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  • Review Article
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Insights from exome sequencing for endocrine disorders

Nature Reviews Endocrinology volume 11, pages 455–464 (2015)Cite this article

Subjects

Key Points

  • Exome sequencing in rare familial endocrine syndromes has led to the identification of many disease-associated genes and unravelled new biological pathways

  • In large, population-based cohorts, the use of exome sequencing has identified common, low-risk genetic variants that contribute to common diseases such as type 2 diabetes mellitus and hyperlipidaemia

  • Exome sequencing has provided insights into the pathogenesis of neuroendocrine tumours

  • Exome sequencing has also been used to implicate increased protein kinase A activity in the development of Cushing syndrome and somatic ion channel defects in primary hyperaldosteronism

  • With lowering costs, increasing availability and high diagnostic yield, the use of exome sequencing in the care of patients with endocrine diseases is expected to increase rapidly in the coming years

Abstract

Whole-exome sequencing has emerged as a fast and effective tool for the elucidation of genetic defects underlying both rare and common human diseases. Increased availability and decreased costs of next-generation sequencing have enabled investigators to use this approach not only in individual patients with rare diseases, but also to screen large cohorts or populations for the genetic determinants of diseases. Within the field of endocrinology, exome sequencing has led to major advancements in our understanding of many disorders including adrenal disease, growth and puberty disorders and type 2 diabetes mellitus, as well as a multitude of rare genetic syndromes with prominent endocrine involvement. In this Review, we provide an overview of these new insights and discuss the role that exome sequencing is expected to have in endocrine research and future clinical practice.

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Figure 1: The use of WES to identify mutations.
Figure 2: Identifying low frequency variants using WES.

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References

  1. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    CAS  PubMed  Google Scholar 

  2. Bamshad, M. J. et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat. Rev. Genet. 12, 745–755 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Biesecker, L. G. & Green, R. C. Diagnostic clinical genome and exome sequencing. N. Engl. J. Med. 371, 1170 (2014).

    Article  PubMed  Google Scholar 

  4. Biesecker, L. G., Shianna, K. V. & Mullikin, J. C. Exome sequencing: the expert view. Genome Biol. 12, 128 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ng, S. B. et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat. Genet. 42, 790–793 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Dunkel, L. & Quinton, R. Transition in endocrinology: induction of puberty. Eur. J. Endocrinol. 170, R229–R239 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Abreu, A. P. et al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N. Engl. J. Med. 368, 2467–2475 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Macedo, D. B. et al. Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. J. Clin. Endocrinol. Metab. 99, E1097–E1103 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Forni, P. E. & Wray, S. GnRH, anosmia and hypogonadotropic hypogonadism—where are we? Front. Neuroendocrinol. 36C, 165–177 (2015).

    Article  CAS  Google Scholar 

  10. Kotan, L. D. et al. Mutations in FEZF1 cause Kallmann syndrome. Am. J. Hum. Genet. 95, 326–331 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Eckler, M. J., McKenna, W. L., Taghvaei, S., McConnell, S. K. & Chen, B. Fezf1 and Fezf2 are required for olfactory development and sensory neuron identity. J. Comp. Neurol. 519, 1829–1846 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Shi, C. H. et al. Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP. Hum. Mol. Genet. 23, 1013–1024 (2014).

    Article  CAS  PubMed  Google Scholar 

  13. Synofzik, M. et al. PNPLA6 mutations cause Boucher–Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain 137, 69–77 (2014).

