Human Genetic Disorders

  • Teresa M. Kruisselbrink
  • Noralane M. Lindor
  • Elyse B. Mitchell
  • Brittany C. Thomas
  • Cassandra K. Runke
  • Katrina E. Kotzer
  • Rajiv K. Pruthi
  • Devin Oglesbee
  • Elyse M. Grycki
  • Ralitza H. Gavrilova
Chapter

Abstract

The field of genetics continues to evolve at a rapid pace. The completion of the Human Genome project coupled with advancing scientific techniques has led to the explosion of genetic information and testing capabilities ranging from rare genetic conditions to common and sometimes preventable conditions. The Online Mendelian Inheritance in Man® (OMIM) found at http://www.ncbi.nlm.nih.gov/omim contains information on over 12,000 genes with known sequence. Another online resource, GeneTests, found at http://www.ncbi.nlm.nih.gov/sites/GeneTests provides reference for nearly 1,500 diseases in which clinical laboratory testing is available. This chapter reviews a variety of genetic conditions categorized by primary mode of inheritance (i.e., chromosomal, single gene, and mitochondrial disorders) and is further subcategorized by disease process (i.e., metabolic, familial cancer syndromes, hematologic disorders). For each disorder, the chromosome, gene location, inheritance pattern, incidence, clinical phenotype, laboratory findings, and treatment options are reviewed. The chapter does not encompass all known genetic conditions, but provides a general overview of a wide range of genetic conditions and various inheritance patterns extending across multiple subspecialties. The suggested reading section provides key text books and peer reviewed references for those desiring more in-depth information.

Keywords

Chromosome Aneuploidy Microdeletion Deletion Point mutation Chromosome breakage Gene Molecular Trinucleotide repeat Biochemical Metabolic Familial Inheritance Mitochondrial 

SUGGESTED READING

Online Resources

  1. Online Mendelian Inheritance in Man (OMIM) – http://www.ncbi.nlm.nih.gov.

General Genetic Resources

  1. Charles R. Scriver, et al. (eds.). The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001.Google Scholar
  2. David L. Rimoin, Michael Connor J, Reed E. Pyeritz, Emery AEH, (eds.). Emery and Rimoin’s Principles and Practice of Medical Genetics. 5th ed. New York: Churchill Livingstone, 2007.Google Scholar
  3. Jones KL. Smith’s Recognizable Patterns of Human Malformation. 6th ed. Philadelphia: Elsevier, 2006.Google Scholar

Chromosomal Disorders

  1. ACOG Practice Bulletin – Clinical Management Guidelines for Obstetrician–Gynecologists. ACOG Practice Bulletin No. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol 2007;109:217–227.Google Scholar
  2. De Decker HP, Lawrenson JB. The 22q11.2 deletion: from diversity to a single gene theory. Genet Med 2001;3:2–5.PubMedCrossRefGoogle Scholar
  3. Duker NJ. Chromosome breakage syndromes and cancer. Am J Med Genet 2002;115:125–129.PubMedCrossRefGoogle Scholar
  4. Gardner RJ, Sutherland G. Chromosome Abnormalities and Genetic Counseling. New York: Oxford University Press, 2004.Google Scholar
  5. Horsthemke B, Wagstaff J. Mechanisms of imprinting of the Prader–Willi/Angelman region. Am J Med Genet A 2008;146A:2041–2052.PubMedCrossRefGoogle Scholar
  6. Joenje H, Patel KJ. The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet 2001;2:446–457.PubMedCrossRefGoogle Scholar
  7. Mitchell EB, et al. Ready reference to common segmental aneusomies by syndromic names, major features and chromosomal locations. J Assoc Genet Technol 2008;34:5–7.PubMedGoogle Scholar

Trinucleotide Repeat Disorders

  1. Evidente VG, Gwinn-Hardy KA, Caviness JN, Gilman S. Hereditary ataxias. Mayo Clinic Proc 2000;75:475–490.CrossRefGoogle Scholar
  2. Shao J, Diamond MI. Polyglutamine diseases: emerging concepts in pathogenesis and therapy. Hum Mol Genet 2007;16:R115–123.PubMedCrossRefGoogle Scholar
  3. Wenstrom KD. Fragile X and other trinucleotide repeat diseases. Obstet Gynecol Clin North Am 2002;29:367–388.PubMedCrossRefGoogle Scholar

