20q12

CHD-6,CHD5,RIGB

Acute myeloid leukemia (AML)

The presence of a fusion gene between LMBRD1 and CHD6 was identified in a case report of AML. Development of AML from an acute MDS/MPD diagnosis occurred over two years. FISH mapping of increasingly specific bacterial artificial chromosomes was used to identify the breakpoints of this AML between exons 1 and 2 of CHD6 (Douet-Guilbert et al., 2014).

Fusion gene between LMBRD1-CHD6 (6;20)(q13;q12).

Chromosome 20q12 is a common breakpoint associated with the development of MPD/MDS, however with the increased specificity of chromosome mapping techniques the frequency of the CHD6 gene specifically mutated in this disease is still being more precisely determined (Huh et al., 2010; Padhi et al., 2013).

Colorectal cancer

CHD6 has been implicated in two studies using genome wide analysis of colorectal cancer cell lines. A comparison between tumor cell lines and primary tumors found that cell lines accurately reflect the diversity of mutations associated with primary tumor samples (Mouradov et al., 2014). Additionally this study determined that mutations in chromatin state regulators (including CHD6) are commonly found in colorectal cancer. Further research examined the copy number variation (CNV) found between colorectal cancer and normal tissue samples (Ali Hassan et al., 2014). Significant alterations in CNV were observed on chromosomes 8, 13, and 20. The gain of copies on chromosome 20q12 was the most significant finding, occurring in 45% of tumor tissues examined, specifically over a 2445 kbp region containing eight genes that include PTPRT, TOP1, and CHD6 (Ali Hassan et al., 2014).

Bladder transitional cell carcinoma (TCC)

Analysis of multiple TCC tissues identified a group of chromatin remodeling enzyme genes with mutations occurring in 59% of patients. CHD6 was found mutated in multiple lines examined, however, only in one line was the mutation exclusive to CHD6. Linked mutation of CHD6 and two other genes, ANK2 or LRP2 was found to correlate with the development of TCC (Gui et al., 2011).

Various cancers (malignant melanoma, glioma, cervical cancer, lung, urinary tract, large intestine, and others)

Whole genome analysis of tumor tissues and culture cell lines have identified point mutations within CHD6. These mutations and copy number variations occur at low frequencies and are often not likely pathologically associated with the development of the cancers. The alterations have been found in the following tissues: malignant melanoma (5 substitution mutations: NCBI ClinVar Database, last update 04-24-2014), multiple tumor tissue sources identifying 283 mutations in haematopoietic and lymphoid (0.23% of tested samples), central nervous system (0.74%), cervix (14.3%), endometrium (8.5%), prostate, urinary tract (14.3%), ovary, breast, lung (7.0%), stomach (6.4%), skin, kidney, large intestine (10.6%), liver, oesophagus, and pancreas. The bulk of mutations are composed of nonsense substitution: 7.42%, missense substitution: 68.90%, synonymous substitution: 27.92%, deletion frameshift: 2.12% (COSMIC Database, v69). This database further identified copynumber variants in the following tissues; haematopoietic and lymphoid, central nervous system, breast, lung, endometrium, kidney, large intestine, lung, ovary, and pancreas tumor tissues, with gain of copy number, more common than loss of copy number (COSMIC Database, v69).

Influenza/human papillomavirus

CHD6 has been identified as playing a role in the repression of influenza A infections. It associates with viral ribonuclear proteins in infected cells (Alfonso et al., 2011). Loss of CHD6 by siRNA silencing results in an increased viral replication, while in lungs of infected mice, CHD6 is degraded upon infection and exposure to the three subunits of the viral polymerase (Alfonso et al., 2013). Recent reports also indicate that CHD6 interacts with human papillomavirus proteins, binding and repressing the expression of oncogenes (Fertey et al., 2010). This suggests that CHD6 plays a role in gene suppression and is important in the response to viral infection.

Ataxia

Mutations in CHD6 that affect functional subunits are linked to the development of an ataxic phenotype. The deletion of the ATPase region of CHD6 in a mouse model resulted in deficiencies in coordinated movement, which did not progress over time (Lathrop et al., 2010). Additionally, a recent study utilizing genome wide analysis of genes associate with coordination defects in ADHD identified CHD6 as one of the most relevant target genes (Fliers et al., 2012).