Concerns regarding the potentially causal role of FANCA heterozygous variants in human primary ovarian insufficiency
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LETTER TO THE EDITOR
Concerns regarding the potentially causal role of FANCA heterozygous variants in human primary ovarian insufficiency Abdelkader Heddar1,2 · Micheline Misrahi1,2 Received: 19 May 2020 / Accepted: 20 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
To the Editor, We have read with interest the recent article by Yang et al (2019) that reported two novel FANCA heterozygous variants: c.1772G > A (p.Arg591Gln) and c.3887A > G (p.Glu1296Gly) causing primary ovarian insufficiency (POI) in two unrelated Chinese patients with primary or secondary amenorrhea at the age of 24 years (Yang et al. 2019). No familial segregation studies were performed and we have other several key concerns about a possible causal link between such FANCA heterozygous variants and POI in humans. Fanconi anemia (FA) is a rare and severe life-threatening condition with pancytopenia, multiple malformations and increased risk of malignancies (Auerbach 2009). Patients with FA who have survived to adulthood often develop infertility in both sexes (Giri et al. 2007). However, more surprisingly, recent whole-exome sequencing studies, performed in infertile adults, have highlighted DNA repair or meiosis genes as a major genetic family involved in POI (Table 1). Notably, bi-allelic variants of several FA genes cause isolated POI in women and isolated male infertility as for FANCM (Fouquet et al. 2017; Kasak et al. 2018; Yin et al. 2019), FANCU (Yang et al. 2018) and FANCD2 (BRCA2) (Caburet et al. 2019, 2020). In other cases, the phenotypes of these adult patients corresponded to mild FA-like phenotypes (Weinberg-Shukron et al. 2018; Krausz et al. 2019; Turchetti et al. 2019). Notably infertile male patients with bi-allelic FANCA pathogenic variants have
* Micheline Misrahi [email protected] 1
Faculté de Médecine; Unité de Génétique Moléculaire Des Maladies Métaboliques Et de La Reproduction, APHP Hôpitaux Universitaires Paris-Saclay, Université Paris Saclay, Hôpital Bicêtre, 94275 Le Kremlin‑Bicêtre, France
Université Paris Saclay, UMR‑S 1193, INSERM, Hôpital Paul Brousse, Villejuif, France
2
minor hematological defects and/or other FA traits like mild dysmorphic features, short stature or café au lait spots (Krausz et al. 2019). The mode of transmission is autosomal recessive for most of the meiosis or DNA repair genes (13 out of 16) and notably genes of the Fanconi Anemia pathway (Table 1). For only 2 meiosis or DNA repair genes, a dominant inheritance has been formally demonstrated by familial segregation and also functional in vitro studies (Qin et al. 2015; Zhang et al. 2018). Remarkably, in all these families described worldwide with bi-allelic pathogenic variants of a FA gene, heterozygous carriers (mother or father) were fertile, highlighting the absence of haploinsufficiency even for families with major molecular defects. FANCA is the most commonly mutated gene in FA (60–80% of patients with FA) (Bogliolo et al. 2020). Fivehundred-and-nine (509) pathogenic or likely pathogenic vari
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