The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype–phenotype correlations, and molecular basis

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Abstract

Purpose

Sifrim–Hitz–Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants in CHD4. In this study, we investigated the clinical spectrum of the disorder, genotype–phenotype correlations, and the effect of different missense variants on CHD4 function.

Methods

We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains.

Results

The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype–phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains.

Conclusion

The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.

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Fig. 1: CHD4 variants and associated phenotypes.
Fig. 2: The clinical spectrum of the CHD4-related syndrome cohort.
Fig. 3: Facial dysmorphologies in Sifrim-Hitz-Weiss syndrome.
Fig. 4: ATPase activity assay.
Fig. 5

References

  1. 1.

    Weiss K, Terhal PA, Cohen L, et al. De novo mutations in CHD4, an ATP-dependent chromatin remodeler gene, cause an intellectual disability syndrome with distinctive dysmorphisms. Am J Hum Genet. 2016;99:934–941.

  2. 2.

    Sifrim A, Hitz M-P, Wilsdon A, et al. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet. 2016;48:1060–1065.

  3. 3.

    Lai AY, Wade PA. Cancer biology and NuRD: a multifaceted chromatin remodelling complex. Nat Rev Cancer. 2011;11:588–596.

  4. 4.

    Xue Y, Wong J, Moreno GT, et al. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol Cell. 1998;2:851–861.

  5. 5.

    Basta J, Rauchman M. The nucleosome remodeling and deacetylase complex in development and disease. Transl Res. 2015;165:36–47.

  6. 6.

    Woodage T, Basrai MA, Baxevanis AD, et al. Characterization of the CHD family of proteins. Proc Natl Acad Sci USA. 1997;94:11472–11477.

  7. 7.

    Wade PA, Jones PL, Vermaak D, Wolffe AP. A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase. Curr Biol. 1998;8:843–846.

  8. 8.

    Hargreaves DC, Crabtree GR. ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res. 2011;21:396–420.

  9. 9.

    Clapier CR, Iwasa J, Cairns BR, Peterson CL. Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat Rev Mol Cell Biol. 2017;18:407–422.

  10. 10.

    Hoffmeister H, Fuchs A, Erdel F, et al. CHD3 and CHD4 form distinct NuRD complexes with different yet overlapping functionality. Nucleic Acids Res. 2017;45:10534–10554.

  11. 11.

    Nitarska J, Smith JG, Sherlock WT, et al. A functional switch of NuRD chromatin remodeling complex subunits regulates mouse cortical development. Cell Rep. 2016;17:1683–1698.

  12. 12.

    Snijders Blok L, Rousseau J, Twist J, et al. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language. Nat Commun. 2018;9:4619.

  13. 13.

    Thompson PM, Gotoh T, Kok M, et al. CHD5, a new member of the chromodomain gene family, is preferentially expressed in the nervous system. Oncogene. 2003;22:1002–1011.

  14. 14.

    Watson AA, Mahajan P, Mertens HDT, et al. The PHD and chromo domains regulate the atpase activity of the human chromatin remodeler CHD4. J Mol Biol. 2012;422:3–17.

  15. 15.

    Morra R, Lee BM, Shaw H, et al. Concerted action of the PHD, chromo and motor domains regulates the human chromatin remodelling ATPase CHD4. FEBS Lett. 2012;586:2513–2521.

  16. 16.

    Biasini M, Bienert S, Waterhouse A, et al. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res. 2014;42(W1):1–7.

  17. 17.

    Yang J, Yan R, Roy A, et al. The I-TASSER suite: protein structure and function prediction. Nat Methods. 2014;12:7–8.

  18. 18.

    Taguchi H, Horikoshi N, Arimura Y, Kurumizaka H. A method for evaluating nucleosome stability with a protein-binding fluorescent dye. Methods. 2014;70:119–126.

  19. 19.

    Liu X, Li M, Xia X, et al. Mechanism of chromatin remodelling revealed by the Snf2-nucleosome structure. Nature. 2017;544:440–445.

  20. 20.

    Gurovich Y, Hanani Y, Bar O, et al. Identifying facial phenotypes of genetic disorders using deep learning. Nat Med. 2019;25:60–64.

  21. 21.

    Silva AP, Ryan DP, Galanty Y, et al. The N-terminal region of chromodomain helicase DNA-binding protein 4 (CHD4) is essential for activity and contains a high mobility group (HMG) box-like-domain that can bind poly(ADP-ribose). J Biol Chem. 2016;291:924–938.

