In this month’s Customer Publication blog, I will highlight four studies that provided further insights into conditions that are typically identified in early childhood. As you will see as you read the summaries of each publication, both Golden Helix software platforms (VarSeq and SNP & Variation Suite or SVS for short) were instrumental in exploring the genetic factors that influence each condition. From calling and classifying copy number variations to whole-exome and family-based association studies, Golden Helix has a product stack that will support a vast range of scientific goals. We have been enabling precision medicine and supporting scientific discoveries for over 20 years and as always, we are proud to be a part of this innovative and visionary industry! I hope you will follow the links for each publication and take inspiration from their findings and methods. Please enjoy!
Phenotypic heterogeneity and mosaicism in Xia-Gibbs syndrome: Five Danish patients with novel variants in AHDC1
Xia-Gibbs Syndrome (XGS) is a rare genetic disorder that is characterized by weak muscle tone, mild to severe intellectual disability, delayed development, and a litany of other sometimes severe symptoms. Recently identified in 2014, the condition was originally reported by using parent-offspring trio exome sequencing which showed the caused by heterozygous frameshift or stop-gain de novo variants in the AHDC1 gene. The symptoms of XGS are variable and there are no specific characteristic signs/symptoms of the disease, making it difficult to diagnose without exome sequencing. To better understand the genotype-phenotype relationship of this disorder, an investigative group from Denmark compared the genomic data from a small number of patients using VSClinical for their whole exome sequencing and variant classification. They also collected and compared phenotypic data associated with each subject. During this study, the team noticed that even though two of the patients shared the same causal variant, there were clinical differences between them on several phenotypic measures. This observation supported the findings discovered in larger cohorts of XGS patients where it was not possible to find sufficient correlations between detected genetic variants and phenotypic measures. They also discovered mosaicism of some AHDC1 variants which added to the understanding of the genetic basis of XGS. Given the limited understanding of this disease, the team hopes that larger cohort studies will be conducted to further characterize the phenotypic spectrum and the genotype-phenotype correlations to better understand the disease mechanisms. Through their investigation, they feel their findings strongly support the use of exome sequencing to diagnose this rare disease as well as develop future treatments and management for better patient outcomes.
Dorte Lildballe & Colleagues, Aarhus University Hospital / Published in European Journal of Medical Genetics
Contribution of multiple inherited variants to autism spectrum disorder (ASD) in a family with 3 affected siblings
A team of researchers in Canada utilized the VS-CNV tool to perform a whole genome sequencing (WGS) study on a family that had three siblings who were diagnosed with autism spectrum disorder (ASD). The genetic heritability of autism of up to 90% has been reported in previous studies, indicating a strong genetic influence on ASD. Despite having hundreds of single-nucleotide variants and copy number variants (CNVs) previously reported to be associated with ASD, only 3% of these cases can be associated with the most common anomalies. It was their hope that the use of high throughput WGS would help them to better understand the genetics of the rare variants involved with ASD. With this rare opportunity to study a multiplex family, the team was able to identify multiple inherited missense variants of the genes and pathways that were shared within the family. Their data suggests that each variant has a subtle clinical impact, but together they contribute to the diagnosis of ASD. This study supports the use of WGS as an integral part of the diagnostic process which can aid in the genetic counseling and management decisions and be more beneficial than relying on symptoms alone.
Ying Qiao & Colleagues, University of British Columbia / Published in Genes
Identification of Novel Variants in Cleft Palate-Associated Genes in Brazilian Patients with Non-syndromic Cleft Palate Only
Researchers in Brazil recently investigated the genetic risk factors for non-syndromic oral clefts (NSOCs) to better understand the biological processes related to this complex group of diseases. Orofacial clefts are the most common craniofacial malformation in humans with about 70% of all cases being identified as non-syndromic isolated conditions. NSOCs are categorized in two main forms: cleft lip with or without cleft palate and cleft palate only (NSCPO). Because they occur with less frequency, less is known about the root causes of NSCPOs. Performing a whole exome sequencing study (WES) using a pooled sample approach, the team used VarSeq software for their variant annotations and were able to identify 38 novel SNPs and nine novel rare variants associated with NSCPOs. Their study yielded novel data on characterization of specific variants and novel pathways related to NSCPOs, which included many variants in genes associated with the folate/homocysteine pathway, shedding new light on this complex condition.
Published in Frontiers in Cell and Developmental Biology
ADGRL3, FGF1and DRD4: Linkage and Association with Working Memory and Perceptual Organization Candidate Endophenotypes in ADHD
Attention deficit hyperactive disorder (ADHD) is one of the most common neurodevelopmental disorders identified in childhood. The symptoms of ADHD often linger into adulthood and can have a negative impact on quality of life. A team of researchers in Colombia investigated the endophenotypes and constructs to hopefully provide a useful link between genetic sequences and their external behavioral manifestations. With the help of SVS software to perform the family-based association test to assess linkage and association of SNPs with perceptual organization endophenotypes in their diverse and understudied study population to find a more powerful and objective framework for dissecting the underlying neurobiology of ADHD. Their findings suggest that variants in three genes previously implicated in the etiology of ADHD can be related to perceptual organization. Since people with the disorder present alterations in visual and speech perception, the data supports what may constitute a new explanatory view of ADHD as well as supplementing the available data known about their specific study population. The team hopes that their discoveries can be used for developing predictive models for ADHD diagnosis.
Jorge Velez & Colleagues, Universidad del Norte / Published in Brain Sciences
This is just the tip of the iceberg when it comes to customer publications. If you are interested in reading the other ways customers are using Golden Helix solutions, you can find a full list of their published works here: https://www.goldenhelix.com/resources/published_articles.html. Additionally, if you are interested in seeing how Golden Helix can aid you in your research or clinical work, please reach out to our team to schedule a call!