In the ever-evolving field of genetics, the quest to understand the intricate dance between genetic predispositions and disease manifestations continues to gain momentum. The three research papers presented here offer a glimpse into this complex interplay, each exploring the genetic underpinnings of distinct medical conditions across species. From the debilitating effects of acute retinal necrosis in humans to the life-threatening realms of pulmonary arterial hypertension, and the peculiar case of radial hemimelia in Siamese cats, these studies underscore the power of genetic analysis in unraveling the mysteries of disease. By leveraging Whole Exome Sequencing and Whole Genome Sequencing, researchers are able to pinpoint rare genetic variants that may hold the key to diagnosis, treatment, and prevention of these conditions. These papers not only contribute valuable insights into the genetic factors that may predispose individuals and animals to certain diseases but also highlight the role of VarSeq in facilitating this cutting-edge research.
Whole exome sequencing of patients with varicella-zoster virus and herpes simplex virus induced acute retinal necrosis reveals rare disease-associated genetic variants
Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are neurotropic human alphaherpesviruses endemic worldwide. Upon primary infection, both viruses establish lifelong latency in neurons and reactivate intermittently to cause a variety of mild to severe diseases. Acute retinal necrosis (ARN) is a rare, sight-threatening eye disease induced by ocular VZV or HSV infection. The virus and host factors involved in ARN pathogenesis remain incompletely described. We hypothesize an underlying genetic defect in at least part of ARN cases.
We collected blood from 17 patients with HSV-or VZV-induced ARN, isolated DNA and performed Whole Exome Sequencing by Illumina followed by analysis in Varseq with criteria of CADD score > 15 and frequency in GnomAD < 0.1% combined with biological filters. Gene modifications relative to healthy control genomes were filtered according to high quality and read-depth, low frequency, high deleteriousness predictions and biological relevance.
We identified a total of 50 potentially disease-causing genetic variants, including missense, frameshift and splice site variants and on in-frame deletion in 16 of the 17 patients. The vast majority of these genes are involved in innate immunity, followed by adaptive immunity, autophagy, and apoptosis; in several instances variants within a given gene or pathway was identified in several patients.
We propose that the identified variants may contribute to insufficient viral control and increased necrosis ocular disease presentation in the patients and serve as a knowledge base and starting point for the development of improved diagnostic, prophylactic, and therapeutic applications.
Seven Additional Patients with SOX17 Related Pulmonary Arterial Hypertension and Review of the Literature
Pulmonary arterial hypertension (PAH) is an infrequent disorder characterized by high blood pressure in the pulmonary arteries. It may lead to premature death or the requirement for lung and/or heart transplantation. Genetics plays an important and increasing role in the diagnosis of PAH. Here, we report seven additional patients with variants in SOX17 and a review of sixty previously described patients in the literature. Patients described in this study suffered with additional conditions including large septal defects, as described by other groups. Collectively, sixty-seven PAH patients have been reported so far with variants in SOX17, including missense and loss-of-function (LoF) variants. The majority of the loss-of-function variants found in SOX17 were detected in the last exon of the gene. Meanwhile, most missense variants were located within exon one, suggesting a probable tolerated change at the amino terminal part of the protein. In addition, we reported two idiopathic PAH patients presenting with the same variant previously detected in five patients by other studies, suggesting a possible hot spot. Research conducted on PAH associated with congenital heart disease (CHD) indicated that variants in SOX17 might be particularly prevalent in this subgroup, as two out of our seven additional patients presented with CHD. Further research is still necessary to clarify the precise association between the biological pathway of SOX17 and the development of PAH.
Cardiomyopathy associated 5 (CMYA5) implicated as a genetic risk factor for radial hemimelia in Siamese cats
The present study aimed to determine the inheritance pattern and genetic cause of congenital radial hemimelia (RH) in cats.
Clinical and genetic analyses were conducted on a Siamese cat family (n = 18), including two siblings with RH. Radiographs were obtained for the affected kittens and echocardiograms of an affected kitten and sire. Whole genome sequencing was completed on the two cases and the parents. Genomic data were compared with the 99 Lives Cat Genome data set of 420 additional domestic cats with whole genome and whole exome sequencing data. Variants were considered as homozygous in the two cases of the siblings with RH and heterozygous in the parents. Candidate variants were genotyped by Sanger sequencing in the extended pedigree.
Radiographs of the female kitten revealed bilateral absence of the radii and bowing of the humeri, while the male kitten showed a dysplastic right radius. Echocardiography suggested the female kitten had restrictive cardiomyopathy with a positive left atrial-to-aortic root ratio (LA:Ao = 1.83 cm), whereas hypertrophic cardiomyopathy was more likely in the sire, showing diastolic dysfunction using tissue Doppler imaging (59.06 cm/s). Twenty-two DNA variants were unique and homozygous in the affected kittens and heterozygous in the parents. Seven variants clustered in one chromosomal region, including two frameshift variants in cardiomyopathy associated 5 (CMYA5) and five variants in junction mediating and regulatory protein, P53 cofactor (JMY ), including a missense and an in-frame deletion.
The present study suggested an autosomal recessive mode of inheritance with variable expression for RH in the Siamese cat family. Candidate variants for the phenotype were identified, implicating their roles in bone development. These genes should be considered as potentially causal for other cats with RH. Siamese cat breeders should consider genetically testing their cats for these variants to prevent further dissemination of the suspected variants within the breed.
The convergence of genetics and disease as explored in these studies illuminates the critical role of genetic research in advancing our understanding of complex medical conditions. The identification of rare genetic variants associated with acute retinal necrosis, pulmonary arterial hypertension, and radial hemimelia in Siamese cats represents a significant step forward in the field of medical genetics. These findings, facilitated by the analytical prowess of VarSeq, not only pave the way for more personalized approaches to medicine but also offer hope for those affected by these conditions. As we continue to unravel the genetic threads that contribute to disease, the promise of targeted therapies and improved outcomes becomes increasingly tangible. The research encapsulated in these papers is a testament to the relentless pursuit of knowledge and the collaborative spirit of the scientific community, driving us closer to a future where genetic insights lead to healthier lives across both human and animal populations.