2022 has started off with a significant number of customers publishing their research. We saw several customers utilizing various softwares within our suite, but the most prominent being VarSeq. VarSeq is an intuitive, integrated software solution for tertiary analysis. With VarSeq you can automate your workflows and perform variant analysis for gene panels, exomes, and whole genomes. Understanding genomic data is the purpose of this software and I am going to highlight a few specific publications that utilize VarSeq to its full extent.
Singleton exome sequencing of 90 fetuses with ultrasound anomalies revealing novel disease-causing variants and genotype–phenotype correlations
Exome sequencing has been increasingly implemented in prenatal genetic testing for fetuses with morphological abnormalities but normal rapid aneuploidy detection and microarray analysis. We present a retrospective study of 90 fetuses with different abnormal ultrasound findings, in which we employed the singleton exome sequencing (sES; 75 fetuses) or to a lesser extent (15 fetuses) a multigene panel analysis of 6713 genes as a primary tool for the detection of monogenic diseases. The detection rate of pathogenic or likely pathogenic variants in this study was 34.4%. The highest diagnostic rate of 56% was in fetuses with multiple anomalies, followed by cases with skeletal or renal abnormalities (diagnostic rate of 50%, respectively). We report 20 novel disease-causing variants in different known disease-associated genes and new genotype–phenotype associations for the genes KMT2D, MN1, CDK10, and EXOC3L2. Based on our data, we postulate that sES of fetal index cases with a concurrent sampling of parental probes for targeted testing of the origin of detected fetal variants could be a suitable tool to obtain reliable and rapid prenatal results, particularly in situations where a trio analysis is not possible.
Smogavec, M., Gerykova Bujalkova, M., Lehner, R. et al. Singleton exome sequencing of 90 fetuses with ultrasound anomalies revealing novel disease-causing variants and genotype–phenotype correlations. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-021-01012-7
A novel nonsense variant in MED12 associated with malformations in a female fetus
Pathogenic variants in the MED12 gene located on the X-chromosome have primarily been reported in males with Lujan-Fryns syndrome, Ohdo syndrome and the Opits-Kaveggia syndrome. However, earlier reports of female patients and female mice suggest that MED12 deficiency causes severe malformations. We report a novel example of a MED12 de novo nonsense variant in a female fetus with severe malformations identified by trio-exome sequencing. This finding further expands the clinical spectrum of MED12-related disorders, which is vital for prenatal diagnosis and genetic counselling of couples.
Faergeman SL, Becher N, Andreasen L, Christiansen M, Frost L, Vogel I. A novel nonsense variant in MED12 associated with malformations in a female fetus. Clin Case Rep. 2021;9:e05124. doi:10.1002/ccr3.5124
Mutations affecting the N-terminal domains of SHANK3 point to different pathomechanisms in neurodevelopmental disorders
Shank proteins are major scaffolds of the postsynaptic density of excitatory synapses. Mutations in SHANK genes are associated with autism and intellectual disability. The effects of missense mutations on Shank3 function, and therefore the pathomechanisms are unclear. Several missense mutations in SHANK3 affect the N-terminal region, consisting of the Shank/ProSAP N-terminal (SPN) domain and a set of Ankyrin (Ank) repeats. Here we identify a novel SHANK3 missense mutation (p.L270M) in the Ankyrin repeats in patients with an ADHD-like phenotype. We functionally analysed this and a series of other mutations, using biochemical and biophysical techniques. We observe two major effects: (1) a loss of binding to δ-catenin (e.g. in the p.L270M variant), and (2) interference with the intramolecular interaction between N-terminal SPN domain and the Ank repeats. This also interferes with binding to the α-subunit of the calcium-/calmodulin dependent kinase II (αCaMKII), and appears to be associated with a more severe neurodevelopmental pathology.
Woike, D., Wang, E., Tibbe, D. et al. Mutations affecting the N-terminal domains of SHANK3 point to different pathomechanisms in neurodevelopmental disorders. Sci Rep 12, 902 (2022). https://doi.org/10.1038/s41598-021-04723-5
We at Golden Helix enjoy seeing all the ways our software suite is utilized. We encourage all of our users to submit their research, whatever application, to our Innovation Awards. Show us how you use our products and you might receive the opportunity to highlight your research via a webcast and blog post!