P445: A Sotos syndrome case report: Describing the complex work-up following a variant of uncertain significance in the NSD1 gene

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Sotos syndrome (OMIM 117550) is an autosomal dominant genetic condition primarily characterized by developmental delays, overgrowth in childhood, and a distinct facial appearance. Heterozygous pathogenic variants or deletions encompassing the NSD1 gene are causative of Sotos syndrome. There are several overgrowth and intellectual disability disorders with overlapping presentations to Sotos syndrome which can present a diagnostic challenge. This complexity is exemplified in cases involving variants of uncertain significance (VUS) detected through broad gene panels. Effective diagnostic approaches to further explore the clinical significance of a variant including targeted familial testing, broad genetic testing via whole exome or whole genome sequencing, and methylation analysis, are crucial in elucidating the clinical relevance of these variants. The understanding of Sotos syndrome's methylation signature, a key diagnostic tool, may be helpful in confirming diagnoses. We present a case of a four-year-old child referred for genetic evaluation due to developmental and behavioral concerns, tall stature, macrocephaly and dysmorphic facies. Genetic testing via an overgrowth and macrocephaly gene panel identified a novel NSD1 gene variant (c. 6314G>A, p.Gly2105Glu; reference sequence: NM_022455.4), raising suspicion for Sotos syndrome. The physical exam revealed a characteristic facial gestalt suggestive of Sotos syndrome, including prominent forehead and long face with prominent jaw. Parental testing for the NSD1 variant was completed and to our surprise, revealed the same NSD1 variant in the asymptomatic mother, complicating the interpretation. Subsequently, whole exome sequencing was performed to assess for other genetic variants that may provide an alternative genetic etiology for the child’s presentation. No additional variants were identified on whole exome sequencing. Next, methylation signature analysis of the child was performed and confirmed a positive Sotos syndrome signature. Further work-up for the family is currently in process including methylation analysis for the proband’s mother. This case underscores the complexities involved in interpreting novel genetic variants of uncertain clinical significance. The presence of the same NSD1 variant in both the affected child and asymptomatic mother highlights the intricacies of genetic inheritance and expression. Methylation analysis proved crucial in supporting the diagnosis of Sotos syndrome in the child. This case demonstrates the need for comprehensive and multi-faceted genetic work-up in cases of novel molecular variants to accurately determine their clinical significance.

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