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470 ParT FOUr Immunological Deficiencies
ON THE HOrIZON 6. McCarroll SA, et al. Common deletion polymorphisms in the human
genome. Nat Genet 2006;38:86–92.
As the costs of deep sequencing fall, examination of whole-genome 7. Stankiewicz P, Lupski JR. Structural variation in the human genome and
sequence should allow for examination of noncoding regulatory regions. its role in disease. Annu Rev Med 2010;61:437–55.
Data storage and computer speed will need to be improved to handle 8. Carvalho CM, Lupski JR. Mechanisms underlying structural variant
50-fold more data from each individual. formation in genomic disorders. Nat Rev Genet 2016;17:224–38.
New analytical paradigms for the analysis of variation in noncoding DNA 9. Lakich D, et al. Inversions disrupting the factor VIII gene are a common
and the interpretation of DNA variants that are not clearly associated cause of severe haemophilia A. Nat Genet 1993;5:236–41.
with deleterious effects will be required. 10. Puig M, et al. Human inversions and their functional consequences. Brief
Proving causality of new gene variants in primary immunodeficiencies Funct Genomics 2015;14:369–79.
will depend on future cataloguing of deleterious mutations in each 11. Amendola LM, et al. Performance of ACMG-AMP Variant-interpretation
gene and on molecular studies of the direct effects of the variants. guidelines among nine laboratories in the Clinical Sequencing
Exploratory Research Consortium. Am J Hum Genet 2016;99:247.
Since the application of WGS or WES to rare mendelian 12. Tryka KA, et al. NCBI’s Database of Genotypes and Phenotypes: dbGaP.
disorders was first described in 2009, hundreds of such disorders Nucleic Acids Res 2014;42:D975–9.
have been studied and the causative mutations found in nearly 13. Landrum MJ, et al. ClinVar: public archive of interpretations of clinically
relevant variants. Nucleic Acids Res 2016;44:D862–8.
27
500 previously unrecognized disease genes. The pace of discovery 14. Harrison SM, et al. Using ClinVar as a resource to support variant
will only increase, and we can anticipate that the number of interpretation. Curr Protoc Hum Genet 2016;89:8.16.1–23.
known mendelian disorders, including those characterized by 15. Fokkema IF, et al. LOVD v.2.0: the next generation in gene variant
primary immunodeficiency and/or autoimmunity, will grow over databases. Hum Mutat 2011;32:557–63.
coming years. It has been predicted that the genetic basis for 16. Revy P, et al. The repair of DNA damages/modifications during the
every human single gene disorder will be elucidated in the near maturation of the immune system: lessons from human primary
future. However, the genetic basis for complex disorders that immunodeficiency disorders and animal models. Adv Immunol
show increased familial occurrence, and yet are not single gene 2005;87:237–95.
disorders and do not follow mendelian inheritance, remains 17. Kovanen PE, Leonard WJ. Cytokines and immunodeficiency diseases:
elusive and will require another leap in technology and genetic critical roles of the gamma(c)-dependent cytokines interleukins 2, 4,
7, 9, 15, and 21, and their signaling pathways. Immunol Rev 2004;202:
analytical tools to be fully unraveled. The data being generated 67–83.
through human and model organism genomics will certainly 18. Choi Y, Simon-Stoos K, Puck JM. Hypo-active variant of IL-2 and
aid in the elucidation of these more challenging disorders of the associated decreased T cell activation contribute to impaired apoptosis in
human immune system. New tools available to immunologists autoimmune prone MRL mice. Eur J Immunol 2002;32:677–85.
and geneticists will open great opportunities for discovery and 19. Diehl AG, Boyle AP. Deciphering ENCODE. Trends Genet 2016;32:
understanding of genetic disorders of immunity which, in turn, 238–49.
will deepen our knowledge of immune system networks. 20. ENCODE Project Consortium. An integrated encyclopedia of DNA
elements in the human genome. Nature 2012;489:57–74.
Please check your eBook at https://expertconsult.inkling.com/ 21. Doolittle WF. Is junk DNA bunk? A critique of ENCODE. Proc Natl Acad
Sci USA 2013;110:5294–300.
for self-assessment questions. See inside cover for registration 22. Eddy SR. The ENCODE project: missteps overshadowing a success. Curr
details. Biol 2013;23:R259–61.
23. Al-Herz W. Primary immunodeficiency disorders in Kuwait: first report
REFERENCES from Kuwait National Primary Immunodeficiency Registry (2004—2006).
J Clin Immunol 2008;28:186–93.
1. Steinberg KM, et al. Single haplotype assembly of the human genome 24. Al-Herz W, et al. Parental consanguinity and the risk of primary
from a hydatidiform mole. Genome Res 2014;24:2066–76. immunodeficiency disorders: report from the Kuwait National Primary
2. Gonzaga-Jauregui C, Lupski JR, Gibbs RA. Human genome sequencing in Immunodeficiency Disorders Registry. Int Arch Allergy Immunol
health and disease. Annu Rev Med 2012;63:35–61. 2011;154:76–80.
3. Jiang Y, Turinsky AL, Brudno M. The missing indels: an estimate of indel 25. Yang Y, et al. Molecular findings among patients referred for clinical
variation in a human genome and analysis of factors that impede whole-exome sequencing. JAMA 2014;312:1870–9.
detection. Nucleic Acids Res 2015;43:7217–28. 26. Chan AY, et al. A novel human autoimmune syndrome caused by
4. Huddleston J, Eichler EE. An incomplete understanding of human genetic combined hypomorphic and activating mutations in ZAP-70. J Exp Med
variation. Genetics 2016;202:1251–4. 2016;213:155–65.
5. Madsen BE, Villesen P, Wiuf C. Short tandem repeats in human exons: a 27. Chong JX, et al. The genetic basis of mendelian phenotypes: discoveries,
target for disease mutations. BMC Genomics 2008;9:410. challenges, and opportunities. Am J Hum Genet 2015;97:199–215.

