Novel CHRDL1 mutation causing X-linked megalocornea in a family with mild anterior segment manifestations in carrier females

ABSTRACT

Purpose

X-linked megalocornea (XMC) is a rare anterior segment malformation characterized by a nonprogressive enlargement of the cornea to 13 mm or greater in the setting of normal intraocular pressure. XMC is caused by mutations in the CHRDL1 gene and it is inherited as an X-linked recessive trait affecting only males. Here, we describe the results of phenotypic and genetic assessment in a novel XMC pedigree.

Methods

Three subjects (a father and his two daughters) underwent a complete clinical and imaging ocular examination including biomicroscopy, fundoscopy, tonometry, visual acuity, Pentacam Scheimpflug imaging, anterior segment Swept Source OCT, and ultrabiomicroscopy. Genetic analysis was performed through whole exome sequencing in 3 family members. Candidate variants were validated by sanger sequencing

Results

The affected father exhibited megalocornea, very deep anterior chambers, retrocorneal pigmentation, iris atrophy, queer iris configuration, extremely open iridocorneal angles, and cataracts. Notably, both daughters showed queer iris configuration and abnormally widely open iridocorneal angles in both eyes. Genetic analysis identified a novel hemizygous c.207+1G>A splicing variant in CHRDL1 in the affected father. Both mildly affected daughters were heterozygous for the pathogenic variant.

Conclusions

Here, we report an additional XMC family due to a novel mutation in the CHRDL1 gene. Mild anterior segment anomalies were observed in two heterozygous carriers demonstrating for the first time a CHRDL1-linked phenotype in females. A detailed comparison of the clinical and genetic features of this pedigree with those observed in previously published XMC cases is also presented.

KEYWORDS:

• Megalocornea
• CHRDL1
• anterior segment dysgenesis
• whole exome sequencing

Acknowledgments

This research was funded by Universidad Nacional Autónoma de México (UNAM), Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT) Grant IA208520.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the PAPIIT [IA208520].