Compound heterozygous null mutations of NOBOX in sisters with delayed puberty and primary amenorrhea

Abstract Background Premature ovarian insufficiency (POI) is a heterogeneous clinical syndrome defined by a premature loss of ovarian function that associates menstrual disturbances and hypergonatropic hypogonadism. POI is a major cause of female infertility affecting 1% of women before the age of 4...

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Autores principales:	Asma Sassi, Julie Désir, Sarah Duerinckx, Julie Soblet, Sonia Van Dooren, Maryse Bonduelle, Marc Abramowicz, Anne Delbaere
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	delayed puberty genetics loss of function next generation sequencing NOBOX gene premature ovarian insufficiency Genetics QH426-470
Acceso en línea:	https://doaj.org/article/cec142e45395453dbb8f68fa1f907a89
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spelling	oai:doaj.org-article:cec142e45395453dbb8f68fa1f907a892021-11-10T16:39:23ZCompound heterozygous null mutations of NOBOX in sisters with delayed puberty and primary amenorrhea2324-926910.1002/mgg3.1776https://doaj.org/article/cec142e45395453dbb8f68fa1f907a892021-10-01T00:00:00Zhttps://doi.org/10.1002/mgg3.1776https://doaj.org/toc/2324-9269Abstract Background Premature ovarian insufficiency (POI) is a heterogeneous clinical syndrome defined by a premature loss of ovarian function that associates menstrual disturbances and hypergonatropic hypogonadism. POI is a major cause of female infertility affecting 1% of women before the age of 40 and up to 0.01% before the age of 20. The etiology of POI may be iatrogenic, auto‐immune or genetic but remains however undetermined in a large majority of cases. An underlying genetic etiology has to be searched in idiopathic cases, particularly in the context of a family history of POI. Methods Whole exome sequencing (WES) was performed in trio in a Belgian patient presenting POI and in her two parents. The patient presented delayed puberty and primary amenorrhea with hypergonadotropic hypogonadism. Results WES identified two novel compound heterozygous truncating mutations in the Newborn oogenesis homeobox (NOBOX) gene, c.826C>T (p.(Arg276Ter)) and c.1421del (p.(Gly474AlafsTer76)). Both mutations were confirmed by Sanger sequencing in the proband's sister who presented the same phenotype. Both variants were pathogenic and very likely responsible for the severe POI in this family. Conclusion We report here for the first time compound heterozygous truncating mutations of NOBOX in outbred patients, generalizing biallelic NOBOX null mutations as a cause of severe POI with primary amenorrhea. In addition, our findings also suggest that NOBOX haploinsufficiency is tolerated.Asma SassiJulie DésirSarah DuerinckxJulie SobletSonia Van DoorenMaryse BonduelleMarc AbramowiczAnne DelbaereWileyarticledelayed pubertygeneticsloss of functionnext generation sequencingNOBOX genepremature ovarian insufficiencyGeneticsQH426-470ENMolecular Genetics & Genomic Medicine, Vol 9, Iss 10, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	delayed puberty genetics loss of function next generation sequencing NOBOX gene premature ovarian insufficiency Genetics QH426-470
spellingShingle	delayed puberty genetics loss of function next generation sequencing NOBOX gene premature ovarian insufficiency Genetics QH426-470 Asma Sassi Julie Désir Sarah Duerinckx Julie Soblet Sonia Van Dooren Maryse Bonduelle Marc Abramowicz Anne Delbaere Compound heterozygous null mutations of NOBOX in sisters with delayed puberty and primary amenorrhea
description	Abstract Background Premature ovarian insufficiency (POI) is a heterogeneous clinical syndrome defined by a premature loss of ovarian function that associates menstrual disturbances and hypergonatropic hypogonadism. POI is a major cause of female infertility affecting 1% of women before the age of 40 and up to 0.01% before the age of 20. The etiology of POI may be iatrogenic, auto‐immune or genetic but remains however undetermined in a large majority of cases. An underlying genetic etiology has to be searched in idiopathic cases, particularly in the context of a family history of POI. Methods Whole exome sequencing (WES) was performed in trio in a Belgian patient presenting POI and in her two parents. The patient presented delayed puberty and primary amenorrhea with hypergonadotropic hypogonadism. Results WES identified two novel compound heterozygous truncating mutations in the Newborn oogenesis homeobox (NOBOX) gene, c.826C>T (p.(Arg276Ter)) and c.1421del (p.(Gly474AlafsTer76)). Both mutations were confirmed by Sanger sequencing in the proband's sister who presented the same phenotype. Both variants were pathogenic and very likely responsible for the severe POI in this family. Conclusion We report here for the first time compound heterozygous truncating mutations of NOBOX in outbred patients, generalizing biallelic NOBOX null mutations as a cause of severe POI with primary amenorrhea. In addition, our findings also suggest that NOBOX haploinsufficiency is tolerated.
format	article
author	Asma Sassi Julie Désir Sarah Duerinckx Julie Soblet Sonia Van Dooren Maryse Bonduelle Marc Abramowicz Anne Delbaere
author_facet	Asma Sassi Julie Désir Sarah Duerinckx Julie Soblet Sonia Van Dooren Maryse Bonduelle Marc Abramowicz Anne Delbaere
author_sort	Asma Sassi
title	Compound heterozygous null mutations of NOBOX in sisters with delayed puberty and primary amenorrhea
title_short	Compound heterozygous null mutations of NOBOX in sisters with delayed puberty and primary amenorrhea
title_full	Compound heterozygous null mutations of NOBOX in sisters with delayed puberty and primary amenorrhea
title_fullStr	Compound heterozygous null mutations of NOBOX in sisters with delayed puberty and primary amenorrhea
title_full_unstemmed	Compound heterozygous null mutations of NOBOX in sisters with delayed puberty and primary amenorrhea
title_sort	compound heterozygous null mutations of nobox in sisters with delayed puberty and primary amenorrhea
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/cec142e45395453dbb8f68fa1f907a89
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Compound heterozygous null mutations of NOBOX in sisters with delayed puberty and primary amenorrhea

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