Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease.
Journal
The Journal of clinical endocrinology and metabolism
ISSN: 1945-7197
Titre abrégé: J Clin Endocrinol Metab
Pays: United States
ID NLM: 0375362
Informations de publication
Date de publication:
01 08 2019
01 08 2019
Historique:
received:
30
01
2019
accepted:
25
04
2019
pubmed:
2
5
2019
medline:
21
5
2020
entrez:
2
5
2019
Statut:
ppublish
Résumé
Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hypergonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait. To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI. We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity. This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds. ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI.
Identifiants
pubmed: 31042289
pii: 5481942
doi: 10.1210/jc.2019-00248
pmc: PMC6563799
doi:
Substances chimiques
Cell Cycle Proteins
0
DNA-Binding Proteins
0
IGSF10 protein, human
0
Immunoglobulins
0
MND1 protein, human
0
DNA Helicases
EC 3.6.4.-
CHD7 protein, human
EC 3.6.4.12
MCM9 protein, human
EC 3.6.4.12
Minichromosome Maintenance Proteins
EC 3.6.4.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3049-3067Subventions
Organisme : NINDS NIH HHS
ID : R35 NS105078
Pays : United States
Organisme : NHGRI NIH HHS
ID : K08 HG008986
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008307
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
Organisme : NHGRI NIH HHS
ID : U54 HG003273
Pays : United States
Informations de copyright
Copyright © 2019 Endocrine Society.
Références
Curr Opin Obstet Gynecol. 2015 Jun;27(3):167-74
pubmed: 25919233
Cell Rep. 2015 Aug 18;12(7):1169-83
pubmed: 26257172
Am J Hum Genet. 2007 Sep;81(3):576-81
pubmed: 17701902
Am J Hum Genet. 2015 Aug 6;97(2):199-215
pubmed: 26166479
N Engl J Med. 2017 Jan 5;376(1):21-31
pubmed: 27959697
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
PLoS Comput Biol. 2016 May 25;12(5):e1004962
pubmed: 27224906
Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):224-9
pubmed: 16373508
Trends Endocrinol Metab. 2018 Nov;29(11):795-807
pubmed: 30078697
Am J Hum Genet. 2016 Feb 4;98(2):347-57
pubmed: 26805781
Mol Cell Endocrinol. 2015 Aug 15;411:243-57
pubmed: 25960166
ACM Trans Intell Syst Technol. 2016 Oct;8(1):
pubmed: 28344853
Acta Clin Croat. ;55(4):629-635
pubmed: 29117655
Am J Hum Genet. 2016 Oct 6;99(4):831-845
pubmed: 27640307
Nucleic Acids Res. 2017 Feb 28;45(4):1633-1648
pubmed: 27980096
Genet Med. 2018 Dec;20(12):1528-1537
pubmed: 29790871
Nature. 2010 Oct 28;467(7319):1061-73
pubmed: 20981092
J Clin Endocrinol Metab. 2019 Aug 1;104(8):3049-3067
pubmed: 31042289
Fertil Steril. 2007 Nov;88(5):1474-6
pubmed: 17482612
Hum Reprod Update. 2015 Nov-Dec;21(6):787-808
pubmed: 26243799
Development. 2008 Aug;135(15):2627-36
pubmed: 18599511
Proc Natl Acad Sci U S A. 2006 May 23;103(21):8090-5
pubmed: 16690745
BMC Bioinformatics. 2014 Jan 29;15:30
pubmed: 24475911
Endocrinology. 2015 Jan;156(1):334-45
pubmed: 25375035
Genet Mol Res. 2015 Mar 06;14(1):1733-40
pubmed: 25867316
J Assist Reprod Genet. 2019 Jan;36(1):57-64
pubmed: 30276597
PLoS Genet. 2009 Jan;5(1):e1000327
pubmed: 19180184
