Congenital Cataracts and Ayme-Gripp Syndrome via the MAF Gene

Cataracts are described as opacification of the crystalline lens of the eye that result in abnormal refraction index and light scattering. Congenital cataracts (CC) are a serious and leading cause of reversible blindness in childhood. They account for one-tenth of the cases of childhood blindness (Francis and Moore 2004). Estimated prevalence rate is 1.2 - 6.0 per 10,000 live births. Early diagnosis and surgery and optical correction have resulted in an improved outcome for infants with either unilateral or bilateral cataracts (Lambert and Drack 1996).  Ayme-Gripp syndrome is not limited to eye lens defects, and includes deafness, intellectual disability, seizures, Down syndrome-like facies, short stature, and mental retardation (Niceta et al. 2015).

Only 10–25% of congenital cataracts are hereditary. Cataracts are most often inherited as an autosomal dominant trait. Congenital cataracts also exhibit autosomal recessive or X-linked inheritance (Hejtmancik 2008). X-linked cataract is seen in Nance-Horan syndrome (NHS), which is an especially rare disorder. NHS has cataracts along with prominent dental findings, dysmorphic features, and intellectual disability (Toutain et al. 1997; Stambolian et al. 1990). Currently, isolated or primary cataracts have been mapped to about 39 genetic loci, and over 25 of those are connected to pathogenic variants in specific genes. However, this number is constantly increasing (Hejtmancik 2008).

Pathogenic variants in MAF are causative for autosomal dominant syndromic and nonsyndromic cataracts (Niceta et al. 2015; Jamieson et al. 2002). MAF is a basic region leucine zipper (bZIP) transcription factor, which is expressed in vertebrate lens fiber cells and persists throughout lens development. MAF proteins have N-terminal transactivation domain, C-terminal DNA-binding domain, extended homology, basicmotif and leucine-zipper regions (Jamieson et al. 2002; Kawauchi et al. 1999). So far missense variants and one complex genomic rearrangement have been shown to be causative for both syndromic and nonsyndromic cataracts (Human Gene Mutation Database). De novo heterozygous missense variants affecting highly conserved residues of the gsk3 (serine/threonine kinase) phosphorylation motifs within the transactivation domain are shown to cause Ayme´-Gripp Syndrome (Niceta et al. 2015).

Predicting clinical sensitivity for the MAF gene is challenging due to genetic heterogeneity of cataracts and also due to the limited number of MAF-associated cataract cases. Ayme-Gripp syndrome is a rare disorder. Hence, predicting the clinical sensitivity is difficult. However, in one study, seven de novo MAF variants were identified in 8 unrelated patients diagnosed with the Ayme-Gripp syndrome (Niceta et al. 2015).

This test provides full coverage of all coding exons of the MAF gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).