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Role of de novo variants in genetic disorders with new insights and clinical implications  

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction:
Apart from the genetic information passed on from generation to generation, every individual is born with spontaneously arising novel variants commonly referred as de novo variants. These variants occur either during gamete formation or postzygotically and have an important role in genetic disorders. The de novo variant rate in humans is estimated to be around 2x10−8 per nucleotide per generation and while the majority are assumed benign, those affecting functional elements of the genome can result in severe phenotypic consequences. Trio based exome and genome sequencing has been instrumental in detecting de novo variants in individuals with different genetic disorders. Multiple studies have been conducted to understand the role of de novo variants in neurodevelopmental disorders and epileptic encephalopathy-related disorders, however limited information is available about many other monogenic autosomal dominant and X-linked disorders. 

 

Methods:
Trio-based genome and exome sequencing was performed in 1956 cases with clinical suspicion of various genetic disorders. Sequencing was performed on genomic DNA isolated from various sample types using 2x150 bp reads on an Illumina next-generation sequencing (NGS) platform at a mean coverage of 40X for genomes and 80X for exomes. Sequence variants were assessed by our proprietary analysis and interpretation pipeline, Ordered Data Interpretation Network (ODIN). Copy number variants (CNV) analysis was assessed using Biodiscovery’s NxClinical software (BioDiscovery, El Segundo, CA).  

 

Results:
Pathogenic and likely pathogenic de novo variants were identified in 171 cases (8.7%) out of 1956 total exome and genome cases and ultimately provided a definitive molecular diagnosis of various monogenic disorders including autism and intellectual disability, epilepsy, RASopathies, skeletal disorders, muscular dystrophies, and other rare genetic disorders, indicating a significant role of de novo variants. Out of 171 definitive de novo molecular diagnostic cases, exome sequencing was performed in 89 (52.0%) cases and genome sequencing was performed in 82 (48.0%) cases. The majority of patients, (104; 60.8%), with de novo variants were detected in autosomal dominant genes (85), including CACNA1A, CHD7, PTPN11, SCN2A, CREBBP, DYNC1H1, KAT6A, KAT6B, KMT2D, MAGEL2, PHOX2B, PUF60, PURA, RIT1, SETD1B, SHANK3, and ZNF292. De novo variants in X-linked genes were identified in 17 (9.9%) patients with contributing X-linked genes (14) including MECP2, ZC4H2, AR, BCOR, BTK, DDX3X, DMD, GPC3, KDM6A, NAA10, PDHA1, RPS6KA3, UPF3B and WDR45. Rare de novo variants of uncertain clinical significance were identified in 164 (8.3%) out of 1956 cases, indicating further genotype-phenotype correlation studies are required in these patients.

Conclusion:
In conclusion, this comprehensive trio-based NGS study greatly helped in understanding the role of de novo variants in both pediatric (85.4%) and adult (14.6%) patients with different genetic disorders including autism and intellectual disability, epilepsy, skeletal disorders, muscular dystrophies, Rett syndrome, Coffin-Siris syndrome, Noonan syndrome, CHARGE syndrome, osteogenesis imperfecta, Rubinstein-Taybi syndrome, Marfan syndrome, Apert syndrome, achondroplasia, Kabuki syndrome, Cornelia de Lange syndrome, Ehlers-Danlos syndrome, various immunodeficiencies, and other rare genetic disorders. De novo copy number variants also played an important role in providing a definitive molecular diagnosis in 27 (15.8%) patients with deletions and duplications in different chromosomes.

Agenda

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