Snijders Blok-Campeau Syndrome

A number sign (#) is used with this entry because of evidence that Snijders Blok-Campeau syndrome (SNIBCPS) is caused by heterozygous mutation in the CHD3 gene (602120) on chromosome 17p13.

Description

Snijders Blok-Campeau syndrome (SNIBCPS) is an autosomal dominant neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development and delayed speech acquisition. Affected individuals tend to have expressive language deficits, with speech apraxia and dysarthria. Other features include macrocephaly and characteristic facial features, such as prominent forehead and hypertelorism, hypotonia, and joint laxity. The severity of the neurologic deficits and presence of nonneurologic features is variable (summary by Snijders Blok et al., 2018).

Clinical Features

Snijders Blok et al. (2018) reported 35 patients with a similar neurodevelopmental disorder. The patients were ascertained through the GeneMatcher database and most were unrelated, although there was 1 set of twins and 1 pair of sibs. Most of the patients were in their first or second decades, but 1 man was 59 years of age. All patients had global developmental delay of varying degrees, most with mildly delayed walking by age 5 years and impaired intellectual development that ranged from borderline (IQ in the 70s) to severe (IQ of 35). Nine patients (29%) had autistic features, including stereotypies or hand flapping, but many were happy, social, and pleasant. Many had hypotonia and a broad-based or unsteady gait. All patients had impaired speech and language development, with delayed first words and particular problems with expressive speech, such as dysarthria, speech apraxia, oromotor problems, and stuttering. Most patients (58%) had macrocephaly, and many had enlarged ventricles on brain imaging, even without frank macrocephaly. Common dysmorphic features included prominent, high forehead with frontal bossing, hypertelorism, deep-set eyes, epicanthal folds, broad nasal base with large nose, low-set ears, midface hypoplasia, and pointed chin. Some had a high-arched palate and/or dental abnormalities. Visual abnormalities were common, including strabismus, hypermetropia, and astigmatism; 2 patients had cerebral visual impairment. Other less common features included joint hyperlaxity, umbilical or inguinal hernia, scoliosis, mild foot deformities, and cryptorchidism. Only 1 patient had seizures, and 2 had infantile convulsions. One severely affected patient (patient 5) was a 15-year-old girl who had microcephaly and spastic tetraplegia, was unable to walk, and had no speech. The 59-year-old man developed parkinsonism.

Molecular Genetics

In a patient (proband 01) with SNIBCPS, Eising et al. (2019) identified a de novo heterozygous missense mutation in the CHD3 gene (R1228W; 602120.0001). The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation occurred at a highly conserved residue in the helicase domain. The patient was from a cohort of 19 probands with childhood apraxia of speech (CAS), which is a disorder of language development characterized by difficulties with sequencing speech sounds into syllables, words, and sentences. Eising et al. (2019) noted that CHD3 is an interacting partner with FOXP2 (605317) (Estruch et al., 2016), a well-established gene causing a different form of CAS (SPCH1; 602081). Expression data showed that CHD3 is expressed in the brain and is part of a module of functionally connected genes that are highly expressed during early human brain development.

In 35 patients from 33 unrelated families with SNIBCPS, Snijders Blok et al. (2018) identified 23 different de novo heterozygous mutations in the CHD3 gene (see, e.g., 602120.0002-602120.0005). Among the patients, there was a set of monozygotic twins and 2 sibs whose mother was mosaic for the mutation. Except for 4 individuals who carried predicted loss-of-function mutations, all patients carried missense mutations. There were 2 recurrent mutations affecting the same residue: R985W (602120.0002), found in 6 children from 5 families, and R985Q, found in 2 unrelated patients. Seventeen of the 19 missense mutations occurred in and around the ATPase/helicase motif of the protein, which is a functional domain that provides energy for nucleosome remodeling through its ATPase activity. The patients were ascertained from several research and clinical centers through the GeneMatcher program. The mutations, which were found by exome sequencing, were not found in the gnomAD database. In vitro functional expression studies of 6 of the mutations in HEK293 cells showed that 3 (R1121P; R1172Q, 602120.0003; and N1159K) impaired ATP hydrolysis activity, 1 (L915F, 602120.0004) increased activity, and 2 (R1187P; and W1158R, 602120.0005) had no effect. In contrast, further studies showed that 5 of the mutations disturbed chromatin remodeling capacities as measured by restriction enzyme accessibility to nucleosomal DNA, including 4 that severely compromised this ability (R1172Q, R1121P, W1158R, and N1159K), 1 (L915F) that increased it; and 1 (R1187P) that had no significant effect. The findings indicated that chromatin remodeling factors, and specifically CHD3, have an important role in human brain development.