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.

Keywords: Big data; FinnGen; Finnish disease heritage; Monogenic disorders; Population isolate; Rare disease.

Fig. 1.

Updated ‘Perheentupa Steps’. This widely used traditional representation of the Finnish disease heritage (FDH) diseases organizes them chronologically based on the year in which the disease description was published. The respective Online Mendelian Inheritance in Man (OMIM) codes are in parentheses. FDH diseases are in black and candidate diseases in blue. CNF, Finnish congenital nephrosis (Ahvenainen et al., 1956); CNA2, cornea plana 2 (Forsius, 1957); IGS1, Imerslund-Grasbeck syndrome 1 (Gräsbeck et al., 1960); EPM1, epilepsy, progressive myoclonic, 1 (Harenko and Toivakka, 1961); RS1, retinoschisis 1 (Forsius et al., 1962); APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy – type 1 with or without reversible metaphyseal dysplasia (Visakorpi and Gerber, 1963); LPI, lysinuric protein intolerance (Perheentupa and Visakorpi 1965); DIAR1, diarrhea, secretory chloride, congenital (Perheentupa et al., 1965); GCE, glycine encephalopathy (Visakorpi et al., 1965); CLD, lactase deficiency, congenital (Launiala et al., 1966); AGU, aspartylglucosaminuria (Palo, 1967); USH3, Usher syndrome type 3 (Nuutila, 1968); FAF, amyloidosis, Finnish type (Meretoja, 1969); MUL, Mulibrey nanism (Perheentupa et al., 1970); PLOSL1, polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 (Hakola, 1972); CHH, cartilage-hair hypoplasia (Perheentupa, 1972); DTD, diastrophic dysplasia (Perheentupa, 1972); CLN3, ceroid lipofuscinnosis, neuronal, 3 (Santavuori, 1972); CLN1, ceroid lipofuscinosis, neuronal 1 (Santavuori et al., 1973); HOGA, hyperornithinemia with gyrate atrophy of choroid and retina (Simell and Takki, 1973); CHM, choroideremia (Takki, 1974); MKS1, Meckel syndrome type 1 (Aula et al., 1977); MDDAG3, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 3 (Santavuori, et al., 1977); Salla disease (Aula et al., 1979); HLS1, hydrolethalus syndrome 1 (Salonen et al., 1981); CLN5, ceroid lipofuscinnosis, neuronal, 5 (Santavuori et al., 1982); COH1, Cohen syndrome (Norio et al., 1984); IOSCA, infantile-onset spinocerebellar ataxia (Kallio and Jauhianen, 1985); LCCS1, lethal congenital contracture syndrome 1 (Herva et al., 1985); RAPADILINO syndrome (Kaariainen et al., 1989); TMD, tibial muscular dystrophy (Udd et al., 1991); PEHO, progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (Salonen et al., 1991); EPMR, epilepsy, progressive, with mental retardation (Hirvasniemi et al., 1994); ODG1, ovarian dysgenesis 1 (Aittomäki, 1994); LAAHD, lethal arthrogryposis with anterior horn cell disease (Vuopala et al., 1995); LCHAD, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Tyni et al., 1996); GRACILE syndrome (Fellman et al., 1998); MIRAS, mitochondrial recessive ataxia syndrome (Rantamäki et al., 2001); TK2 deficiency (Götz et al., 2008); SMAJ, spinal muscular atrophy, Jokela type (Jokela et al., 2011); HIGM2, hyper-IgM syndrome type 2 (Trotta et al., 2016); PCKDC, phosphoenolpyruvate carboxykinase deficiency, cytosolic (Vieira et al., 2017); CRADD, frontotemporal pachygyria (Polla et al., 2019). Original illustration of the steps was first used by Prof. Jaakko Perheentupa and colleagues (Norio et al., 1973).

Fig. 2.

The traditional FDH diseases with their core manifestations and estimated frequencies of major Finnish variants. Aspartylglucosaminuria (AGU) is caused by a mutation in AGA and affects the central nervous system, skeleton, connective tissue and skeletal muscle. GRACILE syndrome (GRACILE) is caused by a mutation in BCS1L that affects the liver, kidneys and pancreas, and causes early-onset growth retardation. Infantile-onset spinocerebellar ataxia (IOSCA), which is caused by a mutation in TWNK, affects the central and peripheral nervous systems, eyes and hearing. Lysinuric protein intolerance (LPI), caused by a SLC7A7 mutation, results in growth retardation and also affects the kidneys, blood, liver, spleen, skeleton, intestine and lungs. Spinal muscular atrophy, Jokela type (SMAJ) is caused by a mutation in CHCHD10 and affects the lower motor neurons, whereas frontotemporal pachygyria (CRADD) is caused by a CRADD mutation and affects the brain. The metabolic disruption caused by phosphoenolpyruvate carboxykinase (PCK1) deficiency, cytosolic (PCKDC) affects the liver and causes hypoglycemic seizures. The graphs show estimated carriers per 10,000 Finns and other Europeans. Minor allele frequencies (MAFs) are based on gnomAD v2.1.1 (https://gnomad.broadinstitute.org/), accessed on 23 July 2022.

Fig. 3.

Estimated carriers per 10,000 Finns and other Europeans of Finland-enriched pathogenic variants causing the ‘candidate’ FDH diseases long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD), mitochondrial recessive ataxia syndrome (MIRAS) and myopathic type mtDNA depletion syndrome (TK2 deficiency). LCHAD is caused by a HADHA mutation that affects the peripheral nervous system, muscle, liver, heart and eyes; MIRAS is caused by POLG mutations that manifest as central and peripheral nervous system defects; and the two mutations causing TK2 deficiency affect the muscular system. Although the causative variants are enriched in the Finnish population, these diseases are not phenotypically restricted to Finland and are therefore not considered part of the traditional FDH. MAFs are based on gnomAD v2.1.1 (https://gnomad.broadinstitute.org/), accessed on 23 July 2022.