Neuromuscular Disorders

  1. Ogino S, Wilson RB. Genetic testing and risk assessment for spinal muscular atrophy (SMA). Hum Genet 2002;111:477–500.PubMedCrossRefGoogle Scholar
  2. Saifi GM, Szigeti K, Snipes GJ, et al. Molecular mechanisms, diagnosis, and rational approaches to management of and therapy for Charcot–Marie–Tooth disease and related peripheral neuropathies. J Invest Med 2003;51:261–268.CrossRefGoogle Scholar
  3. Zatz M, de Paula F, Starling A, et al. The 10 autosomal recessive limb-girdle muscular dystrophies. Neuromuscul Disord 2003;13:532–544.PubMedCrossRefGoogle Scholar

Skeletal Disorders

  1. Kimonis V, et al. Genetics of craniosynostosis. Semin Pediatr Neurol 2007;14:150–161.PubMedCrossRefGoogle Scholar
  2. Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet 2004;363:1377–1385.PubMedCrossRefGoogle Scholar
  3. Wilkie AO, Patey SJ, Kan SH, et al. FGFs, their receptors, and human limb malformations: clinical and molecular correlations. Am J Med Genet 2002;112:266–278.PubMedCrossRefGoogle Scholar

Connective Tissue Disorders

  1. Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-B receptor. N Engl J Med 2006;355:788–798.PubMedCrossRefGoogle Scholar
  2. Milewicz DM, Guo DC, Tran-Fandulu V, et al. Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction. Annu Rev Genomics Hum Genet 2008;9:283–302.CrossRefGoogle Scholar

Hematologic Disorders

  1. Old JM. Screening and genetic diagnosis of haemoglobin disorders. Blood Rev 2003;17:43–45.PubMedCrossRefGoogle Scholar
  2. Pruthi RK. Hemophilia: a practical approach to genetic testing. Mayo Clin Proc 2005;80:1485–1499.PubMedCrossRefGoogle Scholar
  3. Schrier SL. Pathophysiology of thalassemia. Curr Opin Hematol 2002;9: 123–126.PubMedCrossRefGoogle Scholar
  4. Thein SL. Genetic insights into the clinical diversity of beta thalassaemia. Br J Haematol 2004;124:264–274.PubMedCrossRefGoogle Scholar

Other Genetic Disorders

  1. Kulczycki LL, Kostuch M, Bellanti JA. A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype–phenotype manifestations. Am J Hum Genet 2003;116A:262–267.Google Scholar
  2. Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol 2004;19:643–649.PubMedGoogle Scholar
  3. Watson MS, Cutting GR, Desnick RJ, et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med 2004;6:387–391.PubMedCrossRefGoogle Scholar

Metabolic Disorders: Inborn Errors of Metabolism

  1. Blau N, Duran M, Blaskovics M, Gibson KM, (eds.). Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases. 2nd ed. Verlag, Berlin, Heidelberg, New York: Springer, 2003.Google Scholar
  2. Fearing MK, Levy HL. Expanded newborn screening using tandem mass spectrometry. Adv Pediatr 2003;50:81–111.PubMedGoogle Scholar
  3. Fernandes J, Saudubray JM, van den Berghe G, (eds.). Inborn Metabolic Diseases Diagnosis and Treatment. 3rd ed. Verlag, Berlin, Heidelberg, New York: Springer, 2000.Google Scholar
  4. Rinaldo P, Lim JS, Tortorelli S, Gavrilov D, Matern D. Newborn screening of metabolic disorders: recent progress and future developments. Nestle Nutr Workshop Ser Paediatr Program. 2008;62:81–93; discussion 93–96.CrossRefGoogle Scholar
  5. Seashore MR, Rinaldo P. Metabolic disease of the neonate and young infant. Semin Perinatol 1993;17:318–329.PubMedGoogle Scholar

