De novo and biallelic DEAF1 variants cause a phenotypic spectrum

Maria J. Nabais Sá, Philip J. Jensik, Stacey R. McGee, Michael J. Parker, Nayana Lahiri, Evan P. McNeil, Hester Y. Kroes, Randi J. Hagerman, Rachel E. Harrison, Tara Montgomery, Miranda Splitt, Elizabeth E. Palmer, Rani K. Sachdev, Heather C. Mefford, Abbey A. Scott, Julian A. Martinez-Agosto, Rüdiger Lorenz, Naama Orenstein, Jonathan N. Berg, Jeanne AmielDelphine Heron, Boris Keren, Jan-Maarten Cobben, Leonie A. Menke, Elysa J. Marco, John M. Graham, Tyler Mark Pierson, Ehsan Ghayoor Karimiani, Reza Maroofian, M. Chiara Manzini, Edmund S. Cauley, Roberto Colombo, Sylvie Odent, Christele Dubourg, Chanika Phornphutkul, Arjan P. M. de Brouwer, Bert B. A. de Vries, Anneke T Vulto-vanSilfhout

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2059-2069
Number of pages11
JournalGenetics in Medicine
Volume21
Issue number9
Early online date29 Mar 2019
DOIs
Publication statusPublished - Sep 2019

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Language Development Disorders
Phenotype
Inheritance Patterns
Microcephaly
Pain Threshold
Genetic Association Studies
Autistic Disorder
Luciferases
Intellectual Disability
Virulence
Patient Care
Sleep
Alleles
Genes
In Vitro Techniques

Keywords

  • DEAF1
  • genotype
  • intellectual disability
  • neurodevelopmental disorder
  • phenotype

Cite this

Nabais Sá, M. J., Jensik, P. J., McGee, S. R., Parker, M. J., Lahiri, N., McNeil, E. P., ... Vulto-vanSilfhout, A. T. (2019). De novo and biallelic DEAF1 variants cause a phenotypic spectrum. Genetics in Medicine, 21(9), 2059-2069. https://doi.org/10.1038/s41436-019-0473-6
Nabais Sá, Maria J. ; Jensik, Philip J. ; McGee, Stacey R. ; Parker, Michael J. ; Lahiri, Nayana ; McNeil, Evan P. ; Kroes, Hester Y. ; Hagerman, Randi J. ; Harrison, Rachel E. ; Montgomery, Tara ; Splitt, Miranda ; Palmer, Elizabeth E. ; Sachdev, Rani K. ; Mefford, Heather C. ; Scott, Abbey A. ; Martinez-Agosto, Julian A. ; Lorenz, Rüdiger ; Orenstein, Naama ; Berg, Jonathan N. ; Amiel, Jeanne ; Heron, Delphine ; Keren, Boris ; Cobben, Jan-Maarten ; Menke, Leonie A. ; Marco, Elysa J. ; Graham, John M. ; Pierson, Tyler Mark ; Karimiani, Ehsan Ghayoor ; Maroofian, Reza ; Manzini, M. Chiara ; Cauley, Edmund S. ; Colombo, Roberto ; Odent, Sylvie ; Dubourg, Christele ; Phornphutkul, Chanika ; de Brouwer, Arjan P. M. ; de Vries, Bert B. A. ; Vulto-vanSilfhout, Anneke T. / De novo and biallelic DEAF1 variants cause a phenotypic spectrum. In: Genetics in Medicine. 2019 ; Vol. 21, No. 9. pp. 2059-2069.
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abstract = "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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note = "This work was financially supported by grants from the Dutch Organization for Health Research and Development (ZON-MW grants 917–86–319 and 912–12–109 to B.B.A.d.V.), the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases (to T.M.P.), the March of Dimes (grant 6-FY14–422 to M.C.M.), and the National Institutes of Health (grants NINDS 5R21NS091724 to P.J.J. and NINDS R01NS069605 to H.C.M.).",
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Nabais Sá, MJ, Jensik, PJ, McGee, SR, Parker, MJ, Lahiri, N, McNeil, EP, Kroes, HY, Hagerman, RJ, Harrison, RE, Montgomery, T, Splitt, M, Palmer, EE, Sachdev, RK, Mefford, HC, Scott, AA, Martinez-Agosto, JA, Lorenz, R, Orenstein, N, Berg, JN, Amiel, J, Heron, D, Keren, B, Cobben, J-M, Menke, LA, Marco, EJ, Graham, JM, Pierson, TM, Karimiani, EG, Maroofian, R, Manzini, MC, Cauley, ES, Colombo, R, Odent, S, Dubourg, C, Phornphutkul, C, de Brouwer, APM, de Vries, BBA & Vulto-vanSilfhout, AT 2019, 'De novo and biallelic DEAF1 variants cause a phenotypic spectrum', Genetics in Medicine, vol. 21, no. 9, pp. 2059-2069. https://doi.org/10.1038/s41436-019-0473-6

