September 6, 2021

Levodopa-responsive dystonia caused by biallelic PRKN exon inversion invisible to exome sequencing

Hagar Mor-Shaked, Emuna Paz-Ebstein, Adily Basal, Simona Ben-Haim, Hanna Grobe, Sami Heymann, Zvi Israel, Montaser Namnah, Anat Nitzan, Chaggai Rosenbluh, Ann Saada, Tomer Tzur, Shira Yanovsky-Dagan, Ronen Zaidel-Bar, Tamar Harel, and David Arkadir

Biallelic pathogenic variants in the PRKN (PARK2, [MIM 600116]) gene, coding the E3 ubiquitin ligase parkin, are frequently identified in juvenile or young-onset Parkinson’s disease (PD). Exome sequencing (ES) in conjunction with either read-depth CNV analysis or multiplex ligation-dependent probes are common approaches used to diagnose PD. However, these approaches are not always sufficient to identify candidate variants. 

Mor-Shaked, et al. (2021, PMID: 34514401) used genome sequencing (GS) to study a PD family with negative ES and CNV results. Geneyx Analysis was able to accurately identify a homozygous copy-neutral inversion of exon 5  in the PRKN gene together with a common 49 kb deletion which was detected in a heterozygous state in the normal sibling. 

In this example, Geneyx Analysis led to the discovery that variants in the PRKN gene account for a greater number of young-onset PD patients than formerly considered. Because it was a copy-neutral inversion event, it was missed by both exome and CNV analysis. But through implementing whole genome sequencing and Geneyx Analysis, this event was accurately detected. The authors thus suggested carrying out GS in any young-onset PD case with negative ES or CNV results. Particularly when the PRKN gene is located in a homozygous block. 

Bi-allelic PAGR1 variants are associated with microcephaly and a severe neurodevelopmental disorder: Genetic evidence from two families 

Daum, et al. (2022, PMID: 34585832) applied exome sequencing and genome sequencing to study 3 patients from 2 families with microcephaly and severe neurodevelopment disorder, as well as their unaffected family members. Microcephaly, polyhydramnios, and clenched hands were some of the prenatal clinical features observed in affected individuals, and microcephaly, severe developmental delays, dysmorphism, neurological deficits, and infant death were some of the postnatal features. 

Geneyx Analysis, a comprehensive NGS analysis, and interpretation platform allowed the authors to pinpoint a single variant in the PAGR1 gene. The results showed the presence of the homozygous PAGR1 c.274A>G (p.Ser92Gly) variant in all affected individuals. Two siblings also carried the homozygous SLC12A3 missense variant (deprioritized due to the lack of overlap between patients’ phenotype and clinical features associated with this gene) and the hemizygous PRPS2 variant (eliminated from further research due to its presence in the normal brother). 

The PAGR1 functions remain evasive with various suggested biological ways of action but the protein encoded by this gene was suggested in having a function in epigenetic gene regulation. PAGR1 also functions as a transcriptional co-regulator of the estrogen and glucocorticoid receptors and, although the biological roles of this protein are elusive, research in animal models indicates this gene has a key function in early development. Based on the helpful insights provided by Geneyx Analysis, this gene has been considered as a strong candidate for autosomal recessive severe syndromic neurodevelopment disorder by the authors. 

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