A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

Abstract

CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly difficult for missense variants because most variants in the CHD7 gene are private and a functional assay is not yet available. We have therefore developed a novel classification system to predict the pathogenic effects of CHD7 missense variants that can be used in a diagnostic setting. Our classification system combines the results from two computational algorithms (PolyPhen-2 and Align-GVGD) and the prediction of a newly developed structural model of the chromo-and helicase domains of CHD7 with segregation and phenotypic data. The combination of different variables will lead to a more confident prediction of pathogenicity than was previously possible. We have used our system to classify 145 CHD7 missense variants. Our data show that pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5 and 3 regions. Finally, we show that CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations.

CHARGE syndrome: a review of the immunological aspects

“…Although we only have detailed information on the variant in CHD7 for 23 patients, the fact that all reported variants lead to a premature stop in CHD7 is interesting, because truncating CHD7 variants are in general associated with a more severe phenotype. 12 Are certain phenotypic features more common in our collected cohort?…”

“…There is no clear genotype-phenotype correlation, but variants leading to a premature stop codon are, in general, associated with a more severe phenotype than variants with a non-truncating effect, that is, missense variants. 12 Since the genetic cause of CHARGE syndrome was identified, its phenotype has been further explored. In addition to the above symptoms, other common clinical features of CHARGE syndrome are: absent or hypoplastic semicircular canals, cranial nerve dysfunction (including facial nerve palsy), cleft lip and/or palate, anosmia, feeding difficulties and skeletal abnormalities.…”

Clinical utility gene card for: CHARGE syndrome - update 2015

“…Some variants may be erroneously interpreted as disease-causing. An interpretation algorithm for missense variants has been published by Bergman et al 6 2.3 Clinical sensitivity (proportion of positive tests if the disease is present)…”

“…The clinical specificity of these criteria is~85%, as 14-17% of the patients with a CHD7 disease-causing variant do not completely fulfill these criteria. 4 Bergman et al 6 defined criteria for CHD7 testing and showed that if these criteria were used the risk of not offering the test to a patient with a CHD7 disease-causing variant was extremely low. 4 But, it should be taken into account that the mild end of the phenotypic spectrum is still expanding.…”

Prominent scapulae mimicking an inherited myopathy expands the phenotype of CHD7-related disease

“…On the basis of the prediction programs (score +2) and de novo occurrence (score +3), this missense variant probably affects function according to the scoring classification published by Bergman. 15 In Patient 3, CHD7 sequencing revealed an intronic variant predicted to disrupt the exon 6 donor splice site (c.2442+5G4C; NM_017780.3; g.127819G4C; NG_007009.1). The same variant was present in his affected older brother 9 and their mildly affected father.…”