Specific gene in microphthalmia

Summary Anophthalmia and microphthalmia (A/M) are early‐eye‐development anomalies resulting in absent or small ocular globes, respectively. Genetically determined A/M are characterized by major genetic heterogeneity. In addition, there is a genetic overlap with some genes being involved in both anophthalmia and microphthalmia. Recently, we reported that mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) cause A/M with occasional orbital cystic, neurological, and cardiac anomalies in three consanguineous families. ALDH1A3 is a key enzyme in the formation of a retinoic acid (RA) gradient along the dorso‐ventral axis during early eye development. Although the role of (RA) signaling in eye development is well established, these findings provided genetic evidence of a direct link between RA‐synthesis dysfunction and early‐eye‐development anomalies. Since the original report, A/M has been ascribed to homozygous ALDH1A3 mutations in sixteen additional consanguineous families describing variable clinical expression, within and between families, ranging from silent expression to multisystemic diseases. The variable expression of ALDH1A3 mutations which are a leading cause of A/M will be discussed.