A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome

Abstract

There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.

Fig. 1. Phenotypes and CHD3 variants detected in our patient cohort.

a Schematic depicting the CHD3 protein with colored boxes corresponding to the protein domains listed in the included key, based on the amino acid sequence NP_001005273.1. Genetic variants are indicated by large colored bars indicating deletions/duplications, and by dots, colored as per the included key. Variants displayed above the protein schematic are those that were identified in the cohort we present in this paper. Variants displayed below the schematic are those identified in the initial CHD3 patient cohort [12]. The different domain types displayed are plant homeodomains (PHD), chromodomains (Chromo), a Helicase domain consisting of two parts (Helicase ATP-binding and Helicase C-terminal), Domains of Unknown Function (DUF), and a C-terminal 2 domain. b Graph displaying the frequency of various phenotypic features (shown as a percent of the total for each group) for patients with missense/in-frame deletions within or surrounding the CHD3 helicase domain (individuals 2 through 15, displayed in green, n = 14) compared with patients with any other CHD3 variant type (individuals 1–1, 1–2, 16 through 23, displayed in purple, n = 10). Fishers exact test was used to determine if any significant differences existed between the two groups. p values are displayed for all comparisons with a p value < 0.05—all other p values were >0.05.

Fig. 2. Facial photographs of CHD3 patients in our cohort.

a Photographs of 14 affected individuals from our cohort, divided by variant type, as indicated. Overall, we note the similar facial appearance between patients in all variant type groups, with a boxy face, prominent forehead, full cheeks, thin upper lip, broad nose and nasal bridge, deep- and widely-set eyes, and pointed chin. We also note that the facial appearance matures over time, with the full cheeks and boxy face becoming less prominent, while the broad forehead, prominent nose, and pointed chin become more defining of the typical facial appearance at older ages. b Two composite facial masks were generated. The first, on the left, was generated from 19 photos of patients with missense/in-frame deletion variants within the CHD3 helicase domain (photographs obtained from both our cohort and the initial CHD3 cohort) [12]. The second, on the right, was generated from 11 photos of patients with any other CHD3 variant (photographs obtained from both our cohort and the initial CHD3 cohort) [12]. We note a very similar facial appearance between the two masks.