on DEAF1 transcriptional repressive activity or DNA binding compared to wildtype. The mutant protein localized normally to the nucleus in cells transfected with the mutation.
In 5 patients from 4 unrelated families with NEDHELS, Nabais Sa et al. (2019) identified homozygous or compound heterozygous mutations in the DEAF1 gene (see, e.g., 602635.0014-602635.0018). The mutations, which were found by exome sequencing, were inherited from unaffected parents. There were 3 frameshifts, 1 nonsense mutation, 1 in-frame deletion, and 2 missense variants. In vitro functional studies showed that all the mutations, except for the nonsense mutation (W234X), did not alter DEAF1 transcriptional activity compared to wildtype. In addition, all except W234X localized normally to the nucleus in transfected cells. Nabais Sa et al. (2019) concluded that biallelic DEAF1 variants lead to a partial loss of DEAF1 function (hypomorph) either through impaired function or reduced protein levels.
In 2 first cousins from a large consanguineous Pakistani family with NEDHELS, Andoni et al. (2020) identified a homozygous nonsense mutation in the DEAF1 gene (K191X; 602635.0019). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Each unaffected parent was heterozygous for the mutation. Functional studies of the variant and studies of patient cells were not performed, but the variant was classified as pathogenic according to ACMG guidelines.
In a 6-year-old girl, born of consanguineous Pakistani parents, with NEDHELS, Sumathipala et al. (2020) identified a homozygous frameshift mutation in the DEAF1 gene (602635.0020). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC or gnomAD databases. The unaffected parents were heterozygous for the mutation. PCR analysis of patient cells suggested that the mutant transcript did not undergo nonsense-mediated mRNA decay.
Ordureau et al. (2013) reported that Deaf1 -/- mice were rarely born alive and that the few survivors were small.
Vulto-van Silfhout et al. (2014) found that homozygous knockout of the Deaf1 gene was lethal in mice. Transgenic mice with conditional homozygous knockdown of the Deaf1 gene in brain showed increased anxiety-related behavior in field tests as well as impaired contextual memory.
In a boy with Vulto-van Silfhout-de Vries syndrome (VSVS; 615828), Vissers et al. (2010) identified a de novo heterozygous c.683T-G transversion in the DEAF1 gene, resulting in an ile228-to-ser (I228S) substitution. The mutation was found by family-based exome sequencing of 10 case-parent trios with de novo impaired intellectual development; the variant was not found in 1,664 control chromosomes.
Vulto-van Silfhout et al. (2014) noted that the I228S mutation occurs at a highly conserved residue in the SAND domain, which is essential for DNA binding. The mutation was not present in the dbSNP (build 139) or Exome Variant Server databases, or in over 2,000 in-house control exomes. In vitro functional expression studies demonstrated that the I228S mutation resulted in loss of the ability to repress the DEAF1 promoter, loss of DNA binding, loss of transcriptional activation of a reporter construct, and decreased interaction with XRCC6 (152690).
In a girl (patient ER52808) with Vulto-van Silfhout-de Vries syndrome (VSVS; 615828), Rauch et al. (2012) identified a de novo heterozygous c.791A-C transversion (chr11.686871T-G, GRCh37) in the DEAF1 gene, resulting in a gln264-to-pro (Q264P) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in either parent. The patient was ascertained from a large cohort of 51 patients with intellectual disability who underwent exome sequencing.
Vulto-van Silfhout et al. (2014) noted that the Q264P mutation occurs at a highly conserved residue in the SAND domain, which is essential for DNA binding. The mutation was not present in the dbSNP (build 139) or Exome Variant Server databases, or in over 2,000 in-house control exomes. In vitro functional expression studies demonstrated that the Q264P mutation resulted in loss of the ability to repress the DEAF1 promoter, loss of DNA binding, loss of transcriptional activation of a reporter construct, and decreased interaction with XRCC6 (152690).
Chen et al. (2017) identified a de novo heterozygous Q264P mutation in the DEAF1 gene in a 12-year-old girl (patient 563832) with VSVS. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant were not performed.
Nabais Sa et al. (2019) identified a de novo heterozygous Q264P mutation in a 19-year-old woman (patient 14) with VSVS. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the Q264P variant lost transcriptional activity toward the DEAF1 promoter and failed to increase transcriptional activity toward the mouse Eif4g3 (603929) promoter compared to wildtype.
