Functional analysis of novel<i>DEAF1</i>variants identified through clinical exome sequencing expands<i>DEAF1</i>-associated neurodevelopmental disorder (DAND) phenotype

Chen, Li; Jensik, Philip J.; Alaimo, Joseph T.; Walkiewicz, Magdalena; Berger, Seth; Roeder, Elizabeth; Faqeih, Eissa; Bernstein, Jonathan A.; Smith, Ann C. M.; Mullegama, Sureni V; Saffen, David; Elsea, Sarah H.

doi:10.1002/humu.23339

Cited by 25 publications

(41 citation statements)

References 38 publications

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“… 31 , 32 The same allele identified in subject #9 (p.G212S) was recently reported in a 15-year-old male with developmental regression and seizures. 33 Functional studies suggest that this allele eliminates both DEAF1 transcriptional repression activity and DEAF1–DNA interactions.…”

Section: Resultsmentioning

confidence: 99%

Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy

et al. 2018

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Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE. The detection of a pathogenic or likely pathogenic mutation in all 14 subjects demonstrates the utility of WGA to reduce the time and costs of clinical diagnosis of EIEE. While exome sequencing may have detected 12 of the 14 causal mutations, 3 of the 12 patients received non-diagnostic exome panel tests prior to genome sequencing. Thus, given the continued decline of sequencing costs, our results support the use of WGA with comprehensive variant discovery as an efficient strategy for the clinical diagnosis of EIEE and other genetic conditions.

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Section: Resultsmentioning

confidence: 99%

Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy

et al. 2018

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“…3B), which is critical for both 19 dimerization and DNA binding (Bottomley et al, 2001;Jensik et al, 2004). A similar pattern of 20 SAND domain missense enrichment is observed in individuals with intellectual disability, speech 21 delay, and behavioral abnormalities (Chen et al, 2017;Heyne et al, 2018;Vulto-van Silfhout et 22 al., 2014). 23…”

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confidence: 89%

“…five ASD mutations (marked in red) are in the SAND DNA-binding domain (amino acids 193-6 273, spirals show alpha helices, arrows show beta sheets, KDWK is the DNA-binding motif) 7 alongside ten variants observed in NDD, several of which have been shown to reduce DNA 8 binding, including Q264P and Q264R (Chen et al, 2017;Heyne et al, 2018;Vulto-van Silfhout 9 et al, 2014). C, Location of ASD missense variants in KCNQ3.…”

Section: Figure 3 Genetic Characterization Of Asd Genes a Count Ofmentioning

confidence: 99%

Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism

Fk¹,

Ja²,

Wang³

et al. 2018

Preprint

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702

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SummaryWe present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

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“…7 Biallelic disruption of Deaf1 in mice results in neural tube defects, 10 and biallelic Drosophila Deaf1 loss-of-function mutants show early embryonic arrest. 11 Pathogenic variants in the DEAF1 gene have been reported to lead to two clinically distinct intellectual disability (ID) syndromes: autosomal dominant mental retardation 24 (MRD24; MIM 615828) caused by de novo variants, 1,[12][13][14][15][16][17] and the recessively inherited dyskinesia, seizures, and intellectual developmental disorder syndrome (DYSEIDD; MIM 617171) (refs. 16,[18][19][20].…”

Section: Introductionmentioning

confidence: 99%

“…To date, nine different de novo pathogenic variants have been described in ten individuals, p.(Gln264Pro) (n =3) [1;13;16] p.(Leu272Ser) p.(Ala276Pro) (n =2) p.(Pro293Leu) p.(Lys305del) [16] p.(Gly212Ser) (n =3) [16] p.(Gly225Glu) p.(lle228Ser) [1;12] p.(Trp234Arg) [15] p.(Ser236Gly) p.(Lys253Glu) p.(Arg246Thr) [14] p.(Arg254Ser) [ [17] p.(Arg224Trp [1] p.(Gly292Profs*) (n =3) [ ZnF NLS NES MYND 301306 453 476 504 540 565 12 11 10 9 8 7 6 5 4 3 2 1 who manifested moderate to severe ID with severely affected expressive speech and mild motor delay. 1,[12][13][14][15][16][17] Epilepsy was described in half of the individuals. 16 Behavioral problems consisted of hyperactive, compulsive, and/or aggressive behavior; fascination with water; and striking mood swings.…”

Section: Introductionmentioning

confidence: 99%

De novo and biallelic DEAF1 variants cause a phenotypic spectrum

Sá

Jensik

McGee

et al. 2019

Genetics in Medicine

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Purpose: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. Methods: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. Results: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). Conclusion: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.

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Functional analysis of novelDEAF1variants identified through clinical exome sequencing expandsDEAF1-associated neurodevelopmental disorder (DAND) phenotype

Cited by 25 publications

References 38 publications

Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy

Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy

Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism

De novo and biallelic DEAF1 variants cause a phenotypic spectrum

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