Biology subjects

Temple, I. K.

Publications and source records attributed to Temple, I. K..

3 recordsLinked to original sources

bioRxiv2018

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3A (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G>A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated to genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. Notably, these findings were most striking in a carrier of the AML associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders; NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamentally new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance and determinants of biological aging in these growth disorders.

genetics↗

bioRxiv2018

Diagnostic outcomes of exome gene panel sequencing in patients with unusual syndromic cleft lip/palate phenotypes

Orofacial clefting (OFC) is a common craniofacial birth defect that has a prevalence of 1.2 in 1,000 live births. Syndromic OFC in which patients present with additional developmental deficits are identified to have a strong genetic component. We applied exome gene panel sequencing in a cohort of 14 Colombian patients identified at Operation Smile in Bogota, Colombia, with syndromic orofacial clefting phenotypes and additional features initially suggesting Aarskog-Scott syndrome (AAS). Gene panel sequencing failed to identify any causal variants in the FGD1 gene which underlies this condition, but variants in a number of genes suggest alternative clinical diagnoses across five patients (~ 36%). The novel variants identified here maps to developmentally important genes including SRCAP, OFD1, NIPBL, GRIN2A and KMT2D6. Our result demonstrates the extensive heterogeneity underlying OFC and emphasises the need for systematic phenotyping of patients with rare conditions. Gene panel sequencing has the potential to cost-effectively resolve ambiguous clinical diagnoses, but rigorous attention should be paid to gene coverage as our results suggest highly variable read depths across individual gene exons and this may reduce the quality of variant calls at specific locations.

genomics↗

bioRxiv2018

The contribution of non-canonical splicing mutations to severe dominant developmental disorders

Mutations which perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7,833 probands with developmental disorders (DD) and their unaffected parents, as well as >60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice site, and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. Using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking non-canonical positions (27%), and calculated the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at non-canonical positions in splice sites. We estimate 35-40% of pathogenic variants in non-canonical splice site positions are missing from public databases.

genetics↗