Familial CHARGE syndrome and the CHD7 gene: A recurrent missense mutation, intrafamilial recurrence and variability

Abstract

CHARGE syndrome is an autosomal dominant condition that is caused by mutations in the CHD7 gene. Few familial cases of this syndrome have been reported and these were characterized by a wide clinical variability. We here report on five CHD7 mutation positive families and comment on their clinical features. We observed somatic and germline mosaicism as well as parent-to-child transmission of non-mosaic CHD7 mutations as causes of familial CHARGE syndrome. In one family with two affected sibs a somatic mutation was identified in lymphocytes of a clinically unaffected parent (2520G > A in exon 8). This is the second report of somatic CHD7 mosaicism in an unaffected parent. In two further families with affected siblings, we could not detect the mutation in parental lymphocytes suggesting germline mosaicism. The previously reported clinical variability was strikingly present in all five families. We find that alterations in CHD7 can result in a very mild phenotype, characterized by only a few minor symptoms of the CHARGE syndrome clinical spectrum. Such a mild phenotype was present in two families that shared the same 6322G > A missense mutation. These two families showed parent-to-child transmission. Phenotypically milder forms of CHARGE syndrome have a higher risk of transmission to multiple family members.

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

“…The discovery of loss‐of‐function mutations in the CHD7 gene in patients with CHARGE syndrome (Janssen et al, 2012; Vissers et al, 2004), has led to significant progress in elucidating the developmental and molecular genetic mechanisms underlying specific phenotypes associated with CHARGE syndrome (Layman, Hurd, & Martin, 2010). However, CHARGE syndrome is characterized by significant variability in incidence and severity of specific abnormalities, which does not correlate with the nature of CHD7 mutation (Basson & van Ravenswaaij‐Arts, 2015; Bergman, Janssen et al, 2011; Jongmans et al, 2008). These observations implicate other genetic or non‐genetic factors, or even stochastic effects as modifiers of disease severity.…”

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

“…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. The variant was not present in the ExAC database.…”

“…Missense variants in CHD7 are relatively uncommon in the literature, and it is possible that mild or atypical CHARGE phenotypes, such as we report, have been under-recognized. Variable expressivity is common in autosomal dominant transmission of CHD7 variants, 9 and it is uncertain whether the p.(Thr1133Met) variant predisposes to a mild phenotype or could lead to typical CHARGE syndrome in some individuals.…”

“…9 Both fulfilled diagnostic criteria for a typical CHARGE syndrome. Their father was recently available for testing and review.…”

“…Nonsense and frameshift variants are most common, but missense variants are also reported. [7][8][9] A small number of patients with mild phenotypes, who do not fulfill the diagnostic criteria, have been reported in association with missense variants. 9 Commonly these patients have had ear abnormalities, with or without one or two other minor criteria.…”