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A Xp22.11-p21.3 microdeletion in a three-generation family supports male lethality of POLA1 nullisomy resulting in reduced fertility of female carriers


Begemann, Anaïs; Oneda, Beatrice; Baumer Wolz, Alessandra; Guldimann, Marina; Tutschek, Boris; Rauch, Anita (2022). A Xp22.11-p21.3 microdeletion in a three-generation family supports male lethality of POLA1 nullisomy resulting in reduced fertility of female carriers. European Journal of Medical Genetics, 65(12):104628.

Abstract

POLA1 encodes a subunit of the DNA polymerase alpha, a key enzyme for the initiation of DNA synthesis.

In males, hemizygous hypomorphic variants in POLA1 have been identified as the cause of X-linked pigmentary reticulate disorder (XLPDR) and a novel X-linked neurodevelopmental disorder termed Van Esch-O’Driscoll syndrome (VEODS), while female carriers have been reported to be healthy.
Nullisomy for POLA1 was speculated to be lethal due to its crucial function, while the effect of loss of one allele in females remained unknown. Here, we report on a three-generation family harboring a deletion of POLA1 in females showing subfertility as the only phenotype.
Our findings show that heterozygous deletions or truncating variants in females with skewed X inactivation do not cause VEODS and support the hypothesis of very early embryonic lethality in males with POLA1 nullisomy.

Abstract

POLA1 encodes a subunit of the DNA polymerase alpha, a key enzyme for the initiation of DNA synthesis.

In males, hemizygous hypomorphic variants in POLA1 have been identified as the cause of X-linked pigmentary reticulate disorder (XLPDR) and a novel X-linked neurodevelopmental disorder termed Van Esch-O’Driscoll syndrome (VEODS), while female carriers have been reported to be healthy.
Nullisomy for POLA1 was speculated to be lethal due to its crucial function, while the effect of loss of one allele in females remained unknown. Here, we report on a three-generation family harboring a deletion of POLA1 in females showing subfertility as the only phenotype.
Our findings show that heterozygous deletions or truncating variants in females with skewed X inactivation do not cause VEODS and support the hypothesis of very early embryonic lethality in males with POLA1 nullisomy.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > Institute of Medical Genetics
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Genetics (clinical), Genetics, General Medicine, POLA1, DNA polymerase alpha, Van Esch-O’Driscoll syndrome, fertility, early pregnacy loss
Language:English
Date:1 December 2022
Deposited On:03 Oct 2022 09:44
Last Modified:27 Apr 2024 01:39
Publisher:Elsevier
ISSN:1769-7212
OA Status:Green
Publisher DOI:https://doi.org/10.1016/j.ejmg.2022.104628
PubMed ID:36182037
Project Information:
  • : FunderUniversity of Zurich
  • : Grant IDCRPP Praeclare
  • : Project TitleUniversity of Zurich clinical research priority program praeclare
  • : Project Websitehttps://www.praeclare.uzh.ch/
  • Content: Accepted Version
  • Language: English
  • Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)