Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Abstract

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 Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum.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.

Connectome Analysis in an Individual with SETD1B-Related Neurodevelopmental Disorder and Epilepsy

“…Similarly, published cases often exhibited drug-resistant seizures, but sultiame has not been reported thus far. 8,9 As opposed to previous publications, we have long-term clinical data available until adulthood. Although our patient exhibited severe language delay since childhood, significant improvements were noted later on.…”

“…Similarly, published cases often exhibited drug-resistant seizures, but sultiame has not been reported thus far. 8,9…”

“…6,7 Published cases of patients with rare coding variants in SETD1B further delineated the clinical and molecular spectrum, particularly highlighting the challenge of drugresistant epilepsy. 8,9 With increasing use of next-generation sequencing in clinical practice, a growing number of individuals with causative variants in SETD1B can be expected to be identified in future years. An epigenetic study described a characteristic hypermethylation pattern related to SETD1B haploinsufficiency, which may be helpful to accurately reclassify variants of uncertain significance, thus enhancing diagnostic outcomes.…”

Case Report: Two New Cases of Chromosome 12q14 Deletions and Review of the Literature

“…has now led to the conclusions that most of the phenotypes associated with these microdeletion syndromes are caused by alterations of the genes CNOT2 (Alesi et al, 2017) and SETD1B (Weerts et al, 2021), respectively. It is expected that further progress in genetics, cell biology and personalized medicine will advance options to influence the phenotypes by gene-specific or pathway driven therapeutics.…”

The non-coding genome in genetic brain disorders: new targets for therapy?

“…Other examples include a variant in a silencer of NOTCH1, which was shown to contribute to Tetralogy of Fallot (a congenital heart disease) [57] and translocations of the NCREs of PAX6 that lead to aniridia [56]. Multiple disease examples show that the human brain seems particularly sensitive to gene expression disbalance [4,43,58], and many neurodevelopmental disorders are linked to chromatin modifiers [5,[59][60][61][62][63][64] and architectural proteins with roles in establishing chromatin conformation, such as CTCF, YY1 and STAG1 [1,3,4,65,66]. In this section, we will focus on a number of recent examples that illustrate the wide range of alterations of gene regulatory processes that can cause brain-related disorders, and the novel approaches to identify them.…”