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

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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.


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.


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.


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


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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 Some of the participants in the study were contacted through GeneDX (Gaithersburg, MD) and through GeneMatcher ( 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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  • chromatin remodeling
  • ATPase
  • missense
  • intellectual disability
  • 12p13.31