The Finnish genetic heritage in 2022 – from diagnosis to translational research

Abstract

Isolated populations have been valuable for the discovery of rare monogenic diseases and their causative genetic variants. Finnish disease heritage (FDH) is an example of a group of hereditary monogenic disorders caused by single major, usually autosomal-recessive, variants enriched in the population due to several past genetic drift events. Interestingly, distinct subpopulations have remained in Finland and have maintained their unique genetic repertoire. Thus, FDH diseases have persisted, facilitating vigorous research on the underlying molecular mechanisms and development of treatment options. This Review summarizes the current status of FDH, including the most recently discovered FDH disorders, and introduces a set of other recently identified diseases that share common features with the traditional FDH diseases. The Review also discusses a new era for population-based studies, which combine various forms of big data to identify novel genotype–phenotype associations behind more complex conditions, as exemplified here by the FinnGen project. In addition to the pathogenic variants with an unequivocal causative role in the disease phenotype, several risk alleles that correlate with certain phenotypic features have been identified among the Finns, further emphasizing the broad value of studying genetically isolated populations.

The Clinical Picture of the ERCC6L2 Disease - from Bone Marrow Failure to Acute Leukemia

“…8,10 Moreover, a twenty-times-higher minor allele frequency of the variant in the Finnish population compared to the rest of the Europeans 16 suggests an accumulation of ERCC6L2 disease due to genetic drift as recognized in Finnish disease heritage (FDH). 17 Nevertheless, ERCC6L2 disease is not limited to Finland.…”

Validation of Aspartylglucosaminidase Activity Assay for Human Serum Samples: Establishment of a Biomarker for Diagnostics and Clinical Studies

“…2 of 11 ings of a genetic analysis or urine glycoasparagine measurement should always be verified by a second method, especially if a novel, potentially pathogenic variant of the AGA gene is identified [10]. Furthermore, glycoasparagines can also be present in the urine of patients with NGLY1 deficiency, which is a related neurodevelopmental disorder [11,16,17,18].…”

Validation of Aspartylglucosaminidase Activity Assay for Human Serum Samples: Establishment of a Biomarker for Diagnostics and Clinical Studies

“…In Finland, AGU is usually diagnosed after analysis of urine oligosaccharides, especially N-acetylglucosamine-asparagine (GlcNAc-Asn), and the diagnosis is verified by means of gene sequencing [ 10 , 11 ]. The patients outside of Finland, who often exhibit their own, family-specific pathogenic variants, are identified either by gene/exome sequencing, or urine analysis.…”

“…Measurement of AGA activity in white blood cells has also been used for diagnostic means or for the verification of previous findings [ 12 , 13 , 14 , 15 ], but this method is rarely available in routine diagnostic laboratories. Nevertheless, findings of a genetic analysis or urine glycoasparagine measurement should always be verified by a second method, especially if a novel, potentially pathogenic variant of the AGA gene is identified [ 10 ]. Furthermore, glycoasparagines can also be present in the urine of patients with NGLY1 deficiency, which is a related neurodevelopmental disorder [ 11 , 16 , 17 , 18 ].…”