Genetic insights into syndromic anophthalmia/microphthalmia: novel molecular findings in a prenatal context.

PURPOSE: Anophthalmia and microphthalmia (A/M) are among the most severe developmental eye defects. The aim of this study is to describe the genetic landscape of fetal syndromic phenotypes that include A/M.

METHODS

We recruited 31 fetuses who underwent prenatal ultrasound examination, postnatal assessment, quantitative fluorescent PCR (QF-PCR) and prenatal exome sequencing (pES).

RESULTS

All cases displayed A/M associated with at least one extra-ocular malformation and of these, cerebellar hypoplasia was the most common ultrasound finding, detected in 14 (45.2%) cases. Chromosomal aneuploidies were identified in seven cases. Among the other fetuses (n=24), pES identified single nucleotide variants (SNVs) in 21 and copy number variations (CNVs) in three. Recurrent genetic diagnoses within our cohort included muscular dystrophy-dystroglycanopathy type A-3 (MDDGA3; n=3), MDDGA1 (n=2), cerebro-oculo-facio-skeletal syndrome 3 (n=2), syndromic microphthalmia type 9 (n=2), and Fraser syndrome (n=2). We report on seven novel variants.

CONCLUSIONS

This study broadens the molecular spectrum of syndromic A/M with 19 distinct variants identified across 16 different genes. Furthermore, some variants were detected in genes that have been rarely, or not previously, linked to human A/M, thereby highlighting atypical clinical findings and suggesting a possible expansion of the phenotypic spectrum associated with these genes.