Whole exome sequencing identified a rare <i>WT1</i> loss‐of‐function variant in a non‐syndromic POI patient

Wang, Yingchen; Chen, Qing; Zhang, Feng; Yang, Xi; Shang, Lingyue; Ren, Shuting; Pan, Yuncheng; Zhou, Zixue; Li, Guoqing; Fang, Yunzheng; Li, Jin; Wu, Yanhua; Zhang, Xiaojin

doi:10.1002/mgg3.1820

Cited by 3 publications

(2 citation statements)

References 56 publications

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“…Modification of genetic pathways, due to loss of function of the above listed genes, at this early stage of human gestation, may lead to DSD (31)(32)(33)(34)(35)(36)(37)(38)(39)(40). In Table 1 we have summarized current understanding on genes involved in genital ridge development and their pathogenetic role in 46,XX individuals.…”

Section: Gonadal Determinationmentioning

confidence: 99%

46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes

Stancampiano,

Meroni,

Bucolo

et al. 2024

Front. Endocrinol.

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The term ‘differences of sex development’ (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, and/or anatomical sex. DSD in individuals with a 46,XX karyotype can occur due to fetal or postnatal exposure to elevated amount of androgens or maldevelopment of internal genitalia. Clinical phenotype could be quite variable and for this reason these conditions could be diagnosed at birth, in newborns with atypical genitalia, but also even later in life, due to progressive virilization during adolescence, or pubertal delay. Understand the physiological development and the molecular bases of gonadal and adrenal structures is crucial to determine the diagnosis and best management and treatment for these patients. The most common cause of DSD in 46,XX newborns is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, determining primary adrenal insufficiency and androgen excess. In this review we will focus on the other rare causes of 46,XX DSD, outside CAH, summarizing the most relevant data on genetic, clinical aspects, puberty and fertility outcomes of these rare diseases.

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Section: Gonadal Determinationmentioning

confidence: 99%

46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes

Stancampiano,

Meroni,

Bucolo

et al. 2024

Front. Endocrinol.

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“…Over 100 genes involved in various pathways and biologic processes have been found to cause POI and largely expanded the genetic aetiology of POI (Franca & Mendonca, 2022). Amongst them, about 20 monogenic variants have been considered to be associated with non‐syndromic POI, such as BMP15 (Di Pasquale et al, 2006), NR5A1 (Jaillard, Sreenivasan, et al, 2020), NOTCH2 (Li et al, 2020), WT1 (Wang et al, 2022) and ERCC6 (Qin, Guo, et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

A novel heterozygous ERCC6 variant identified in a Chinese family with non‐syndromic primary ovarian insufficiency

Kuang

Liu

et al. 2022

Molec Gen & Gen Med

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Background Premature ovarian insufficiency (POI) is a clinical syndrome occurring in women before 40 with decreased ovarian function. Up to 25% of POI cases result from genetic factors that remain largely unknown. The Excision repair cross‐complementing, group 6 (ERCC6) variant has been found to cause POI, which is hardly ever diagnosed in adolescents. Methods Whole‐exome sequencing was performed on a 19‐year‐old proband with non‐syndromic POI and her parents. Sanger sequencing was used to confirm the identified variant. The effect of the variant on the protein was analyzed in silico and Swiss‐MODEL. Results A novel heterozygous missense variant, c.2444G > A (p. GLy815Asp) of ERCC6 was identified in the proband who inherited the variant from her father. The variant was confirmed in another POI patient from the pedigree and was absent in the proband's mother and sister who presented normally. In silico analysis predicted this variant was deleterious. Swiss‐Model revealed that the mutant amino acid formed multiple H‐bonds with adjacent residues, which may lead to a dysfunction of ERCC6 protein. Conclusion We firstly diagnosed an adolescent POI case associated with a novel heterozygous ERCC6 variant. The results expanded the variants spectrum of ERCC6 and provided guidance for POI diagnosis and genetic counselling.

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Whole exome sequencing identified a rare WT1 loss‐of‐function variant in a non‐syndromic POI patient

Wang

Chen

Zhang³

et al. 2021

Molec Gen & Gen Med

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Background Premature ovarian insufficiency (POI) is a highly heterogeneous disease, and up to 25% of cases can be explained by genetic causes. The transcription factor WT1 has long been reported to play a crucial role in ovary function. Wt1‐mutated female mice exhibited POI‐like phenotypes. Methods and Results In this study, whole exome sequencing (WES) was applied to find the cause of POI in Han Chinese women. A nonsense variant in the WT1 gene: NM_024426.6:c.1387C>T(p.R463*) was identified in a non‐syndromic POI woman. The variant is a heterozygous de novo mutation that is very rare in the human population. The son of the patient inherited the mutation and developed Wilms’ tumor and urethral malformation at the age of 7. According to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, the novel variant is categorized as pathogenic. Western blot analysis further demonstrated that the WT1 variant could produce a truncated WT1 isoform in vitro. Conclusions A rare heterozygous nonsense WT1 mutant is associated with non‐syndromic POI and Wilms’ tumor. Our finding characterized another pathogenic WT1 variant, providing insight into genetic counseling.

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Whole exome sequencing identified a rare WT1 loss‐of‐function variant in a non‐syndromic POI patient

Cited by 3 publications

References 56 publications

46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes

46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes

A novel heterozygous ERCC6 variant identified in a Chinese family with non‐syndromic primary ovarian insufficiency

Whole exome sequencing identified a rare WT1 loss‐of‐function variant in a non‐syndromic POI patient

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