Diagnostic utility of whole exome sequencing in children with suspected genodermatoses: a single-center retrospective study

IntroductionGenodermatoses are a group of monogenic inherited skin disorders characterized by marked genetic heterogeneity. Although the phenotype of many genodermatoses is readily recognizable on clinical examination, it is often insufficient to establish the precise molecular genetic etiology. Currently, the use of whole exome sequencing in pediatric dermatology is considered preferable because of its accessibility and higher diagnostic accuracy compared with targeted sequencing approaches.MethodsSingleton whole exome sequencing was performed in 18 children (10 boys and 8 girls) aged 1–15 years with suspected genodermatoses. Before whole exome sequencing, all patients underwent dermatological evaluation, including a comprehensive phenotypic assessment, to determine indications for whole exome sequencing.ResultsPreviously described and novel pathogenic or likely pathogenic variants and copy number variation in 10 genes associated with genodermatoses were identified in 9 of the 18 patients (50%). In an additional 2 of the 18 patients, genetic variants were identified in 2 genes associated with other inherited disorders. These were Noonan syndrome, type 4, and pseudohypoaldosteronism, type IB2. The referral diagnosis was concordant with the whole exome sequencing findings in 6 of the 11 cases with pathogenic or likely pathogenic variants (54.54%). Variants of uncertain significance were identified in 4 patients. Two previously unreported likely pathogenic variants were detected in the JUP and SCNN1B genes. Previously reported variants were identified in SOS1, FLG, JUP, KRT10, SPINK5, LEMD3, and NIPAL4. Overall, 17 sequence variants were detected, including 6 pathogenic, 7 likely pathogenic, and 4 of uncertain clinical significance. In addition, one pathogenic deletion involving the STS gene was identified. In one patient with Netherton syndrome, the molecular diagnosis enabled the initiation of targeted pathogenic therapy. No disease–causing genetic variants were identified in 3 patients.ConclusionComprehensive phenotypic assessment combined with whole exome sequencing represents a useful diagnostic tool in pediatric dermatology, enabling rapid diagnosis in clinically challenging and undifferentiated cases. Furthermore, this approach facilitates the identification of pathogenic variants not only in genes associated with inherited skin disorders but also in other clinically relevant genes consistent with the suspected diagnosis.