Modern methods in diagnostics and research of molecular bases of rare diseases
Authors:
Stanislav Kmoch 1,2; Jiří Zeman 1
Authors place of work:
Klinika dětského a dorostového lékařství 1. LF UK a VFN v Praze
1; Laboratoř pro studium vzácných nemocí, Národní centrum lékařské genomiky, 1. LF UK
2
Published in the journal:
Čas. Lék. čes. 2018; 157: 133-136
Category:
Summary
Rare diseases represent a heterogeneous group of approximately 8000 various disorders and affect nearly 8 % of the population. The local and international studies of human genomes help to increase the knowledge about genetic variability of the man and due to effective sharing of clinical and molecular data in the registries enable casual diagnostics of the broad spectrum of rare and complex diseases in 55–65 % of the cases. With the diagnostics in the remaining group of patients, new methods and technologies studying human genome are of importance including genetic and functional analyses of genomic variants and their combinations with the aims to recognize and interpret the significances of the somatic mosaics, genetic heterogeneity of individual disorders, the presence of eventual phenocopy, different penetrance and expressivity of individual mutation and diseases with the oligogenic inheritance. Recently, the increasing significance of analyses of noncoding regions in human DNA were recognized including the impact of repetitive and homologs regions on transcription and structure of mRNA. For the diagnostics of genetic causality in patients is necessary to focus on analyses of biologic fluids, tissues, cultivated cells and animal models prepared by methods of cell reprogramming or directed mutagenesis.
In this paper, the overview of methods and their importance and limitation is described including whole exome sequencing (WES), whole genome sequencing, functional and homolog cloning, functional complementation, mapping of genes with the help of binding analyses and matching of the results from individual genome with genetic variability in the adequate population. In our institutions, we performed WES in > 520 patients with successful diagnostics above 50 %. In addition, in our group of 225 patients with rare diseases we compared the result of WES with the results of direct sequencing of individual genes indicated by clinical geneticist from various regions of the country and we recognized much higher diagnostic and economic value of WES.
Modern diagnostics of rare diseases is time and money consuming and requires close cooperation between patients, their families, attending physicians, clinical geneticists and experts from various laboratories involved in biologic oriented research. It represents a big challenge for organisers and payers of the health care system.
Keywords:
are diseases, complex disorders, whole exome sequencing, gene mapping
Zdroje
1. Baird PA., Anderson TW, Newcombe HB et al. Genetic disorders in children and young adults: a population study. Am J Hum Genet 1988; 42: 677–693.
2. Blair DR, Lyttle CS, Mortensen JM et al. A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk. Cell 2013; 155: 70–80.
3. Pauling L, Itano, HA et al. Sickle cell anemia a molecular disease. Science 1949; 110: 543–548.
4. Ingram VM. A specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin. Nature 1956; 178: 792–794.
5. Gitschier J, Wood WI, Goralka TM et al. Characterization of the human factor VIII gene. Nature 1984; 312: 326–330.
6. Botstein D, White RL, Skolnick M et al. Construction of a genetic linkage map in man using restriction fragment length polymorphisms. Am J Hum Genet 1980; 32: 314–331.
7. Collins FS. Positional cloning moves from perditional to traditional. Nat Genet 1995; 9: 347–350.
8. Botstein D, Risch N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet 2003; 33 Suppl: 228–237.
9. Altshuler D. A haplotype map of the human genome. Nature 2005; 437: 1299–1320.
10. Auton A, Brooks LD, Durbin RM et al. A global reference for human genetic variation. Nature 2015; 526: 68–74.
11. Lek M, Karczewski KJ, Minikel EV et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016; 536: 285–291.
12. Sobreira N, Schiettecatte F, Boehm C et al. New tools for Mendelian disease gene identification: PhenoDB variant analysis module; and GeneMatcher, a web-based tool for linking investigators with an interest in the same gene. Hum Mutat 2015; 36: 425–431.
13. Kirby A, Gnirke A, Jaffe DB et al. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nat Genet 2013; 45: 299–303.
14. Kmoch S, Hartmannová H, Stiburková B et al. Human adenylosuccinate lyase (ADSL), cloning and characterization of full-length cDNA and its isoform, gene structure and molecular basis for ADSL deficiency in six patients. Hum Mol Genet 2000; 9: 1501–1513.
