Details of Disease

General Information of Disease (ID: DISOUI7W)

• Disease Name: Klinefelter syndrome
• Synonyms: hypogonadotropic hypogonadism; 47,XXY syndrome; Klinefelter syndrome; Klinefelter's syndrome, XXY; XXY syndrome (Klinefelter syndrome); XXY syndrome; Klinefelter's syndrome; XXY trisomy
• Definition: A sex chromosome disorder caused by the presence of an extra X chromosome in the male karyotype. Affected individuals are infertile and have a small penis and testes. They tend to have tall stature and long legs and may have difficulties with speech and language development. Gynecomastia may be present.
• Disease Hierarchy:
  DISVWOWV: Chromosome X disorder
  DISCE08M: Trisomy
  DISYOBKW: Sex chromosome disorder of sex development
  DISOUI7W: Klinefelter syndrome
• Disease Identifiers:
  MONDO ID: MONDO_0006823
  MESH ID: D007713
  UMLS CUI: C0022735
  MedGen ID: 44033
  SNOMED CT ID: 22053006

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 18 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
BRD2	TTDP48B	Limited	Biomarker	[1]
FGF8	TTIUF3J	Limited	Biomarker	[2]
AURKC	TTLYXIT	Strong	Genetic Variation	[3]
ESRRB	TTKF0XS	Strong	Genetic Variation	[4]
FGF10	TTNPEFX	Strong	Altered Expression	[5]
FSHB	TT13GFV	Strong	Genetic Variation	[6]
G3BP1	TTG0R8Z	Strong	Genetic Variation	[7]
GNRH1	TT0ID4A	Strong	Biomarker	[8]
INHBA	TTVB30D	Strong	Biomarker	[9]
KCNJ11	TT329V4	Strong	Genetic Variation	[10]
KDM5C	TT94UCF	Strong	Biomarker	[11]
KISS1	TTU2O6T	Strong	Genetic Variation	[12]
OTC	TT5KIO9	Strong	Genetic Variation	[13]
PNPLA6	TTWAQU2	Strong	Genetic Variation	[14]
PROKR2	TTM67AX	Strong	Genetic Variation	[15]
STAR	TTEI40H	Strong	Biomarker	[16]
TACR3	TTBPGLU	Strong	Biomarker	[17]
USH2A	TTVCLLA	Strong	Biomarker	[18]

This Disease Is Related to 30 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
AMH	OT5FH4BD	Limited	Altered Expression	[19]
ANOS1	OTZJT4KN	Limited	Biomarker	[20]
CHD7	OTHNIZWZ	Limited	Altered Expression	[21]
BBS1	OTXSXB1K	Strong	Biomarker	[22]
CCDC141	OTQ9HA3I	Strong	Genetic Variation	[23]
FGF17	OTAQSFZ2	Strong	Genetic Variation	[2]
GGN	OTKPYNWP	Strong	Biomarker	[1]
GK	OTK2YRA0	Strong	Genetic Variation	[24]
HENMT1	OTM5I26B	Strong	Genetic Variation	[7]
IGSF10	OTB9QOGO	Strong	Genetic Variation	[25]
IL1RAPL1	OTW3T4B2	Strong	Genetic Variation	[26]
INHA	OT7HWCO3	Strong	Altered Expression	[16]
INSL3	OT7KUNTE	Strong	Altered Expression	[27]
IQCB1	OTYQ28V9	Strong	Biomarker	[28]
JTB	OT314JB6	Strong	Genetic Variation	[29]
LDOC1	OTWZH4O9	Strong	Biomarker	[30]
ND6	OTG47B7B	Strong	Altered Expression	[31]
NDN	OTYBYJ82	Strong	Biomarker	[32]
NEUROG3	OT6DIPWC	Strong	Biomarker	[33]
NR5A1	OTOULYR4	Strong	Altered Expression	[34]
NSMF	OTLTA24A	Strong	Genetic Variation	[35]
PCDH19	OTSOW3MV	Strong	Biomarker	[36]
PROK2	OT70IFEZ	Strong	Genetic Variation	[37]
PROP1	OT8GF6N8	Strong	Genetic Variation	[38]
RABGAP1L	OT7QO47I	Strong	Genetic Variation	[39]
RAD9A	OTJ3AJQU	Strong	Biomarker	[40]
RNF216	OTR1XEZ3	Strong	Biomarker	[41]
SERPINA4	OTBK0GG7	Strong	Genetic Variation	[42]
SHOX	OTE0YZJO	Strong	Biomarker	[43]
TAC3	OTOJGM38	Strong	Biomarker	[44]

