Linked-read genome sequencing identifies biallelic pathogenic variants in DONSON as a novel cause of Meier-Gorlin syndrome
Background Patients with Meier-Gorlin syndrome typically present a short stature, small ear, and deficient or absent patella. Genome sequencing can be used to identify new Mendelian genes. This also presents a chance for easy sequencing with informative-phased variants. The sequencing is efficient for recessive disorders when there is no parental DNA. The study aimed to explain the use of linked-read Chromium genome sequencing technology to determine biallelic pathogenic genetic variations. Methods The researchers used the linked-read whole genome sequencing to determine reasons for the Meier-Gorlin syndrome. There were 8 genes linked to the Meier-Gorlin syndrome, which were all programming important parts for DNA replication. The DNA was extracted from the subjects’ whole blood through conventional clinical laboratory procedures. The Chromium genome sequencing was done for the samples. Moreover, amino acid sequences for DONSON from various organisms were aligned through default parameters. The site-guided mutagenesis was employed to have the variants of interest into the fluorescent protein-DONSON molecule. These were confirmed through Sanger sequencing. Key Findings The researchers reported that the effective phasing of the linked-read information of the proponents resulted in the determination of biallelic rare variations in 4 subjects in DONSON. This was a newly recognized DNA replication fork surveillance factor. The genetic variations had 5 new missense and 1 deep intronic variations. These were all recognized as harmful to function. The missense variations interrupted DONSON’s nuclear localization. Whereas the intronic variation had a new splice site where an abnormal transcript with no remaining highly expressed transcript was made. Conclusion The researchers concluded that the genetic findings expand the range of traits linked with DONSON variants. This also raised the new question of the part of DONSON in DNA replication. The determination of the disease gene for Meier-Gorlin syndrome exemplifies the use of linked-read whole genome sequencing. This was an effective equipment to be taken into account in studying the genetics of recessive diseases and conditions.
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