In a 10-year-old boy with Vulto-van Silfhout-de Vries syndrome (VSVS; 615828), Vulto-van Silfhout et al. (2014) identified a de novo heterozygous c.670C-T transition (c.670C-T, NM_021008.2) in the DEAF1 gene, resulting in an arg224-to-trp (R224W) substitution at a highly conserved residue in the SAND domain, which is essential for DNA binding. The mutation was not present in the dbSNP (build 139) or Exome Variant Server databases, or in over 2,000 in-house control exomes. In vitro functional expression studies demonstrated that the R224W mutation resulted in loss of the ability to repress the DEAF1 promoter, loss of DNA binding, loss of transcriptional activation of a reporter construct, and decreased interaction with XRCC6 (152690). The patient also carried a heterozygous c.1570C-T transition in the SCN2A gene (182390), resulting in an arg524-to-ter (R524X) substitution, which may have influenced the severity of the intellectual disability; however, the patient did not have a history of epilepsy.
In a 10-year-old girl with Vulto-van Silfhout-de Vries syndrome (VSVS; 615828), Vulto-van Silfhout et al. (2014) identified a de novo heterozygous c.762A-C transversion (c.762A-C, NM_021008.2) in the DEAF1 gene, resulting in an arg254-to-ser (R254S) substitution at a highly conserved residue in the SAND domain, which is essential for DNA binding. The mutation was not present in the dbSNP (build 139) or Exome Variant Server databases, or in over 2,000 in-house control exomes. In vitro functional expression studies showed that the R254S mutation resulted in a loss of the ability to repress the DEAF1 promoter and a 9-fold reduction in DNA binding. However, the mutant protein was still able to activate a reporter gene and interact with XRCC6 (152690). These findings suggested that the R254S mutant protein retained some residual activities.
In 2 boys from different branches of a consanguineous Saudi family with neurodevelopmental disorder with hypotonia and impaired expressive language, with or without seizures (NEDHELS; 617171), Faqeih et al. (2014) identified a homozygous c.676C-T transition (c.676C-T, NM_021008) in the DEAF1 gene, resulting in an arg226-to-trp (R226W) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing combined with homozygosity mapping, segregated with the disorder in the family. All 4 unaffected parents were heterozygous for the mutation, which was not present in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases or in 650 ethnically matched controls. One of the patients had a sister who died of a similar disorder. Functional studies of the variant were not performed. The authors noted that the R226W variant is located between previously identified heterozygous de novo mutations (602635.0002 and 602635.0003) and does not seem to interfere directly with the DNA binding domain.
In a 14-year-old boy, born of consanguineous Pakistani parents, with NEDHELS, Gund et al. (2016) identified homozygosity for the R226W mutation in the DEAF1 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in each unaffected parent. Functional studies of the variant and studies of patient cells were not performed.
In a 2-year-old boy (patient 615391) with NEDHELS, Chen et al. (2017) identified homozygosity for the c.676C-T transition in exon 5 of the DEAF1 gene, resulting in an R226W substitution at a conserved residue in the SAND domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent. In vitro functional expression studies showed that the mutation had no effect on DEAF1 transcriptional repressive activity or DNA binding compared to wildtype. The mutant protein localized normally to the nucleus in cells transfected with the mutation. The variant was found at a low frequency (8.28 x 10(-6)) in the heterozygous state in the ExAC database.
In 3 sibs, born of consanguineous Omani parents, with neurodevelopmental disorder with hypotonia and impaired expressive language, with or without seizures (NEDHELS; 617171), Rajab et al. (2015) identified a homozygous A-to-C transversion (c.997+4A-C) in intron 6 of the DEAF1 gene, resulting in a splice site alteration, the skipping of exon 7, and premature termination (Gly292ProfsTer). The mutation was found by a combination of linkage analysis and whole-exome sequencing and was confirmed by Sanger sequencing. It segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or ExAC databases or in 135 in-house exomes. The mutation was verified to cause a splicing defect and about 80% mRNA decay, leaving only about 4 to 5% normal transcript in patient fibroblasts, consistent with a loss of function. The unaffected parents and an unaffected sib were heterozygous for the mutation, leading Rajab et al. (2015) to conclude that haploinsufficiency for DEAF1 does not cause symptoms.
In a 15-year-old girl (patient 597158) with Vulto-van Silfhout-de Vries syndrome (VSVS; 615828), Chen et al. (2017) identified a de novo heterozygous c.634G-A transition (c.634G-A, NM_021008.3) in exon 4 of the DEAF1 gene, resulting in a gly212-to-ser (G212S) substitution at a highly conserved residue in the SAND domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Sequencing Project, 1000 Genomes Project, or ExAC databases. In vitro functional expression studies showed that the G212S variant had significantly decreased transcriptional repression activity toward the DEAF1 promoter compared to wildtype, as well as decreased binding to dsDNA probes. Immunostaining in transfected cells showed normal nuclear localization of the mutant protein.
