Novel Intragenic and Genomic Variants Highlight the Phenotypic Variability in HCCS-Related Disease

<b>Background</b>: Disruption of <i>HCCS</i> results in microphthalmia with linear skin lesions (MLS) characterized by microphthalmia/anophthalmia, corneal opacity, aplastic skin lesions, variable central nervous system and cardiac anomalies, intellectual disability, and poor growth in heterozygous females. Structural variants consisting of chromosomal rearrangements or deletions are the most common variant type, but a small number of intragenic variants have been reported. <b>Methods</b>: Exome sequencing identified variants affecting <i>HCCS</i>. <b>Results</b>: Three novel intragenic variants and two genomic deletions of <i>HCCS</i> were found in individuals with primarily ocular features of MLS. X-inactivation was highly skewed in affected individuals with all three intragenic variants. Corneal opacity was the most penetrant feature (100%). In addition, a duplication of uncertain significance including both <i>HCCS</i> and <i>AMELX</i> was identified in a male with corneal anomalies, glaucoma, an atrial septal defect, and enamel hypoplasia along with a family history of developmental ocular disorders consistent with X-linked inheritance. <b>Conclusion</b>: Although variable expressivity is a known feature of MLS, our findings provide additional support for including <i>HCCS</i> in testing for individuals with isolated ocular anomalies and provide further evidence for its association with congenital aphakia, aniridia/other iris defects, and corneal staphyloma/ectasia.