  22. 22.

    Mansfield RE, Musselman CA, Kwan AH, et al. Plant homeodomain (PHD) fingers of CHD4 are histone H3-binding modules with preference for unmodified H3K4. J Biol Chem. 2011;286:11779–11791.

  23. 23.

    Kovač K, Sauer A, Mačinković I, et al. Tumour-associated missense mutations in the dMi-2 ATPase alters nucleosome remodelling properties in a mutation-specific manner. Nat Commun. 2018;9:2112.

  24. 24.

    Bjornsson HT. The Mendelian disorders of the epigenetic machinery. Genome Res. 2015;25:1473–1481.

  25. 25.

    Larizza L, Finelli P. Developmental disorders with intellectual disability driven by chromatin dysregulation: clinical overlaps and molecular mechanisms. Clin Genet. 2019;95:231–240.

  26. 26.

    Sun F, Yang Q, Weng W, et al. Chd4 and associated proteins function as corepressors of Sox9 expression during BMP-2-induced chondrogenesis. J Bone Min Res. 2013;28:1950–1961.

  27. 27.

    Ingram KG, Curtis CD, Silasi-Mansat R, et al. The NuRD chromatin-remodeling enzyme CHD4 promotes embryonic vascular integrity by transcriptionally regulating extracellular matrix proteolysis. PLoS Genet. 2013;9:e1004031.

  28. 28.

    Sparmann A, Xie Y, Verhoeven E, et al. The chromodomain helicase Chd4 is required for Polycomb-mediated inhibition of astroglial differentiation. EMBO J. 2013;32:1598–1612.

  29. 29.

    Yamada T, Yang Y, Hemberg M, et al. Promoter decommissioning by the NuRD chromatin remodeling complex triggers synaptic connectivity in the mammalian brain. Neuron. 2014;83:122–134.

  30. 30.

    Walz K, Caratini-Rivera S, Bi W, et al. Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) contiguous gene syndromes by chromosome engineering in mice: phenotypic consequences of gene dosage imbalance. Mol Cell Biol. 2003;23:3646–3655.

  31. 31.

    Wilczewski CM, Hepperla AJ, Shimbo T, et al. CHD4 and the NuRD complex directly control cardiac sarcomere formation. Proc Natl Acad Sci USA 2018;115:6727–6732.

  32. 32.

    Denner DR, Rauchman M. Mi-2/NuRD is required in renal progenitor cells during embryonic kidney development. Dev Biol. 2013;375:105–116.

  33. 33.

    Richmond E, Peterson CL. Functional analysis of the DNA-stimulated ATPase domain of yeast SW12/SNF2. Nucleic Acids Res. 1996;24:3685–3692.

  34. 34.

    Nagy E, Maquat LE. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem Sci. 1998;23:198–199.

  35. 35.

    Bögershausen N, Wollnik B. Mutational landscapes and phenotypic spectrum of SWI/SNF-related intellectual disability disorders. Front Mol Neurosci. 2018;11:1–18.

  36. 36.

    Hasselblatt M, Nagel I, Oyen F, et al. SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis. Acta Neuropathol. 2014;128:453–456.

  37. 37.

    Hodges HC, Stanton BZ, Cermakova K, et al. Dominant-negative SMARCA4 missense mutations alter the accessibility landscape of tissue-unrestricted enhancers. Nat Struct Mol Biol. 2018;25:61–72.

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Acknowledgements

We are grateful to the patients and their families for consenting to participate in this publication. This work was supported, in part, by the Intramural Research Program of the National Institute of Environmental Health Science, NIH (ES101965 to P.A.W.). The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003], a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute [grant number WT098051]. The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The Pediatric Cardiac Genomics Consortium (PCGC) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and U.S. Department of Health and Human Services through grants UM1HL128711, UM1HL098162, UM1HL098147, UM1HL098123, UM1HL128761, and U01HL131003. This manuscript was prepared in collaboration with investigators of the PCGC and has been reviewed and/or approved by the PCGC. PCGC investigators are listed at https://benchtobassinet.com/Centers/PCGCCenters.aspx. Some of the participants in the study were contacted through GeneDX (Gaithersburg, MD) and through GeneMatcher (https://www.genematcher.org/). The views expressed in this article reflect the results of research conducted by the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. Dr. Weiss is supported by the Clinical Research Institute at Rambam.

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Correspondence to Karin Weiss MD.

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Keywords

  • chromatin remodeling
  • ATPase
  • missense
  • intellectual disability
  • 12p13.31