Nabais Sa et al. (2019) identified a de novo heterozygous G212S mutation in the DEAF1 gene in 2 unrelated patients (patients 1 and 2) with VSVS. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in HEK293 cells showed that the G212S variant had decreased transcriptional repressive activity toward its own DEAF1 promoter, but increased suppression of promoter activity toward EIF4G3 (603929), compared to wildtype. The authors postulated a dominant-negative effect of the variant.
In a 4-year-old boy (patient M2647) with Vulto-van Silfhout-de Vries syndrome (VSVS; 615828), Chen et al. (2017) identified a de novo heterozygous c.700T-A transversion in exon 5 of the DEAF1 gene, resulting in a trp234-to-arg (W234R) substitution at a highly conserved residue in the SAND domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Sequencing Project, 1000 Genomes Project, or ExAC databases. In vitro functional expression studies showed that the W234R variant had significantly decreased transcriptional repression activity toward the DEAF1 promoter compared to wildtype, as well as decreased binding to dsDNA probes. Immunostaining in transfected cells showed normal nuclear localization of the mutant protein. (This mutation was previously identified in this patient by Berger et al. (2017). The patient was part of a cohort of patients described as having a Smith-Magenis-like syndrome.)
In a 3-year-old girl (patient 538820) with Vulto-van Silfhout-de Vries syndrome (VSVS; 615828), Chen et al. (2017) identified a de novo heterozygous 3-bp in-frame deletion (c.913_915del) in exon 7 of the DEAF1 gene, resulting in a deletion of residue Lys305 in the nuclear localization signal (NLS). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Sequencing Project, 1000 Genomes Project, or ExAC databases. In vitro functional expression studies showed that the K305del variant had significantly decreased transcriptional repression activity toward the DEAF1 promoter compared to wildtype, although dsDNA binding was apparently unaffected. Immunostaining in transfected cells showed that K305del variant predominantly localized to the cytoplasm rather than the nucleus.
In a 16-year-old girl (patient 4) with Vulto-van Silfhout-de Vries syndrome (VSVS; 615828), Nabais Sa et al. (2019) identified a de novo heterozygous c.640C-G transversion (c.640C-G, NM_021008.3) in the DEAF1 gene, resulting in a leu214-to-val (L214V) substitution at a highly conserved residue in the SAND domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in HEK293 cells showed that the L214V variant had decreased transcriptional repressive activity toward its own DEAF1 promoter compared to wildtype, and also suppressed transcription of mouse Eif4g3 (603929) compared to wildtype. The authors postulated a dominant-negative effect of the variant.
In 2 unrelated patients (patients 16 and 17) with Vulto-van Silfhout-de Vries syndrome (VSVS; 615828), Nabais Sa et al. (2019) identified a de novo heterozygous c.826G-C transversion (c.826G-C, NM_021008.3) in the DEAF1 gene, resulting in an ala276-to-pro (A276P) substitution at a highly conserved residue in the SAND domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in HEK293 cells showed that the A276P variant had decreased transcriptional repressive activity toward its own DEAF1 promoter compared to wildtype, and also suppressed transcription of mouse Eif4g3 (603929) compared to wildtype. The authors postulated a dominant-negative effect of the variant.
In a 5.5-year-old boy (patient 8) with Vulto-van Silfhout-de Vries syndrome (VSVS; 615828), Nabais Sa et al. (2019) identified a de novo heterozygous G-to-T transversion (c.664+1G-T, NM_021008.3) in intron 4 of the DEAF1 gene. Analysis of patient cells showed that the mutation resulted in the skipping of exon 4 and an in-frame deletion, Pro174_Gly222del, in the SAND domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in HEK293 cells showed that the variant had decreased transcriptional repressive activity toward its own DEAF1 promoter compared to wildtype, and also suppressed transcription of mouse Eif4g3 (603929) compared to wildtype. The authors postulated a dominant-negative effect of the variant.
In a 12-year-old Indian girl with Vulto-van Silfhout-de Vries syndrome (VSVS; 615828), Sharma et al. (2019) identified a de novo heterozygous 3-bp deletion (TAA) and 1-bp insertion (G) in exon 6 of the DEAF1 gene (c.815_817delinsG, NM_021008), resulting in a stop codon and premature termination (Leu272Ter). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in several public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to generate a truncated protein and result in decreased protein levels, rather than causing a dominant-negative effect.