Nucleic Acids Res. 2014 Jan;42(2):906-17
pubmed: 24150939
Eur J Endocrinol. 2006 May;154(5):739-44
pubmed: 16645022
Fertil Steril. 2007 Jan;87(1):143-6
pubmed: 17156781
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
Mol Cell Biol. 2013 Apr;33(8):1632-44
pubmed: 23401855
Cell. 2011 Sep 30;147(1):32-43
pubmed: 21962505
Curr Protoc Hum Genet. 2014 Apr 24;81:7.23.1-21
pubmed: 24763994
Nucleic Acids Res. 2012 Jul;40(Web Server issue):W452-7
pubmed: 22689647
Int J Womens Health. 2015 Sep 23;7:799-810
pubmed: 26445561
Am J Obstet Gynecol. 1972 May 15;113(2):279
pubmed: 4557013
Nucleic Acids Res. 2010 Jul;38(Web Server issue):W214-20
pubmed: 20576703
Dev Biol. 2011 Feb 15;350(2):311-22
pubmed: 21147087
J Autoimmun. 2018 Jan;86:116-119
pubmed: 28942902
Hum Mol Genet. 2018 Jun 1;27(11):1913-1926
pubmed: 29566152
Reproduction. 2010 Nov;140(5):633-41
pubmed: 20716613
PLoS One. 2012;7(10):e46688
pubmed: 23056405
Circulation. 2012 Jan 17;125(2):241-9
pubmed: 22128224
Hum Genet. 2017 Jun;136(6):665-677
pubmed: 28349240
J Biol Chem. 2008 Feb 29;283(9):5908-17
pubmed: 18086666
Lancet. 1993 Feb 20;341(8843):462-4
pubmed: 8094490
Am J Hum Genet. 2016 Mar 3;98(3):562-570
pubmed: 26942288
Biostatistics. 2004 Oct;5(4):557-72
pubmed: 15475419
J Med Genet. 2015 Jun;52(6):391-9
pubmed: 25873734
Trends Endocrinol Metab. 2002 Apr;13(3):112-8
pubmed: 11893524
Fertil Steril. 2015 Jul;104(1):154-62.e2
pubmed: 25989972
Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463-7
pubmed: 271968
Nat Genet. 2014 Mar;46(3):310-5
pubmed: 24487276
EMBO Mol Med. 2016 Jun 01;8(6):626-42
pubmed: 27137492
Am J Med Genet. 1996 Aug 9;64(2):329-33
pubmed: 8844075
Cell. 2007 Dec 28;131(7):1235-47
pubmed: 18160035
Am J Hum Genet. 2015 Apr 2;96(4):612-22
pubmed: 25817016
Am J Hum Genet. 2014 Jun 5;94(6):915-23
pubmed: 24906020
Hum Mutat. 2015 Oct;36(10):928-30
pubmed: 26220891
Hum Mutat. 2009 May;30(5):804-10
pubmed: 19263482
J Clin Invest. 2015 Nov 2;125(11):4295-304
pubmed: 26485283
Mol Cell Endocrinol. 2007 Jul 15;273(1-2):25-31
pubmed: 17587491
Mol Endocrinol. 2012 Nov;26(11):1868-82
pubmed: 22973050
Endocr Rev. 2009 Oct;30(6):624-712
pubmed: 19776209
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
Nat Methods. 2015 Feb;12(2):115-21
pubmed: 25633503
Cell Mol Life Sci. 2012 Nov;69(22):3819-34
pubmed: 22618246
Hum Mutat. 2015 Apr;36(4):425-31
pubmed: 25684268
Hum Mol Genet. 2009 Jun 15;18(12):2188-203
pubmed: 19324899
Neuron. 2015 Nov 4;88(3):499-513
pubmed: 26539891
Am J Hum Genet. 2008 Jun;82(6):1342-8
pubmed: 18499083
Curr Biol. 2004 May 4;14(9):752-62
pubmed: 15120066
Genome Res. 2018 Aug;28(8):1228-1242
pubmed: 29907612
G3 (Bethesda). 2016 Aug 09;6(8):2273-84
pubmed: 27226163
Ann N Y Acad Sci. 2010 Sep;1205:23-32
pubmed: 20840249
Curr Protoc Hum Genet. 2013 Jan;Chapter 7:Unit7.20
pubmed: 23315928
Genome Res. 2010 Jan;20(1):110-21
pubmed: 19858363
Genet Med. 2016 May;18(5):443-51
pubmed: 26378787
Nucleic Acids Res. 2015 Apr 30;43(8):4055-66
pubmed: 25820426
Hum Reprod. 2014 Feb;29(2):368-79
pubmed: 24324027
Genet Med. 2016 Jul;18(7):678-85
pubmed: 26633545
J Clin Endocrinol Metab. 2015 May;100(5):E808-14
pubmed: 25774885