De novo and biallelic DEAF1 variants cause a phenotypic spectrum. / Nabais Sá, Maria J.; Jensik, Philip J.; McGee, Stacey R.; Parker, Michael J.; Lahiri, Nayana; McNeil, Evan P.; Kroes, Hester Y.; Hagerman, Randi J.; Harrison, Rachel E.; Montgomery, Tara; Splitt, Miranda; Palmer, Elizabeth E.; Sachdev, Rani K.; Mefford, Heather C.; Scott, Abbey A.; Martinez-Agosto, Julian A.; Lorenz, Rüdiger; Orenstein, Naama; Berg, Jonathan N.; Amiel, Jeanne; Heron, Delphine; Keren, Boris; Cobben, Jan-Maarten; Menke, Leonie A.; Marco, Elysa J.; Graham, John M.; Pierson, Tyler Mark; Karimiani, Ehsan Ghayoor; Maroofian, Reza; Manzini, M. Chiara; Cauley, Edmund S.; Colombo, Roberto; Odent, Sylvie; Dubourg, Christele; Phornphutkul, Chanika; de Brouwer, Arjan P. M.; de Vries, Bert B. A. (Lead / Corresponding author); Vulto-vanSilfhout, Anneke T.

In: Genetics in Medicine, Vol. 21, No. 9, 09.2019, p. 2059-2069.

Research output: Contribution to journalArticle

TY - JOUR

T1 - De novo and biallelic DEAF1 variants cause a phenotypic spectrum

AU - Nabais Sá, Maria J.

AU - Jensik, Philip J.

AU - McGee, Stacey R.

AU - Parker, Michael J.

AU - Lahiri, Nayana

AU - McNeil, Evan P.

AU - Kroes, Hester Y.

AU - Hagerman, Randi J.

AU - Harrison, Rachel E.

AU - Montgomery, Tara

AU - Splitt, Miranda

AU - Palmer, Elizabeth E.

AU - Sachdev, Rani K.

AU - Mefford, Heather C.

AU - Scott, Abbey A.

AU - Martinez-Agosto, Julian A.

AU - Lorenz, Rüdiger

AU - Orenstein, Naama

AU - Berg, Jonathan N.

AU - Amiel, Jeanne

AU - Heron, Delphine

AU - Keren, Boris

AU - Cobben, Jan-Maarten

AU - Menke, Leonie A.

AU - Marco, Elysa J.

AU - Graham, John M.

AU - Pierson, Tyler Mark

AU - Karimiani, Ehsan Ghayoor

AU - Maroofian, Reza

AU - Manzini, M. Chiara

AU - Cauley, Edmund S.

AU - Colombo, Roberto

AU - Odent, Sylvie

AU - Dubourg, Christele

AU - Phornphutkul, Chanika

AU - de Brouwer, Arjan P. M.

AU - de Vries, Bert B. A.

AU - Vulto-vanSilfhout, Anneke T

N1 - This work was financially supported by grants from the Dutch Organization for Health Research and Development (ZON-MW grants 917–86–319 and 912–12–109 to B.B.A.d.V.), the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases (to T.M.P.), the March of Dimes (grant 6-FY14–422 to M.C.M.), and the National Institutes of Health (grants NINDS 5R21NS091724 to P.J.J. and NINDS R01NS069605 to H.C.M.).

PY - 2019/9

Y1 - 2019/9

N2 - 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.

AB - 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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KW - genotype

KW - intellectual disability

KW - neurodevelopmental disorder

KW - phenotype

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U2 - 10.1038/s41436-019-0473-6

DO - 10.1038/s41436-019-0473-6

M3 - Article

C2 - 30923367

VL - 21

SP - 2059

EP - 2069

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

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Nabais Sá MJ, Jensik PJ, McGee SR, Parker MJ, Lahiri N, McNeil EP et al. De novo and biallelic DEAF1 variants cause a phenotypic spectrum. Genetics in Medicine. 2019 Sep;21(9):2059-2069. https://doi.org/10.1038/s41436-019-0473-6