Novel missense mutation in the bZIP transcription factor, MAF, associated with congenital cataract, developmental delay, seizures and hearing loss (Aymé-Gripp syndrome)

Abstract

Background: Cataract is a major cause of severe visual impairment in childhood. The purpose of this study was to determine the genetic cause of syndromic congenital cataract in an Australian mother and son.

Method: Fifty-one genes associated with congenital cataract were sequenced in the proband using a custom Ampliseq library on the Ion Torrent Personal Genome Machine (PGM). Reads were aligned against the human genome (hg19) and variants were annotated. Variants were prioritised for validation by Sanger sequencing if they were novel, rare or previously reported to be associated with paediatric cataract and were predicted to be protein changing. Variants were assessed for segregation with the phenotype in the affected mother.

Result: A novel likely pathogenic variant was identified in the transactivation domain of the MAF gene (c.176C > G, p.(Pro59Arg)) in the proband and his affected mother., but was absent in 326 unrelated controls and absent from public variant databases.

Conclusion: The MAF variant is the likely cause of the congenital cataract, Asperger syndrome, seizures, hearing loss and facial characteristics in the proband, providinga diagnosis of Aymé-Gripp syndrome for the family.

Keywords: Aymé-Gripp syndrome; Congenital cataract; Ion Ampliseq; MAF; Next generation sequencing; Pediatric cataract; Syndromic cataract.

Fig. 1

a Pedigree of family CSA108 with variant in MAF. Individuals with ID numbers were examined by an ophthalmologist. Solid circles indicate affected females and solid squares indicate affected males. The proband is marked by an arrow head. “+” indicates mutant allele and “−” indicates wild type allele of c.176C > G in the MAF gene. b Sequence chromatogram of two examined individuals at variant c.176C > G. Both sequenced affected members are heterozygous for this variant. c Protein alignment shows the MAF protein is highly conserved among the indicated species. The mutated residue is indicated by the box

Fig. 2

Clinical features of the syndrome in family CSA108. a Phenotype of syndromic cataract in CSA108.01. Slit-lamp photographs showing posterior polar oil droplet cataract with posterior lenticonus. b Dental abnormalities in CSA108.01 (left) and CSA108.02 (right). c Facial features in CSA108.01 (left) and CSA108.02 (right). In particular, note flat mid-face in both, and short philtrum, long/narrow chin and upturned ear lobules in CSA108.01

Fig. 3

Schematic of the human MAF protein indicating the positions of reported variants (Adapted from Niceta et al. [27]). The protein contains an N-terminal transactivation domain and a C-terminal DNA binding domain. The C-terminal domain consists of an extended homology region, basic region (aa288–313) and leucine-zipper region (aa316–aa337). The variants associated with Aymé-Gripp syndrome are located in the N-terminal transactivation domain including the variant (p.(Pro59Arg)) reported here (bolded and underlined). Other variants are located within the C-terminal DNA-binding domain and are associated with other forms of congenital cataract mainly isolated