In a 17-year-old boy (patient AR/1) with neurodevelopmental disorder with hypotonia, impaired expressive language, and seizures (NEDHELS; 617171), Nabais Sa et al. (2019) identified compound heterozygous mutations in the DEAF1 gene: a 2-bp duplication (c.1104_1105dupGC, NM_021008.3), predicted to result in a frameshift and premature termination (Asp369AlafsTer51), and a 1-bp duplication (c.1617dup; 602635.0015), predicted to result in a frameshift and premature termination (Cys540MetfsTer18). The mutations, which were found by exome sequencing, were not present in the gnomAD database. Analysis of patient cells suggested that the c.1104_1105dupGC transcript was subject to nonsense-mediated mRNA decay, although faint levels of a truncated corresponding protein could be detected in patient cell lysate. Western blot analysis of transfected HEK293 cells showed decreased expression of Cys540MetfsTer18 compared to wildtype, although the truncated protein was not observed in patient cell lysate. Further in vitro functional studies showed that the mutations did not alter DEAF1 transcriptional activity compared to wildtype.
For discussion of the 1-bp duplication (c.1617dup, NM_021008.3) in the DEAF1 gene, predicted to result in a frameshift and premature termination (Cys540MetfsTer18), that was found in compound heterozygous state in a patient with neurodevelopmental disorder with hypotonia and impaired expressive language with seizures (NEDHELS; 617171) by Nabais Sa et al. (2019), see 602635.0014.
In a 16-year-old girl (patient AR/3) with neurodevelopmental disorder with hypotonia, impaired expressive language, and seizures (NEDHELS; 617171), Nabais Sa et al. (2019) identified compound heterozygous mutations in the DEAF1 gene: a c.701G-A transition (c.701G-A, NM_021008.3), resulting in a trp234-to-ter (W234X) substitution in the SAND domain, and a c.716A-G transition, resulting in a glu239-to-gly (E239G; 602635.0017) substitution. The mutations were found by exome sequencing; the E239G variant was inherited from the unaffected mother, but DNA from the father was not available. The W234X variant was found at a low frequency in the gnomAD database (8.13 x 10(-6)), whereas E239G was not present in gnomAD. In vitro functional expression studies showed that the W234X mutant lost transcriptional repressive activity at the DEAF1 promoter, whereas E239G retained transcriptional repressive activity. Both variants showed normal activity toward the mouse Eif4g3 (603929) promoter. The W234X mutant localized abnormally throughout the cell, whereas E239G localized normally to the nucleus.
For discussion of the c.716A-G transition (c.716A-G, NM_021008.3) in the DEAF1 gene, resulting in a glu239-to-gly (E239G) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with hypotonia, impaired expressive language, and seizures (NEDHELS; 617171) by Nabais Sa et al. (2019), see 602635.0016.
In 2 sibs (patients AR/4 and AR/5), born of consanguineous parents, with neurodevelopmental disorder with hypotonia, impaired expressive language, and seizures (NEDHELS; 617171), Nabais Sa et al. (2019) identified a homozygous c.671G-A transition (c.671G-A, NM_021008.3) in the DEAF1 gene, resulting in an arg224-to-gln (R224Q) substitution at a conserved residue in the SAND domain. The mutation, which was found by exome sequencing, was present at a low frequency in the gnomAD database (4.065 x 10(-6)). Each unaffected parent was heterozygous for the mutation. In vitro functional expression studies showed that the mutant protein was expressed and localized normally to the nucleus; it had no significant effect on DEAF1 transcriptional ability.
In 2 first cousins from a large consanguineous Pakistani family with neurodevelopmental disorder with hypotonia and impaired expressive language and without seizures (NEDHELS; 617171), Andoni et al. (2020) identified a homozygous c.571A-T transversion (c.571A-T, NM_021008.3) in the DEAF1 gene, resulting in a lys191-to-ter (K191X) substitution just upstream of the SAND domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. The unaffected parents were heterozygous for the mutation. Functional studies of the variant and studies of patient cells were not performed, but the variant was classified as pathogenic according to ACMG guidelines.
In a 6-year-old girl, born of consanguineous Pakistani parents, with neurodevelopmental disorder with hypotonia and impaired expressive language and without seizures (NEDHELS; 617171), Sumathipala et al. (2020) identified a homozygous 1-bp deletion (c.1187delC, NM_021008.3), predicted to result in a frameshift and premature termination (Gly396AlafsTer23). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC or gnomAD databases. The unaffected parents were heterozygous for the mutation. PCR analysis of patient cells suggested that the mutant transcript did not undergo nonsense-mediated mRNA decay.
Andoni, T., Ellard, S., Kapadia, J., Wakeling, E. A novel autosomal recessive DEAF1 nonsense variant: expanding the clinical phenotype. Clin. Dysmorph. 29: 114-117, 2020. [PubMed: 31688097] [Full Text: https://doi.org/10.1097/MCD.0000000000000306]
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