Alternative titles; symbols
SNOMEDCT: 1332510002; ORPHA: 653712; DO: 0070529;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p13.31 | Sifrim-Hitz-Weiss syndrome | 617159 | Autosomal dominant | 3 | CHD4 | 603277 |
A number sign (#) is used with this entry because of evidence that Sifrim-Hitz-Weiss syndrome (SIHIWES) is caused by heterozygous mutation in the CHD4 gene (603277) on chromosome 12p13.
Sifrim-Hitz-Weiss syndrome (SIHIWES) is an autosomal dominant intellectual developmental disorder with variable congenital defects affecting other systems, including cardiac, skeletal, and urogenital. Some patients may have short stature, enlarged head circumference, hearing loss, and nonspecific dysmorphic facial features (summary by Sifrim et al., 2016 and Weiss et al., 2016).
Sifrim et al. (2016) reported 5 unrelated patients, ranging in age from 1 to 16 years, with a syndrome associated with congenital heart defects. Three had tetralogy of Fallot (TOF) or TOF-like features, 1 had an aortic coarctation, and 1 had a septal defect. All were reported to have early global neurodevelopmental delay, although the 16-year-old had only gait imbalance without apparent intellectual disability. Most had variable and nonspecific dysmorphic features such as coarse facies, abnormal facial shape, epicanthal folds, ptosis, astigmatism, and ear abnormalities. Additional abnormalities observed in some patients included omphalocele, cryptorchidism, ambiguous genitalia, anteriorly placed anus, and vesicoureteral reflux. One patient had skeletal abnormalities manifest as broad and short clavicles, flat acetabular roof, short femoral neck, and fusion of the wrist bones; another patient had postaxial polydactyly, and a third had wormian bones. One patient had hearing impairment and 2 had Chiari malformation.
Weiss et al. (2016) reported 5 unrelated patients, ranging in age from 5 to 18 years, with a syndromic neurodevelopmental disorder. All had global developmental delay and impaired intellectual development. Common dysmorphic features included macrocephaly, widely spaced eyes, square-shaped face, dysmorphic ears, and palatal anomalies, but these features were nonspecific. Four patients had hearing loss, 2 patients had short stature, and all 3 males had hypogonadotropic hypogonadism with cryptorchidism and/or micropenis. Additional congenital anomalies seen in 2 patients included cervical vertebral fusions, tarsal coalitions, and heart defects, such as patent ductus arteriosus and septal defects. One patient had congenital stroke and moyamoya disease (see 252350), and 1 had chronic renal insufficiency. Brain imaging showed enlarged ventricles.
From a cohort of 197 probands with moyamoya disease, Pinard et al. (2020) reported 7 unrelated patients with mutation in the CHD4 gene. All 7 patients had ischemic stroke due to bilateral moyamoya angiopathy and 5 had hypertension. Other features were variable, and the authors concluded that rare variants in the CHD4 gene predispose to moyamoya disease in the presence or absence of developmental delay.
Karimi et al. (2025) described clinical features in a cohort of 27 patients with SIHIWES. Common findings included impaired intellectual development (19/23), speech delay (26/27), motor delay (27/27), macrocephaly (11/24), heart defects (12/24), abnormal brain imaging (14/23), hypogonadism (11/24), and hearing loss (9/23). Intelligence was in the normal range in 4 patients. Less common recurrent clinical features included optic nerve abnormalities, aortic root dilatation, and gut malrotation.
Karimi et al. (2025) examined the DNA methylation profile in peripheral blood in a cohort of patients with mutations in the CHD4 gene. A characteristic episignature was identified in 14 patients with missense mutations in the SNF2-like ATPase/helicase domain and in 1 patient with a missense mutation near the PHD domain. This episignature differed both from control patients and from patients with truncating mutations in the CHD4 gene, and helped to clarify the pathogenicity of variants of unknown significance in the ATPase/helicase domain. The methylation pattern identified in 7 patients with truncating mutations in the CHD4 gene had some overlap with the methylation pattern identified in the ATPase/helicase domain mutation cohort, but was less pronounced.
The heterozygous mutations in the CHD4 gene that were identified in patients with SIHIWES by Sifrim et al. (2016) and Weiss et al. (2016) occurred de novo.
In 5 unrelated patients with SIHIWES, Sifrim et al. (2016) identified 5 different de novo heterozygous mutations in the CHD4 gene (see, e.g., 603277.0001-603277.0003). There were 4 missense mutations and 1 in-frame deletion. Functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from a cohort of 518 trios in which a child had syndromic congenital heart defects who underwent exome sequencing. Statistical analysis indicated that de novo mutations in the CHD4 gene were significantly enriched in patients compared to those expected under a null mutation model (p = 2.28 x 10(-7), Bonferroni-corrected p = 0.05).
In 5 unrelated patients with SIHIWES, Weiss et al. (2016) identified 4 different de novo heterozygous missense mutations in the CHD4 gene (see, e.g., 603277.0004-603277.0006). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Three of the mutations occurred at highly conserved residues in the C-terminal helicase domain and were predicted to disrupt the ATPase activity of CHD4. Both Sifrim et al. (2016) and Weiss et al. (2016) noted phenotypic overlap with CHARGE syndrome (214800), which is caused by mutation in the CHD7 gene (608892).
In a cohort of 27 patients with SIHIWES, Karimi et al. (2025) found that autism was more common in patients with truncating mutations than in those with missense mutations in the CHD4 gene.
Karimi, K., Lichtenstein, Y., Reilly, J., McConkey, H., Relator, R., Levy, M. A., Kerkhof, J., Bouman, A., Symonds, J. D., Ghoumid, J., Smol, T., Clarkson, K., and 36 others. Discovery of a DNA methylation profile in individuals with Sifrim-Hitz-Weiss syndrome. Am. J. Hum. Genet. 112: 414-427, 2025. [PubMed: 39824190] [Full Text: https://doi.org/10.1016/j.ajhg.2024.12.020]
Pinard, A., Guey, S., Guo, D., Cecchi, A. C.,, Kharas, N., Wallace, S., Regalado, E. S., Hostetler, E. M., Sharrief, A. Z., Bergametti, F., Kossorotoff, M., Herve, D., Kraemer, M., Bamshad, M. J., Nickerson, D. A., Smith, E. R., Tournier-Lasserve, E., Milewicz, D. M. The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy. Genet. Med. 22: 427-431, 2020. [PubMed: 31474762] [Full Text: https://doi.org/10.1038/s41436-019-0639-2]
Sifrim, A., Hitz, M.-P., Wilsdon, A., Breckpot, J., Al Turki, S. H., Thienpont, B., McRae, J., Fitzgerald, T. W., Singh, T., Swaminathan, G. J., Prigmore, E., Rajan, D., and 63 others. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nature Genet. 48: 1060-1065, 2016. [PubMed: 27479907] [Full Text: https://doi.org/10.1038/ng.3627]
Weiss, K., Terhal, P. A., Cohen, L., Bruccoleri, M., Irving, M., Martinez, A. F., Rosenfeld, J. A., Machol, K., Yang, Y., Liu, P., Walkiewicz, M., Beuten, J., and 16 others. De novo mutations in CHD4, an ATP-dependent chromatin remodeler gene, cause an intellectual disability syndrome with distinctive dysmorphisms. Am. J. Hum. Genet. 99: 934-941, 2016. [PubMed: 27616479] [Full Text: https://doi.org/10.1016/j.ajhg.2016.08.001]