De novo mutations in regulatory elements in neurodevelopmental disorders

Abstract

We previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders.

Estimating contribution of rare non‐coding variants to neuropsychiatric disorders

“…We observed that synonymous DNM within frontal cortex DHS, but not those within DHS observed in various tissues, are significantly enriched in schizophrenia after multiple testing correction . This result was consistent with the above‐mentioned study in DD . It is of note that a synonymous DNM within frontal cortex DHS was found in SETD1A , a convincing schizophrenia risk gene encoding histone methyltransferase .…”

“…These include PTEN promoter mutations in Cowden syndrome and mutations in lncRNA RMPR in cartilage‐hair hypoplasia . More recently, a large‐scale target sequencing of putative regulatory elements analyzing ~8000 trios with a DD proband (including ~6000 probands without exonic causal mutations) was conducted as a part of the Deciphering Developmental Disorders study . In their study, the following elements were analyzed: most evolutionarily conserved non‐coding elements (CNE), experimentally validated enhancers, and putative heart enhancers.…”

A novel mutation in SPART gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism

“…Next generation sequencing technologies are powerful tools for the identification of rare mutations that cause neurodevelopmental disorders (38)(39)(40)(41)(42)(43)(44). The identification of a causative mutation can support diagnosis, prognosis, and available treatment (45).…”

Functional and in-silico interrogation of rare genomic variants impacting RNA splicing for the diagnosis of genomic disorders

“…15,16 However, the capability to interpret variation within the non-coding genome is particularly challenging. Variant interpretation is hindered by the vast number of rare/novel non-coding variants identified in each individual, 7,9 the depleted levels of evolutionary conservation within non-coding regions, 17 and our current lack of understanding of the motifs and interactions that are required for appropriate control of gene expression and regulation. 12,18 Intragenic genomic variants have the potential to impact splicing, 16 the ubiquitous process in eukaryotic cells of converting nascent pre-mRNA molecules into a mature messenger RNA (mRNA) which can be transported out of the nucleus to provide a template for protein synthesis.…”