Sifrim-Hitz-Weiss Syndrome

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.

Description

Sifrim-Hitz-Weiss syndrome 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).

Clinical Features

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 intellectual disability. 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 chronic renal insufficiency. Brain imaging showed enlarged ventricles.

Molecular Genetics

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).