Abstract:Epigenetic processes play a key role in regulating gene expression. Genetic variants that disrupt chromatin‐modifying proteins are associated with a broad range of diseases, some of which have specific epigenetic patterns, such as aberrant DNA methylation (DNAm), which may be used as disease biomarkers. While much of the epigenetic research has focused on cancer, there is a paucity of resources devoted to neurodevelopmental disorders (NDDs), which include autism spectrum disorder and many rare, clinically over… Show more
“…In other disorders of the epigenetic machinery, a case group clustering out from control subjects using one signature indicates the possible existence of a second overlapping but distinct signature for these subjects. 18 , 22 , 49 We hypothesized that the intermediate clustering of the proximal SRCAP subjects was indicative of a unique DNAm signature associated with these cases, overlapping that of FLHS. Figure 2 Loss-of-function variants in SRCAP are associated with two distinct but overlapping DNAm signatures based on variant position (A and B) FLHS DNAm signature: (A) principal components analysis (PCA) and (B) heatmap showing clustering of FLHS discovery subjects (n = 4; dark purple), FLHS validation subjects (n = 4; light purple), proximal SRCAP discovery subjects (n = 5; dark orange), proximal SRCAP validation subjects (n = 4; light orange), distal SRCAP subjects (green) and discovery control subjects (n = 35; blue) using DNAm values at 464 CpG sites in the FLHS DNAm signatures.…”
Section: Resultsmentioning
confidence: 99%
“…In other disorders of the epigenetic machinery, a case group clustering out from control subjects using one signature indicates the possible existence of a second overlapping but distinct signature for these subjects. 18,22,49 We hypothesized that the intermediate clustering of the proximal SRCAP subjects was indicative of a unique DNAm signature associated with these cases, overlapping that of FLHS.…”
Summary
Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (
SRCAP
) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly
de novo
)
SRCAP
variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal
SRCAP
individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as “non-FLHS
SRCAP
-related NDD.” All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal
SRCAP
group. In summary, for
SRCAP
, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.
“…In other disorders of the epigenetic machinery, a case group clustering out from control subjects using one signature indicates the possible existence of a second overlapping but distinct signature for these subjects. 18 , 22 , 49 We hypothesized that the intermediate clustering of the proximal SRCAP subjects was indicative of a unique DNAm signature associated with these cases, overlapping that of FLHS. Figure 2 Loss-of-function variants in SRCAP are associated with two distinct but overlapping DNAm signatures based on variant position (A and B) FLHS DNAm signature: (A) principal components analysis (PCA) and (B) heatmap showing clustering of FLHS discovery subjects (n = 4; dark purple), FLHS validation subjects (n = 4; light purple), proximal SRCAP discovery subjects (n = 5; dark orange), proximal SRCAP validation subjects (n = 4; light orange), distal SRCAP subjects (green) and discovery control subjects (n = 35; blue) using DNAm values at 464 CpG sites in the FLHS DNAm signatures.…”
Section: Resultsmentioning
confidence: 99%
“…In other disorders of the epigenetic machinery, a case group clustering out from control subjects using one signature indicates the possible existence of a second overlapping but distinct signature for these subjects. 18,22,49 We hypothesized that the intermediate clustering of the proximal SRCAP subjects was indicative of a unique DNAm signature associated with these cases, overlapping that of FLHS.…”
Summary
Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (
SRCAP
) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly
de novo
)
SRCAP
variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal
SRCAP
individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as “non-FLHS
SRCAP
-related NDD.” All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal
SRCAP
group. In summary, for
SRCAP
, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.
“…Alterations in DNA methylation patterns are implicated in imprinting disorders and diseases of short tandem repeat (STR) expansions. The application of DNA methylation analyses has been successful in identifying molecular diagnoses in neurodevelopmental disorders where clinical microarray and other conventional genetic testing have been non-diagnostic (Aref-Eshghi et al, 2019;Turinsky et al, 2020). LaCroix et al (2019) investigated cases of Baratela-Scott syndrome (BSS) (MIM: 615777) and identified hypermethylation of exon 1 of XYLT1 associated with a GGC expansion and gene silencing.…”
Rare genetic disorders, while individually rare, are collectively common. They represent some of the most severe disorders affecting patients worldwide with significant morbidity and mortality. Over the last decade, advances in genomic methods have significantly uplifted diagnostic rates for patients and facilitated novel and targeted therapies. However, many patients with rare genetic disorders still remain undiagnosed as the genetic etiology of only a proportion of Mendelian conditions has been discovered to date. This article explores existing strategies to identify novel Mendelian genes and how these discoveries impact clinical care and therapeutics. We discuss the importance of data sharing, phenotype-driven approaches, patient-led approaches, utilization of large-scale genomic sequencing projects, constraint-based methods, integration of multi-omics data, and gene-to-patient methods. We further consider the health economic advantages of novel gene discovery and speculate on potential future methods for improved clinical outcomes.
“…One method that has been successfully applied to address this issue is to run multiple signatures as a panel and interpret results together. 31,32 When sample sizes are low, potentially resulting in a dearth of CpGs meeting statistical thresholds for significance, exploratory analyses may be performed by relaxing the statistical threshold. This can answer the question of whether true differential methylation patterns likely exist but are being obscured by poor statistical power.…”
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