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

Abstract

Background: Disruption of HCCS 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. Methods: Exome sequencing identified variants affecting HCCS. Results: Three novel intragenic variants and two genomic deletions of HCCS 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 HCCS and AMELX 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. Conclusion: Although variable expressivity is a known feature of MLS, our findings provide additional support for including HCCS 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.

Keywords: HCCS; Peters anomaly; aphakia; corneal leukoma; corneal opacity; duplication; microphthalmia with linear skin defects (MLS).

Figure 1

Intragenic variants in HCCS. Schematic of HCCS with location of variants identified in individuals with features consistent with MLS. Exons are indicated with boxes (non-coding regions are shorter boxes) and introns with a dashed line. Coding sequence positions are marked below each exon. Gene regions encoding conserved domains I through IV are indicated in gray. Black arrows indicate missense and red arrows indicate premature truncation variants. Variants in bold are novel variants presented in this study.

Figure 2

Family pedigrees for individuals with HCCS variants. Solid black symbols indicate ocular features of MLS; solid gray symbols indicate other ocular conditions (see text). Specific HCCS variants or WT (wild type) are indicated under tested individuals in each family.