Next up is Victor Faundes, who will talk about Impaired eIF5A function causes a craniofacial-neurodevelopmental syndrome that is partially rescued in model systems by spermidine #ASHG20
EIF5A was identified as a candidate developmental disorder gene through WES. Used the DDD resource to identify a further 6 individuals with EIF5A variants, defined a novel syndrome of developmental delay and other features #ASHG20
EIF5A resolves ribosomal stalling caused by polyproline tracts. Aimed to understand how this is disrupted by the variants seen in patients. Haploinsufficiency is the most likely mechanism #ASHG20
Explored the action of these variants in yeast - for two variants, impair growth. Frameshift variant results in a complete loss of viability. One other variant had no apparent phenotype #ASHG20
Variants reduce the interaction between EIF5A and the ribosome (80S), and results in increased free 60S. The reduced interaction can in part by explained by reduced total / hypusinated EIF5A #ASHG20
EIF5A variants reduce the synthesis of proteins with poly-proline tracts. Does this explain the clinical phenotype? Potentially - microcephaly genes are enriched for polyproline tracts #ASHG20
Can this phenotype be rescued with a drug? Spermidine is the substrate for hypusine, and can partially replace EIF5A. Partly improves growth and molecular defects in yeast. Zebrafish with KO eif5a have micrognathia, spermidine partially rescues this #ASHG20

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30 Oct
Finally, Margot Cousin presents on "Impairment of the mitochondrial one-carbon metabolism enzyme SHMT2 causes a novel brain and heart developmental syndrome" #ASHG20
SHMT2 - encodes mitochondrial serine hydroxymethyltransferase 2. Key roles in amino acid metabolism and folic acid pathways, as well as mitochondrial respiration and protein translocation #ASHG20
Identified 4 individuals with biallelic SHMT2 variants. One individual has a variant disrupting a splice site. Other variants are missense on highly conserved residues, and are absent/extremely rare in gnoMAD. Variable dysmorphic features. Others incl. developmental delay #ASHG20
Read 8 tweets
30 Oct
Next up is Helen Miranda discussing "Increased p4EBP1 underlies ALS pathology associated to P56S mutant VAPB" #ASHG20
ALS is the most common adult-onset neurodegenerative disorder. 50% of patients do not survive beyond third year of diagnosis. Pathophysiology across upper and lower motor neurones. 90% of cases are sporadic in presentation. #ASHG20
Mutations in >25 genes have been associated in ALS. Focus on VAPB. Highly conserved gene that is ubiquitously expression. P56S mutation is the causative gene for ALS type 8 - mostly identified in Brazilian population, but has been identified globally. #ASHG20
Read 8 tweets
30 Oct
Slightly late into the fourth plenary: David Blair discussing "Common genetic variants associated with Mendelian disease severity revealed through cryptic phenotype analysis" #ASHG20
Cryptic phenotypes are phenotypes that underlie mendelian diseases, but which are not observed. For some, this will be a liability-threshold model (mendelian as extreme of normal range), but for others it will be a phenotypic outlier model (mendelian as truly separate) #ASHG20
Need models that differentiate between the models. May be morbidity-dependent genetic modifiers - e.g. may not see effects looking at the average of the population, but may see it at the extreme percentiles of severity #ASHG20
Read 7 tweets
30 Oct
Elise Flynn will end the session, talking about "Transcription factor regulation of genetic variant effects across tissues and individuals" #ASHG20
Genetic variants associated with gene expression = eQTL #ASHG20
eQTLs can be context specific, whether in terms of effect size or the presence/absence of an effect. Know that eQTLs are enriched in TF binding sites. Suggests that modifications to TF binding are a major mechanism by which genetic variation regulates gene expression #ASHG20
Read 9 tweets
30 Oct
Next is Xiaolei Zhang, discussing "Annotating high-impact 5'UTR variants with the UTRannotator"
The translation of upstream open reading frames can reduce the expression of genes considerably. Can have overlapping uORF, out of frame or in frame depending on where the stop coding of the uORF lies #ASHG20
uORF perturbing variants can be disease-causing. they are under strong negative selection and appear to cause disease through LoF of genes. #ASHG20
Read 7 tweets
30 Oct
Next is Bonnie Huang discussing "Inference of fitness effects of short tandem repeat polymorphisms improves functional categorisation" #ASHG20
STRS are DNA sequences with repeated 1-6 base pair motifs. About 1.6M in human genome. Repeat number differs between individuals #ASHG20
Discussing the logic underlying the SISTR method. Challenging to determine the pathogenicity of STR mutations. STRs harder to interpret than (coding) SNVs - adding extra amino acids has less clear an effect than removing or altering them #ASHG20
Read 11 tweets

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