Below is a list of highlighted peer-reviewed publications from this month. The Golden Helix team consistently enjoys seeing our software applications hard at work in the field, whether it is clinical whole-exome sequencing, targeted CNV identification, or genotype-phenotype correlations. Enjoy reading below how our suite of VarSeq, VSClinical, and VS-CNV continues to contribute to the progression of genetics research.

Clinical whole exome sequencing revealed de novo Heterozygous Stop-Gain and Missense variants in the STXBP1 gene associated with Epilepsy in Saudi Families

Intellectual disability and developmental encephalopathies are mostly linked with infant epilepsy. Epileptic encephalopathy is a term that is used to define association between developmental delay and epilepsy. Mutations in the STXBP1 (Syntaxin-binding protein 1) gene have been previously reported in association with multiple severe early epileptic encephalopathies along with many neurodevelopmental disorders. Among the disorders produced due to any mutations in the STXBP1 gene is developmental and epileptic encephalopathy 4 (OMIM: 612164), is an autosomal dominant neurologic disorder categorized by the onset of tonic seizures in early infancy (usually in the first months of life). In this article, we report two Saudi families one with de novo heterozygous stop-gain mutation c.364C > T and a novel missense c. 305C > A p.Ala102Glu in exon 5 of the STXBP1 gene (OMIM: 602926) lead to development of epileptic encephalopathy 4. The variants identified in the current study broadened the genetic spectrum of STXBP1 gene related with diseases, which will help to add in the literature and benefit to the studies addressing this disease in the future.

Muhammad Imran Naseer, Angham Abdulrhman Abdulkareem, Mahmood Rasool, Bader Shirah, Hussein Algahtani, Osama Y. Muthaffar, Peter Natesan Pushparaj, Clinical whole exome sequencing revealed de novo Heterozygous Stop-Gain and Missense variants in the STXBP1 gene associated with Epilepsy in Saudi Families, Saudi Journal of Biological Sciences, 2022, 103309, ISSN 1319-562X, https://doi.org/10.1016/j.sjbs.2022.103309

Targeted copy number variant identification across the neurodegenerative disease spectrum

Background: Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied.
Methods: Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519).
Results: In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer’s disease participant; (2) a duplication of exons 1–5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7–11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies.
Conclusion: The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration.

Dilliott, A. A., Zhang, K. K., Wang, J., Abrahao, A., Binns, M. A., Black, S. E., Borrie, M., Dowlatshahi, D., Finger, E., Fischer, C. E., Frank, A., Freedman, M., Grimes, D., Hassan, A., Jog, M., Kumar, S., Lang, A. E., Mandzia, J., Masellis, M. … Hegele, R. A. (2022). Targeted copy number variant identification across the neurodegenerative disease spectrum. Molecular Genetics & Genomic Medicine, 00, e1986. https://doi.org/10.1002/mgg3.1986

Genotype-Phenotype Correlations in Neurofibromatosis Type 1: Identification of Novel and Recurrent NF1 Gene Variants and Correlations with Neurocognitive Phenotype

Neurofibromatosis type 1 (NF1) is one of the most common genetic tumor predisposition syndrome, caused by mutations in the NF1. To date, few genotype-phenotype correlations have been discerned in NF1, due to a highly variable clinical presentation. We aimed to study the molecular spectrum of NF1 and genotype-phenotype correlations in a monocentric study cohort of 85 NF1 patients (20 relatives, 65 sporadic cases). Clinical data were collected at the time of the mutation analysis and reviewed for accuracy in this investigation. An internal phenotypic categorization was applied. The 94% of the patients enrolled showed a severe phenotype with at least one systemic complication and a wide range of associated malignancies. Spine deformities were the most common complications in this cohort. We also reported 66 different NF1 mutations, of which 7 are novel mutations. Correlation analysis identified a slight significant inverse correlation between age at diagnosis and delayed acquisition of psychomotor skills with residual multi-domain cognitive impairment. Odds ratio with 95% confidence interval showed a higher prevalence of learning disabilities in patients carrying frameshift mutations. Overall, our results aim to offer an interesting contribution to studies on the genotype–phenotype of NF1 and in genetic management and counselling.

Napolitano, F.; Dell’Aquila, M.; Terracciano, C.; Franzese, G.; Gentile, M.T.; Piluso, G.; Santoro, C.; Colavito, D.; Patanè, A.; De Blasiis, P.; et al. Genotype-Phenotype Correlations in Neurofibromatosis Type 1: Identification of Novel and Recurrent NF1 Gene Variants and Correlations with Neurocognitive Phenotype. Genes 2022, 13, 1130. https://doi.org/10.3390/genes13071130

All of us here at Golden Helix thoroughly enjoy learning about the various applications our software is being utilized within. If you have any questions about how Golden Helix software, please do not hesitate to reach out to sales@goldenhelix.com with questions. We would be happy to find out how we can assist you in either your NGS lab, clinical sequencing, or other application!