CD96 – Bohring-Opitz Syndrome

This summary reviews the association between CD96 (HGNC:16892) and Bohring-Opitz syndrome (MONDO_0011510). The evidence supporting this association comes primarily from a single case study where a de novo missense mutation was identified. The patient presented with clinical features overlapping with those described for C syndrome and Bohring-Opitz syndrome, including redundant skin, limb abnormalities, trigonocephaly, and abnormal facial shape (PMID:17847009). This initial report provided the impetus to consider CD96 as a candidate gene for the disorder. Although similar phenotypic features have been observed in other syndromic patients, the association with Bohring-Opitz syndrome remains under evaluation.

The genetic evidence is limited to one reported proband carrying a de novo missense variant, specifically c.791C>T (p.Thr264Met), which was identified in a patient with features consistent with Bohring-Opitz syndrome (PMID:17847009). There is no extensive segregation data available, as the mutation appears to be sporadic with no additional affected relatives reported. The observed mutation aligns with the dominant inheritance pattern noted in similar de novo mutation studies of related syndromes. This isolated observation calls for cautious interpretation, despite the molecular plausibility of the finding.

Further supporting the genetic findings, experimental studies have demonstrated that mutations in CD96 interfere with normal cell adhesion and growth. In vitro assays showed that the mutant CD96 protein exhibits impaired ligand binding, suggesting a potential functional deficit. These cellular disruptions provide a credible mechanism for the clinical phenotype. Although the in vitro evidence is compelling, the limited number of cases precludes drawing definitive conclusions. Consequently, while the experimental data reinforces the potential pathogenicity of the variant, they should be interpreted in the context of the broader clinical picture.

The mode of inheritance for the mutation in CD96 is consistent with autosomal dominant de novo occurrence. This is in line with previous observations of similar syndromic conditions where de novo dominant mutations play a critical role. No significant segregation data with additional affected relatives were observed, which further underlines the rarity of the event. Despite the limited case number, the functional impact of the mutation supports its role in disease pathogenesis. The combined genetic and functional data add preliminary weight to the association between CD96 variants and Bohring-Opitz syndrome but remain insufficient for a robust association claim.

It is important to note that no contradictory evidence has been reported to date regarding the involvement of CD96 in Bohring-Opitz syndrome. However, caution is warranted as the current evidence is derived from a single proband study with supporting in vitro experiments. Further research involving larger cohorts and additional functional studies is necessary to validate and possibly extend the clinical significance of CD96 in this disease context. Ongoing studies may also clarify the overlap between phenotypic features of C syndrome and Bohring-Opitz syndrome.

In conclusion, the de novo c.791C>T (p.Thr264Met) variant in CD96 represents a limited yet suggestive genetic association with Bohring-Opitz syndrome. While experimental evidence corroborates a functional role for the mutation in impairing cell adhesion, additional studies are required to firmly establish causality. Key take‑home: CD96 mutation screening could offer preliminary clinical utility in the diagnostic evaluation of patients with BOS-like features, pending further validation.

References

• American journal of human genetics • 2007 • Mutations in CD96, a member of the immunoglobulin superfamily, cause a form of the C (Opitz trigonocephaly) syndrome PMID:17847009

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