    Article  PubMed  Google Scholar 

  14. Topaloglu, A. K. et al. Loss of function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome. J. Clin. Endocrinol. Metab. 99, E2067–E2075 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Margolin, D. H. et al. Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. N. Engl. J. Med. 368, 1992–2003 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Zangen, D. et al. XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes coactivation of estrogen-driven transcription. Am. J. Hum. Genet. 89, 572–579 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Caburet, S. et al. Mutant cohesin in premature ovarian failure. N. Engl. J. Med. 370, 943–949 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Kasippillai, T. et al. Mutations in eIF4ENIF1 are associated with primary ovarian insufficiency. J. Clin. Endocrinol. Metab. 98, E1534–E1539 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. de Vries, L. et al. Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency. J. Clin. Endocrinol. Metab. 99, E2129–E2132 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. Meimaridou, E. et al. Familial glucocorticoid deficiency: new genes and mechanisms. Mol. Cell. Endocrinol. 371, 195–200 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Meimaridou, E. et al. Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat. Genet. 44, 740–742 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Prasad, R. et al. Thioredoxin reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J. Clin. Endocrinol. Metab. 99, E1556–E1563 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Hughes, C. R. et al. MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J. Clin. Invest. 122, 814–820 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Meimaridou, E. et al. ACTH resistance: genes and mechanisms. Endocr. Dev. 24, 57–66 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Masai, H., You, Z. & Arai, K. Control of DNA replication: regulation and activation of eukaryotic replicative helicase, MCM. IUBMB Life 57, 323–335 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Sun, Y. et al. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat. Genet. 44, 1375–1381 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Joustra, S. D. et al. The IGSF1 deficiency syndrome: characteristics of male and female patients. J. Clin. Endocrinol. Metab. 98, 4942–4952 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Joustra, S. D. et al. IGSF1 deficiency syndrome: a newly uncovered endocrinopathy. Rare Dis. 1, e24883 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Mazzarella, R., Pengue, G., Jones, J., Jones, C. & Schlessinger, D. Cloning and expression of an immunoglobulin superfamily gene (IGSF1) in Xq25. Genomics 48, 157–162 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Kuhnen, P. et al. Identification of PENDRIN (SLC26A4) mutations in patients with congenital hypothyroidism and “apparent” thyroid dysgenesis. J. Clin. Endocrinol. Metab. 99, E169–E176 (2014).

    Article  PubMed  Google Scholar 

  31. Manolio, T. A. Genome-wide association studies and assessment of the risk of disease. N. Engl. J. Med. 363, 166–176 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. SIGMA Type 2 Diabetes Consortium. Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population. JAMA 311, 2305–2314 (2014).

  33. Lange, L. A. et al. Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. Am. J. Hum. Genet. 94, 233–245 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Rosenthal, E. A. et al. Joint linkage and association analysis with exome sequence data implicates SLC25A40 in hypertriglyceridemia. Am. J. Hum. Genet. 93, 1035–1045 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Pagliarini, D. J. et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112–123 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Musunuru, K. et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N. Engl. J. Med. 363, 2220–2227 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Koishi, R. et al. Angptl3 regulates lipid metabolism in mice. Nat. Genet. 30, 151–157 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154–156 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Cohen, J. et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37, 161–165 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Farnier, M. PCSK9: From discovery to therapeutic applications. Arch. Cardiovasc. Dis. 107, 58–66 (2014).

    Article  PubMed  Google Scholar 

  41. Albrechtsen, A. et al. Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. Diabetologia 56, 298–310 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Lohmueller, K. E. et al. Whole-exome sequencing of 2,000 Danish individuals and the role of rare coding variants in type 2 diabetes. Am. J. Hum. Genet. 93, 1072–1086 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Steinthorsdottir, V. et al. Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. Nat. Genet. 46, 294–298 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Kushner, J. A. et al. Cyclins D2 and D1 are essential for postnatal pancreatic β-cell growth. Mol. Cell Biol. 25, 3752–3762 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Maestro, M. A. et al. Distinct roles of HNF1β, HNF1α, and HNF4α in regulating pancreas development, β-cell function and growth. Endocr. Dev. 12, 33–45 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Wood, A. R. et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat. Genet. 46, 1173–1186 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Chan, Y. et al. Common variants show predicted polygenic effects on height in the tails of the distribution, except in extremely short individuals. PLoS Genet. 7, e1002439 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Nilsson, O. et al. Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations. J. Clin. Endocrinol. Metab. 99, E1510–E1518 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. van Dijk, F. S. et al. PLS3 mutations in X-linked osteoporosis with fractures. N. Engl. J. Med. 369, 1529–1536 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Laine, C. M. et al. A novel splice-mutation in PLS3 causes X-linked early-onset low-turnover osteoporosis. J. Bone Miner. Res. 30, 510–518 (2014).

