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Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

Background: There is growing awareness and exposure in both the medical community and the lay media about the characteristics and complex needs of individuals who believe that their gender identity does not match their birth sex. Despite research and lay publications about teens with gender dysphoria and those who identify as transgender, little guidance is available regarding young (prepubertal) children with questions about their gender identity. Although many terms are used to describe these children, we have chosen to describe them as “gender nonconforming” (GNC). Objective: Primary care and developmental-behavioral pediatric providers are often the first professionals with whom young gender nonconforming children and their families discuss their concerns about their emerging gender identity. It is important, therefore, that pediatric providers be knowledgeable about the dilemmas, conflicts, and choices that are typical of these children and their families to guide them appropriately. Overview: In this special article, we present observations, informed by clinical experience, an emerging body of research, and a developmental-behavioral pediatric framework, of the complex needs of prepubertal gender nonconforming children and their families and an approach to their care. The article begins by outlining the cognitive and biological bases for gender identity development, as well as the natural history of gender nonconforming preferences and behaviors. It then sets the context for understanding the care of GNC children as an area in which developmentally sophisticated providers can play a crucial role in support of the complex developmental patterns and need for advocacy in multiple settings among these children.

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