Clinical and genetic analysis further delineates the phenotypic spectrum of ALDH1A3-related anophthalmia and microphthalmia

Biallelic pathogenic variants in ALDH1A3 are responsible for approximately 11% of recessively inherited cases of severe developmental eye anomalies. Some individuals can display variable neurodevelopmental features, but the relationship to the ALDH1A3 variants remains unclear. Here, we describe seven unrelated families with biallelic pathogenic ALDH1A3 variants: four compound heterozygous and three homozygous. All affected individuals had bilateral anophthalmia/microphthalmia (A/M), three with additional intellectual or developmental delay, one with autism and seizures and three with facial dysmorphic features. This study confirms that individuals with biallelic pathogenic ALDH1A3 variants consistently manifest A/M, but additionally display neurodevelopmental features with significant intra- and interfamilial variability. Furthermore, we describe the first case with cataract and highlight the importance of screening ALDH1A3 variants in nonconsanguineous families with A/M.

Automated summary

Biallelic pathogenic variants in ALDH1A3 account for 11% of recessively inherited severe developmental eye anomalies. The relationship between ALDH1A3 variants and variable neurodevelopmental features remains unclear. This study describes seven unrelated families with biallelic pathogenic ALDH1A3 variants, confirming the consistent manifestation of bilateral anophthalmia/microphthalmia (A/M) with additional neurodevelopmental features and significant variability. Additionally, the study highlights the importance of screening ALDH1A3 variants in nonconsanguineous families with A/M and reports the first case with cataract.