15. Kmoch S, Brynda J, Asfaw B et al. Link between a novel human gammaD-crystallin allele and a unique cataract phenotype explained by protein crystallography. Hum Mol Genet 2000; 9: 1779–1786.
16. Hřebíček M, Mrázová L, Seyrantepe V et al. Mutations in TMEM76* cause mucopolysaccharidosis IIIC (Sanfilippo C syndrome). Am J Hum Genet 2006; 79: 807–819.
17. Čížková A, Stránecký V, Mayr JA et al. TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. Nat Genet 2008; 40: 1288–1290.
18. Stiburková B, Majewski J, Šebesta I et al. Familial juvenile hyperuricemic nephropathy: localization of the gene on chromosome 16p11.2-and evidence for genetic heterogeneity. Am J Hum Genet 2000; 66: 1989–1994.
19. Živná M, Hulková H, Matignon M et al. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure. Am J Hum Genet 2009; 85: 204–213.
20. Bolar NA, Golzio C, Živná M et al. Heterozygous loss-of-function SEC61A1 mutations cause autosomal-dominant tubulo-interstitial and glomerulocystic kidney disease with anemia. Am J Hum Genet 2016; 99:174–187.
21. Nosková L, Stránecký V, Hartmannová H et al. Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. Am J Hum Genet 2011; 89: 241–252.
22. Van de Steeg E, Stránecký V, Hartmannová H et al. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 2012; 122: 519–528.
23. Stránecký V, Hoischen A, Hartmannová H et al. Mutations in ANTXR1 cause GAPO syndrome. Am J Hum Genet 2013; 92: 792–799.
24. Hartmannová H, Kubánek M, Šrámko M et al. Isolated X-linked hypertrophic cardiomyopathy caused by a novel mutation of the four-and-a-half LIM domain 1 gene. Circ Cardiovasc Genet 2013; 6: 543–551.
25. Park EJ, Grabinska KA, Guan Z et al. Mutation of Nogo-B receptor, a subunit of cis-prenyltransferase, causes a congenital disorder of glycosylation. Cell Metab 2014; 20: 448–457.
26. Kmoch S, Majewski J, Ramamurthy V et al. Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness. Nat Commun 2015; 6: 5614.
27. Davidson AE, Lišková P, Evans CJ et al. Autosomal-dominant corneal endothelial dystrophies CHED1 and PPCD1 are allelic disorders caused by non-coding mutations in the promoter of OVOL2. Am J Hum Genet 2016; 98: 75–89.
28. Lišková P, Dudáková L, Evans CJ et al. Ectopic GRHL2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4. Am J Hum Genet 2018; 102: 447–459.
29. Hartmannová H, Piherová L, Tauchmannová K et al. Acadian variant of Fanconi syndrome is caused by mitochondrial respiratory chain complex I deficiency due to a non-coding mutation in complex I assembly factor NDUFAF6. Hum Mol Genet 2016; 25: 4062–4079.
30. Gstrein T, Edwards A, Přistoupilová A et al. Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans. Nat Neurosci 2018; 21: 207–217.
31. Lupski JR, Belmont JW, Boerwinkle E et al. Clan genomics and the complex architecture of human disease. Cell 2011; 147: 32–43.
Štítky
Addictology Allergology and clinical immunology Angiology Audiology Clinical biochemistry Dermatology & STDs Paediatric gastroenterology Paediatric surgery Paediatric cardiology Paediatric neurology Paediatric ENT Paediatric psychiatry Paediatric rheumatology Diabetology Pharmacy Vascular surgery Pain management Dental HygienistČlánok vyšiel v časopise
Journal of Czech Physicians
- Metamizole at a Glance and in Practice – Effective Non-Opioid Analgesic for All Ages
- Advances in the Treatment of Myasthenia Gravis on the Horizon
- Metamizole vs. Tramadol in Postoperative Analgesia
- Spasmolytic Effect of Metamizole
- What Effect Can Be Expected from Limosilactobacillus reuteri in Mucositis and Peri-Implantitis?
Najčítanejšie v tomto čísle
- Periodic fevers and other autoinflammatory diseases
- Lymph node syndrome associated with cat scratch disease in children and adults
- Celiac disease in children and adolescents
- A horizontal transmission of genetic information and its importance for development of antibiotics resistance