A Novel Homozygous Variant Associated With Distinct Clinical Phenotypes of SDR9C7 Nonsyndromic Epidermal Differentiation Disorder in Two Affected Patients From a Consanguineous Saudi Family.

backgroundNonsyndromic Epidermal Differentiation Disorders (nEDD) are a group of heterogeneous disorders characterized by scaling and erythema. Pathogenic variants in SDR9C7 cause SDR9C7-nEDD. We report two affected siblings from a consanguineous Saudi family presenting with distinct clinical phenotypes. The older affected brother exhibited generalized xerosis with both white and brown scaling, neck hyperpigmentation, and a velvety texture on the posterior neck. The younger sister showed diffuse xerosis with fine white scaling and marked palmoplantar hyperlinearity.

methodsA family with two siblings suspected of a rare genetic disease was recruited. Given the phenotypic variability, whole-exome sequencing (WES) was carried out for the proband brother to identify the genetic cause. Sanger sequencing was used to confirm the finding in the proband and to examine segregation analysis for the family members. In silico prediction tools were also used to assess the variant's pathogenicity.

resultsWES identified a novel homozygous SDR9C7 variant (NM_148897.3:c.154G>A; p.Val52Met). The affected sister was also homozygous for the variant. The variant was rare in global population databases, absent from the local database, and showed complete segregation within the family. Multiple prediction tools classified the variant as pathogenic and deleterious.

conclusionThis study expands the clinical spectrum of SDR9C7-nEDD, demonstrating its phenotypic variability even with the same novel variant. These findings highlight the contribution of additional modifying factors and emphasize the essential role of WES in diagnosing genetically heterogeneous skin disorders when genotype-phenotype correlation is uncertain.