References

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• [2] Genotypic and phenotypic spectra of FGFR1, FGF8, and FGF17 mutations in a Chinese cohort with idiopathic hypogonadotropic hypogonadism.Fertil Steril. 2020 Jan;113(1):158-166. doi: 10.1016/j.fertnstert.2019.08.069. Epub 2019 Nov 17.
• [3] Mutations of the aurora kinase C gene causing macrozoospermia are the most frequent genetic cause of male infertility in Algerian men.Asian J Androl. 2015 Jan-Feb;17(1):68-73. doi: 10.4103/1008-682X.136441.
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• [5] Molecular pathology of the fibroblast growth factor family.Hum Mutat. 2009 Sep;30(9):1245-55. doi: 10.1002/humu.21067.
• [6] The FSHB -211G>T variant attenuates serum FSH levels in the supraphysiological gonadotropin setting of Klinefelter syndrome.Eur J Hum Genet. 2015 May;23(5):700-3. doi: 10.1038/ejhg.2014.142. Epub 2014 Jul 23.
• [7] Genome-wide site-specific differential methylation in the blood of individuals with Klinefelter syndrome.Mol Reprod Dev. 2015 May;82(5):377-86. doi: 10.1002/mrd.22483. Epub 2015 Apr 30.
• [8] GnRH-1 Neural Migration From the Nose to the Brain Is Independent From Slit2, Robo3 and NELL2 Signaling.Front Cell Neurosci. 2019 Mar 1;13:70. doi: 10.3389/fncel.2019.00070. eCollection 2019.
• [9] Inhibin B and anti-Mllerian hormone, but not testosterone levels, are normal in infants with nonmosaic Klinefelter syndrome.J Clin Endocrinol Metab. 2004 Apr;89(4):1864-8. doi: 10.1210/jc.2003-031624.
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• [16] Is the protein expression window during testicular development affected in patients at risk for stem cell loss?.Hum Reprod. 2015 Dec;30(12):2859-70. doi: 10.1093/humrep/dev238. Epub 2015 Sep 23.
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• [22] Definable somatic disorders in overweight children and adolescents.J Pediatr. 2007 Jun;150(6):618-22, 622.e1-5. doi: 10.1016/j.jpeds.2007.01.042.
• [23] CCDC141 Mutation Identified in Anosmic Hypogonadotropic Hypogonadism (Kallmann Syndrome) Alters GnRH Neuronal Migration.Endocrinology. 2016 May;157(5):1956-66. doi: 10.1210/en.2015-1846. Epub 2016 Mar 25.
• [24] Molecular Xp deletion in a male: suggestion of a locus for hypogonadotropic hypogonadism distal to the glycerol kinase and adrenal hypoplasia loci.Clin Genet. 1989 Jan;35(1):5-12. doi: 10.1111/j.1399-0004.1989.tb02899.x.
• [25] IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty.EMBO Mol Med. 2016 Jun 1;8(6):626-42. doi: 10.15252/emmm.201606250. Print 2016 Jun.
• [26] Copy number variants for schizophrenia and related psychotic disorders in Oceanic Palau: risk and transmission in extended pedigrees.Biol Psychiatry. 2011 Dec 15;70(12):1115-21. doi: 10.1016/j.biopsych.2011.08.009. Epub 2011 Oct 7.
• [27] Negative Association Between Sclerostin and INSL3 in Isolated Human Osteocytes and in Klinefelter Syndrome: New Hints for Testis-Bone Crosstalk.J Clin Endocrinol Metab. 2018 May 1;103(5):2033-2041. doi: 10.1210/jc.2017-02762.
• [28] Neuropsychological profiles of adults with Klinefelter syndrome.J Int Neuropsychol Soc. 2001 May;7(4):446-56. doi: 10.1017/s1355617701744013.