    Article  CAS  Google Scholar 

  51. Thomas, F., Desmedt, C., Aftimos, P. & Awada, A. Impact of tumor sequencing on the use of anticancer drugs. Curr. Opin. Oncol. 26, 347–356 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Sahakitrungruang, T. et al. Germline and somatic DICER1 mutations in a pituitary blastoma causing infantile onset Cushing disease. J. Clin. Endocrinol. Metab. 99, E1487–E1492 (2014).

    Article  CAS  PubMed  Google Scholar 

  53. Goh, G. et al. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat. Genet. 46, 613–617 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Sato, Y. et al. Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome. Science 344, 917–920 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Cao, Y. et al. Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome. Science 344, 913–917 (2014).

    Article  CAS  PubMed  Google Scholar 

  56. Beuschlein, F. et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. N. Engl. J. Med. 370, 1019–1028 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Assie, G. et al. Integrated genomic characterization of adrenocortical carcinoma. Nat. Genet. 46, 607–612 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Assie, G. et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome. N. Engl. J. Med. 369, 2105–2114 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Gagliardi, L. et al. ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia. J. Clin. Endocrinol. Metab. 99, E1784–E1792 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Tissier, F. et al. Mutations of β-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res. 65, 7622–7627 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Fagugli, R. M. & Taglioni, C. Changes in the perceived epidemiology of primary hyperaldosteronism. Int. J. Hypertens. 2011, 162804 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Al-Salameh, A., Cohen, R. & Desailloud, R. Overview of the genetic determinants of primary aldosteronism. Appl. Clin. Genet. 7, 67–79 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Conn, J. W. & Louis, L. H. Primary aldosteronism: a new clinical entity. Trans. Assoc. Am. Physicians 68, 215–231 (1955).

    CAS  PubMed  Google Scholar 

  64. Choi, M. et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331, 768–772 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Monticone, S. et al. A Novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III. J. Clin. Endocrinol. Metab. 98, E1861–E1865 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Beuschlein, F. et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat. Genet. 45, 440–444 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Azizan, E. A. et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat. Genet. 45, 1055–1060 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Newey, P. J. et al. Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas. J. Clin. Endocrinol. Metab. 97, E1995–E2005 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Cromer, M. K. et al. Identification of somatic mutations in parathyroid tumors using whole-exome sequencing. J. Clin. Endocrinol. Metab. 97, E1774–E1781 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Newey, P. J. et al. Whole-exome sequencing studies of nonfunctioning pituitary adenomas. J. Clin. Endocrinol. Metab. 98, E796–E800 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Cao, M. et al. Analysis of the inheritance pattern of a Chinese family with phaeochromocytomas through whole exome sequencing. Gene 526, 164–169 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Cao, Y. et al. Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1. Nat. Commun. 4, 2810 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Foulkes, W. D., Priest, J. R. & Duchaine, T. F. DICER1: mutations, microRNAs and mechanisms. Nat. Rev. Cancer 14, 662–72 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. Guo, M. H. et al. Whole exome sequencing to identify genetic causes of short stature. Horm. Res. Paediatr. 82, 44–52 (2014).

    Article  PubMed  CAS  Google Scholar 

  75. Unger, S. et al. FAM111A mutations result in hypoparathyroidism and impaired skeletal development. Am. J. Hum. Genet. 92, 990–995 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Biesecker, L. G. & Green, R. C. Diagnostic clinical genome and exome sequencing. N. Engl. J. Med. 370, 2418–2425 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. 1000 Genomes Project [online], (2014).

