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

Area of Science:

• Genetics and Ophthalmology
• Human molecular genetics
• Developmental biology

Background:

• Microphthalmia with linear skin lesions (MLS) is a condition caused by HCCS gene disruption, affecting heterozygous females with ocular, skin, CNS, and cardiac anomalies.
• While structural variants are common in MLS, intragenic HCCS variants are rarely reported.
• Ocular manifestations include microphthalmia/anophthalmia, corneal opacity, and intellectual disability.

Purpose of the Study:

• To identify and characterize novel intragenic variants and genomic deletions affecting the HCCS gene.
• To investigate the association of HCCS variants with ocular features of MLS and other ocular anomalies.
• To evaluate the role of X-inactivation skewing in affected individuals.

Main Methods:

• Exome sequencing was employed to detect variants in the HCCS gene.
• Analysis included identifying novel intragenic variants and genomic deletions.
• X-inactivation patterns were assessed in affected individuals.

Main Results:

• Three novel intragenic HCCS variants and two genomic deletions were identified in individuals with MLS, primarily exhibiting ocular features.
• Corneal opacity was observed in 100% of affected individuals with intragenic variants.
• A duplication involving HCCS and AMELX was found in a male with corneal anomalies, glaucoma, ASD, and enamel hypoplasia.

Conclusions:

• The findings support the inclusion of HCCS gene testing for individuals presenting with isolated ocular anomalies.
• HCCS variants are associated with a spectrum of ocular defects, including congenital aphakia, iris defects, and corneal ectasia.
• Variable expressivity of MLS is confirmed, emphasizing the importance of comprehensive genetic analysis.