• [29] Identification and characterization of an Xp22.33;Yp11.2 translocation causing a triplication of several genes of the pseudoautosomal region 1 in an XX male patient with severe systemic lupus erythematosus.Arthritis Rheum. 2006 Apr;54(4):1270-8. doi: 10.1002/art.21733.
• [30] LDOC1 Gene Expression in Men With Klinefelter Syndrome.J Clin Lab Anal. 2016 Sep;30(5):408-10. doi: 10.1002/jcla.21870. Epub 2016 Apr 13.
• [31] Next Generation Sequencing expression profiling of mitochondrial subunits in men with Klinefelter syndrome.Int J Med Sci. 2018 Jan 1;15(1):31-35. doi: 10.7150/ijms.21075. eCollection 2018.
• [32] Mutational analysis of the necdin gene in patients with congenital isolated hypogonadotropic hypogonadism.Eur J Endocrinol. 2011 Jul;165(1):145-50. doi: 10.1530/EJE-11-0199. Epub 2011 May 4.
• [33] Hypogonadotropic Hypogonadism and Short Stature in Patients with Diabetes Due to Neurogenin 3 Deficiency.J Clin Endocrinol Metab. 2016 Oct;101(10):3555-3558. doi: 10.1210/jc.2016-2319. Epub 2016 Aug 17.
• [34] Identification of a pituitary ER-activated enhancer triggering the expression of Nr5a1, the earliest gonadotrope lineage-specific transcription factor.Epigenetics Chromatin. 2019 Aug 7;12(1):48. doi: 10.1186/s13072-019-0291-8.
• [35] Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome.Fertil Steril. 2011 Apr;95(5):1613-20.e1-7. doi: 10.1016/j.fertnstert.2011.01.010. Epub 2011 Feb 15.
• [36] PCDH19-related epilepsy in a male with Klinefelter syndrome: Additional evidence supporting PCDH19 cellular interference disease mechanism.Epilepsy Res. 2018 Sep;145:89-92. doi: 10.1016/j.eplepsyres.2018.06.008. Epub 2018 Jun 18.
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• [38] The genetic basis of female reproductive disorders: etiology and clinical testing.Mol Cell Endocrinol. 2013 May 6;370(1-2):138-48. doi: 10.1016/j.mce.2013.02.016. Epub 2013 Mar 14.
• [39] RABGAP1L gene rearrangement resulting from a der(Y)t(Y;1)(q12;q25) in acute myeloid leukemia arising in a child with Klinefelter syndrome.Virchows Arch. 2009 Mar;454(3):311-6. doi: 10.1007/s00428-009-0732-z. Epub 2009 Jan 28.
• [40] Identification and characterization of a novel nuclear structure containing members of the homologous recombination and DNA damage response pathways.Cancer Genet. 2018 Dec;228-229:98-109. doi: 10.1016/j.cancergen.2018.10.003. Epub 2018 Oct 18.
• [41] RNF216 Regulates the Migration of Immortalized GnRH Neurons by Suppressing Beclin1-Mediated Autophagy.Front Endocrinol (Lausanne). 2019 Jan 24;10:12. doi: 10.3389/fendo.2019.00012. eCollection 2019.
• [42] Genetics of human hypogonadotropic hypogonadism.Am J Med Genet. 1999 Dec 29;89(4):240-8. doi: 10.1002/(sici)1096-8628(19991229)89:4<240::aid-ajmg8>3.0.co;2-7.
• [43] Novel genetic aspects of Klinefelter's syndrome.Mol Hum Reprod. 2010 Jun;16(6):386-95. doi: 10.1093/molehr/gaq019. Epub 2010 Mar 12.
• [44] Neurokinin B and its receptor in hypogonadotropic hypogonadism.Front Horm Res. 2010;39:133-141. doi: 10.1159/000312699. Epub 2010 Apr 8.