  78. NHLBI Exome Sequencing Project. Exome variant server [online], (2015).

  79. Exome Aggregation Consortium ExAC Browser (Beta) [online], (2015).

  80. Wang, G. T., Peng, B. & Leal, S. M. Variant association tools for quality control and analysis of large-scale sequence and genotyping array data. Am. J. Hum. Genet. 94, 770–783 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Flannick, J. et al. Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes. Nat. Genet. 45, 1380–1385 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Green, R. C. et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet. Med. 15, 565–574 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Smith, L. A., Douglas, J., Braxton, A. A. & Kramer, K. Reporting incidental findings in clinical whole exome sequencing: incorporation of the 2013 ACMG recommendations into current practices of genetic counseling. J. Genet. Couns. http://dx.doi.org/10.1007/s10897-014-9794-4.

  84. Yang, Y. et al. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N. Engl. J. Med. 369, 1502–1511 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Yang, Y. et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 312, 1870–1879 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Lee, H. et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA 312, 1880–1887 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Baxter, R. M. et al. Exome sequencing for the diagnosis of 46,XY disorders of sex development. J. Clin. Endocrinol. Metab. 100, E333–E344 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Waldman, L. A. & Chia, D. J. Towards identification of molecular mechanisms of short stature. Int. J. Pediatr. Endocrinol. 2013, 19 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Dauber, A., Rosenfeld, R. G. & Hirschhorn, J. N. Genetic evaluation of short stature. J. Clin. Endocrinol. Metab. 99, 3080–3092 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Samuels, M. E. et al. Bioinactive ACTH causing glucocorticoid deficiency. J. Clin. Endocrinol. Metab. 98, 736–742 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Tegtmeyer, L. C. et al. Multiple phenotypes in phosphoglucomutase 1 deficiency. N. Engl. J. Med. 370, 533–542 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Webb, E. A. et al. ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies. Brain 136, 3096–3105 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Dauber, A. et al. Genetic defect in CYP24A1, the vitamin D 24-hydroxylase gene, in a patient with severe infantile hypercalcemia. J. Clin. Endocrinol. Metab. 97, E268–E274 (2012).

    Article  CAS  PubMed  Google Scholar 

  94. Dauber, A. et al. Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein. J. Clin. Endocrinol. Metab. 97, E2140–E2151 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Hanson, D. et al. Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth. Am. J. Hum. Genet. 89, 148–153 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Nilsson, O. et al. Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations. J. Clin. Endocrinol. Metab. 99, E1510–E1518 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Kerns, S. L. et al. A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood onset diabetes. J. Clin. Endocrinol. Metab. 99, E2117–E2122 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Al-Maawali, A. et al. Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders. Eur. J. Hum. Genet. 23, 310–316 (2015).

    Article  CAS  PubMed  Google Scholar 

  99. Bashamboo, A. et al. Mutations in the FOG2/ZFPM2 gene are associated with anomalies of human testis determination. Hum. Mol. Genet. 23, 3657–3665 (2014).

    Article  CAS  PubMed  Google Scholar 

  100. Stitziel, N. O. et al. Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 33, 2909–2914 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Gillis, D. et al. TRMT10A dysfunction is associated with abnormalities in glucose homeostasis, short stature and microcephaly. J. Med. Genet. 51, 581–586 (2014).

    Article  CAS  PubMed  Google Scholar 

  102. Peloso, G. M. et al. Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. Am. J. Hum. Genet. 94, 223–232 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Moltke, I. et al. A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature 512, 190–193 (2014).

    Article  CAS  PubMed  Google Scholar 

  104. Du, M. et al. Whole-exome imputation of sequence variants identified two novel alleles associated with adult body height in African Americans. Hum. Mol. Genet. 23, 6607–6615 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The authors' research work is supported by NIH research grant 1K23HD073351 to A.D.

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  1. Division of Endocrinology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, 45229, OH, USA

    Christiaan de Bruin & Andrew Dauber

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C.d.B and A.D. researched data for the article, made substantial contribution to discussion of its content and wrote the manuscript. A.D. reviewed and edited the manuscript before submission.

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Correspondence to Andrew Dauber.

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de Bruin, C., Dauber, A. Insights from exome sequencing for endocrine disorders. Nat Rev Endocrinol 11, 455–464 (2015). https://doi.org/10.1038/nrendo.2015.72

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