Novel WEE2 gene variants identified in patients with fertilization failure and female infertility

• Published in: Fertility and sterility Vol. 111; no. 3; pp. 519 - 526
• Main Authors: Zhao, Shuai, Chen, Tailai, Yu, Mengru, Bian, Yuehong, Cao, Yongzhi, Ning, Yunna, Su, Shizhen, Zhang, Jiangtao, Zhao, Shigang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2019
• Subjects: Adult; Case-Control Studies; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; DNA Mutational Analysis - methods; Female; Fertility - genetics; Fertilization; Fertilization in Vitro - adverse effects; Genetic Predisposition to Disease; Heredity; Humans; Infertility, Female - enzymology; Infertility, Female - genetics; Infertility, Female - physiopathology; Infertility, Female - therapy; Mutation; Mutation Rate; novel variants; Pedigree; Phenotype; Pregnancy; pronucleus formation failure; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Risk Factors; Sperm Injections, Intracytoplasmic - adverse effects; Treatment Failure; WEE2; Whole Exome Sequencing; Young Adult; pronucleus formation failure; WEE2; Fertilization; novel variants
• ISSN: 0015-0282; 1556-5653; 1556-5653
• DOI: 10.1016/j.fertnstert.2018.11.018

To determine whether variants in the WEE2 (WEE1 homolog 2, also known as WEE1B) gene, which has been known to function in the formation of pronuclei during fertilization, contribute to fertilization failure. Case-control genetic study. University hospital. Ninety infertile women with repeated cycles of pronucleus formation failure undergoing in vitro fertilization and/or intracytoplasmic sperm injection treatment as well as 200 fertile control women. Genomic DNA was extracted from the peripheral blood. The whole exons of WEE2 were amplified by means of polymerase chain reaction and then Sanger sequencing was performed. Variants analysis of WEE2 gene. We identified five subjects that were subjected to homozygous or compound-heterozygous variants of WEE2: case 1 (from a consanguineous family) with homozygous frameshift variant: c.293_294insCTGAGACACCAGCCCAACC (p.Pro98Pro fsX2); case 2 with homozygous missense variant: c.1576T>G (p.Tyr526Asp); and three cases with compound-heterozygous variants: case 3: c.991C>A (p.His331Asn) and c.1304_1307delCCAA (p.Thr435Met fsX31); case 4: c.341_342 del AA (p.Lys114Asn fsX20) and c.864G>C (p.Gln288His); and case 5: c.1A>G (p.0?) and c.1261G>A (p.Gly421Arg). Besides c.1576T>G (from case 2) and c.864G>C (from case 4), which have been previously reported as rare single nucleotide polymorphisms (SNPs), the other six variants were novel and predicted by software to be deleterious. The parental genotypes of case 1 and case 2 indicated that the detected homozygous variants were inherited in an autosomal recessive mode. All of the detected variants were absent from the control cohort. Novel variants found in WEE2, which is autosomal-recessive inherited, may be related to recurrent pronucleus formation failure and female infertility. Nuevas variantes del gen WEE2 identificadas en pacientes con fallo de fecundación e infertilidad femenina Determinar si las variantes del gen WEE2 (homólogo del gen WEE1, también conocido como WEE1B), al cual se le reconoce un papel en la formación de los pronúcleos durante la fecundación, contribuyen al fallo de fecundación. Estudio genético de casos y controles. Hospital universitario. Noventa mujeres infértiles con ciclos repetidos de fallo de la formación del pronúcleo que sometidas a fecundación in vitro y/o microinyección intracitoplasmática de espermatozoides, así como 200 mujeres fértiles como control. Se extrajo ADN genómico de sangre periférica. Los exones completos de WEE2 se amplificaron mediante reacción en cadena de la polimerasa y luego se realizó la secuenciación de Sanger. Análisis de variantes del gen WEE2. Identificamos cinco sujetos que fueron sometidos a variantes homocigotas o heterocigotas-compuestas de WEE2: caso 1 (de una familia consanguínea) con variante homocigótica de desplazamiento de marco de lectura c.293_294insCTGAGACACCAGCCCAACC (p.Pro98Pro fsX2); caso 2 con variante homocigótica con cambio de sentido: c.1576T> G (p.Tyr526Asp); y tres casos con variantes heterocigotas-compuestas: caso 3: c.991C> A (p.His331Asn) y c.1304_1307delCCAA (p.Thr435Met fsX31); caso 4: c.341_342 del AA (p.Lys114Asn fsX20) y c.864G> C (p.Gln288His); y caso 5: c.1A> G (p.0?) y c.1261G> A (p.Gly421Arg). Aparte de c.1576T> G (del caso 2) y c.864G> C (del caso 4), de los que se había informado previamente como polimorfismos raros de nucleótido único (SNPs), las otras seis variantes eran nuevas y el software predijo que serían deletéreas. Los genotipos parentales del caso 1 y del caso 2 indicaron que las variantes homocigotas detectadas se heredaron de manera autosómica recesiva. Todas las variantes detectadas estaban ausentes en la cohorte de control. Las nuevas variantes encontradas del gen WEE2, que se hereda de manera autosómica recesiva, pueden estar relacionadas con el fracaso recurrente en la formación de los pronúcleos y la infertilidad femenina.