HCCS – Microphthalmia with Linear Skin Defects Syndrome

The association between HCCS and microphthalmia with linear skin defects syndrome is supported by multiple independent reports spanning case studies, familial segregation analyses, and large cohort investigations. In several families, affected individuals, often a combination of mothers and daughters, have been found to harbor heterozygous mutations or deletions involving HCCS. These findings, reported across studies (PMID:23401659), underscore the consistent recurrence of pathogenic HCCS events in this disorder.

Genetic evidence indicates that the mode of inheritance is X-linked dominant, with male lethality accounting for the absence of affected males. In addition to diverse mutational events including point mutations, submicroscopic deletions, and cases of mosaicism, one significant variant, c.589C>T (p.Arg197Ter), has been documented and fulfills ClinGen criteria as a deleterious allele (PMID:17033964). Moreover, segregation analyses from familial studies have identified additional affected relatives, further bolstering the gene-disease correlation (PMID:24735900).

Detailed case reports reveal that not only do probands present with typical ocular anomalies such as microphthalmia and abnormal retinal morphology, but they also frequently exhibit linear skin defects. The mutation spectrum within HCCS includes both missense and nonsense alleles as well as larger deletions. These genetic alterations have been observed in more than 20 unrelated probands across various reports, which collectively contribute to a strong body of evidence for the association.

Functional studies provide additional support by demonstrating that mutant HCCS proteins fail to effectively complement yeast models deficient in the HCCS ortholog, and they exhibit impaired mitochondrial targeting and reduced cytochrome c maturation. Such experimental data validate that the pathogenic mechanism is likely due to haploinsufficiency, ultimately disrupting oxidative phosphorylation and programmed cell death pathways (PMID:17033964).

Integrating both genetic and functional data, the evidence consistently converges on a strong association between HCCS mutations and the MLS phenotype. The recurrent identification of the c.589C>T (p.Arg197Ter) variant in independent cases, accompanied by family studies showing segregation of the disorder, reinforces the clinical validity of this gene–disease relationship.

In summary, the multi‐line evidence from case reports, familial analyses, and functional assays assigns a strong ClinGen category to the HCCS–MLS association. Key take‑home message: Robust genetic and functional findings make HCCS an essential diagnostic marker for microphthalmia with linear skin defects syndrome.

References

• Molecular vision • 2013 • Familial cases of a submicroscopic Xp22.2 deletion: genotype‑phenotype correlation in microphthalmia with linear skin defects syndrome PMID:23401659
• American journal of human genetics • 2006 • Mutations of the mitochondrial holocytochrome c‑type synthase in X‑linked dominant microphthalmia with linear skin defects syndrome PMID:17033964
• Orphanet journal of rare diseases • 2014 • Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome PMID:24735900

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