Lysosomal Storage Diseases

  1. Beck M. New therapeutic options for lysosomal storage disorders: enzyme replacement, small molecules and gene therapy. Hum Genet 2007; 121:1–22.PubMedCrossRefGoogle Scholar
  2. Staretz-Chacham O, Lang TC, LaMarca ME, Krasnewich D, Sidransky E. Lysosomal storage disorders in the newborn (review). Pediatrics 2009;123:1191–1207.PubMedCrossRefGoogle Scholar

Familial Cancer Syndromes

  1. Alsanea O, Clark OH. Familial thyroid cancer. Curr Opin Oncol 2001;13:44–51.PubMedCrossRefGoogle Scholar
  2. Boardman LA. Heritable colorectal cancer syndromes: recognition and preventive management. Gastroenterol Clin North Am 2002;31:1107–1131.PubMedCrossRefGoogle Scholar
  3. Classon M, Harlow E. The retinoblastoma tumour suppressor in development and cancer. Nat Rev Cancer 2002;2:910–917.PubMedCrossRefGoogle Scholar
  4. Dome JS, Coppes MJ. Recent advances in Wilms tumor genetics. Curr Opin Pediatr 2002;14:5–11.PubMedCrossRefGoogle Scholar
  5. Eng C. PTEN: One gene, many syndromes. Hum Mutat 2003;22:183–198.PubMedCrossRefGoogle Scholar
  6. Fleischmann C, Peto J, Cheadle J, et al. Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer. Int J Cancer 2004;109:554–558.PubMedCrossRefGoogle Scholar
  7. Frank TS, Deffenbaugh AM, Reid JE, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 2002;20:1480–1490.PubMedCrossRefGoogle Scholar
  8. Leggett BA, Young JP, Barker M. Peutz–Jeghers syndrome: genetic screening. Expert Rev Anticancer Ther 2003;3:518–524.PubMedCrossRefGoogle Scholar
  9. Lindor NM, McMaster ML, Lindor CJ, Greene MH. Concise handbook of familial cancer susceptibility syndromes – second edition. J Natl Cancer Inst Monogr 2008;38:1–93.PubMedGoogle Scholar
  10. Markey K, Axel L, Ahnen D. Basic concepts for genetic testing in common hereditary colorectal cancer syndromes. Curr Gastroenterol Rep 2002;4:404–413.PubMedCrossRefGoogle Scholar
  11. Robbins DH, Itzkowitz SH. The molecular and genetic basis of colon cancer. Med Clin North Am 2002;86:1467–1495.PubMedCrossRefGoogle Scholar
  12. Sims KB. Von Hippel–Lindau disease: gene to bedside. Curr Opin Neurol 2001;14:695–703.PubMedCrossRefGoogle Scholar
  13. Varley JM. Germline TP53 mutations and Li–Fraumeni syndrome. Hum Mutat 2003;21:313–320.PubMedCrossRefGoogle Scholar
  14. Wooster R, Weber BL. Breast and ovarian cancer. N Engl J Med 2003;348:2339–2347.PubMedCrossRefGoogle Scholar

Mitochondrial Disorders

  1. DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med 2003;348:2656–2668.PubMedCrossRefGoogle Scholar
  2. Haas Rh, Parikh S, Falk Mj, Saneto Rp, Wolf Ni, Darin N, Wong L-J, Cohen Bh, Naviaux Rk. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab 2008;94:16–37.PubMedCrossRefGoogle Scholar
  3. Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet 2007;2:342–352.CrossRefGoogle Scholar
  4. Van den Heuvel L, Smeitink J. The oxidative phosphorylation (OXPHOS) system: nuclear genes and human genetic diseases. Bioessays 2001;23: 518–525.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Teresa M. Kruisselbrink
    • 1
  • Noralane M. Lindor
    • 1
  • Elyse B. Mitchell
    • 1
  • Brittany C. Thomas
    • 1
  • Cassandra K. Runke
    • 1
  • Katrina E. Kotzer
    • 1
  • Rajiv K. Pruthi
    • 1
  • Devin Oglesbee
    • 1
  • Elyse M. Grycki
    • 1
  • Ralitza H. Gavrilova
    • 1
  1. 1.Mayo ClinicMayo College of MedicineRochesterUSA

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