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The association between SCML2 (HGNC:10581) and Nance-Horan syndrome (MONDO_0010545) has been evaluated through disparate lines of evidence. In one study, a 1.83-Mb interstitial microdeletion at Xp22.2p22.13 was reported in a 19‑year‑old male with classical features of Nance‑Horan syndrome, and SCML2 was one of several genes encompassed by this deletion (PMID:35122698). This finding initially suggested that disruption of SCML2 might contribute to the syndrome’s phenotype.
However, a subsequent multi‑patient study focused on candidate gene analysis within the refined NHS locus on Xp22.13 found that no coding mutations in SCML2 were detected in 12 unrelated NHS patients (PMID:12173028). This negative finding significantly weakens the argument for SCML2 as an independent driver of the condition.
Genetically, while the deletion evidence implicates a region including SCML2, it does not isolate SCML2 as the sole causative gene. The observed genetic alterations thus remain intertwined with multiple genes in the region, and no SCML2‐specific HGVS variant (e.g., a coding change such as c.123A>T (p.Lys41Asn)) has been reported in isolation. Therefore, the overall genetic evidence from case reports is limited and does not reach the threshold for a robust association.
Experimental or functional studies specifically addressing the pathogenicity of SCML2 in Nance-Horan syndrome are lacking. No in‑vitro or in‑vivo models have been reported that demonstrate a functional impact attributable solely to alterations in SCML2, and any functional assays performed were not able to dissect its individual contribution within the multi‑gene deletion context.
Segregation data is minimal as there is no clear evidence of affected relatives carrying SCML2‑specific alterations in these studies. The absence of additional familial data further diminishes the supportive nature of the genetic evidence for SCML2.
The integration of the available genetic and experimental data leads to a conclusion that the association between SCML2 and Nance-Horan syndrome remains disputed. While the deletion study provides an initial hint of involvement, the lack of SCML2‑specific mutations and targeted functional validation strongly argue against a primary pathogenic role for SCML2.
Key take‑home message: For diagnostic decision‑making and clinical utility, the current evidence does not support an independent pathogenic role of SCML2 in Nance-Horan syndrome, and clinicians should interpret any findings related to SCML2 with caution.
Gene–Disease AssociationDisputedSCML2 is included within a multi‑gene microdeletion reported in a NHS patient (PMID:35122698), yet candidate gene analysis in 12 unrelated probands failed to identify SCML2‐specific mutations (PMID:12173028), undermining its role as a primary causative factor. Genetic EvidenceLimitedNo SCML2‑specific coding variants have been reported in isolation, and the genetic evidence is largely derived from deletions that encompass multiple genes, reducing the specificity of the finding. Functional EvidenceLimitedFunctional studies targeting SCML2 have not been performed, and there is no experimental evidence to confirm its pathogenic impact on Nance-Horan syndrome. |