Prenatal Phenotypic Analysis of Branchio-Oto-Renal Spectrum Disorder Attributable to EYA1 Gene Pathogenic Variants and Systematic Literature Review.

BACKGROUND: Branchio-oto-renal (BOR) spectrum disorders are linked to pathogenic variants in the EYA1 gene, presenting significant challenges for prenatal ultrasound screening due to their phenotypic variability and complexity. Understanding these disorders' phenotypic expressions and genetic foundations is crucial. METHODS: Our study included pregnant women who underwent fetal whole-exome sequencing at the Department of Medical Genetics and Prenatal Diagnosis, The Third Affiliated Hospital of Zhengzhou University, Henan, China between January 2023 and March 2024. We identified a novel EYA1 gene pathogenic variant and conducted a systematic literature review of all reported prenatal cases associated with EYA1-related diseases, focusing on the detectability of these conditions in prenatal ultrasound. Additionally, we systematically reviewed case reports related to the EYA1 gene, emphasizing missense pathogenic variants for functional predictions and locus position analysis. RESULTS: Our research discovered a new pathogenic variant within the EYA1 gene, highlighting the difficulty of detecting BOR spectrum disorder phenotypes through prenatal ultrasound due to their subtle manifestations. We found that amniotic fluid anomalies and cardiac abnormalities are more prevalent in prenatal cases compared to postnatal cases. A critical region within the EYA Homologous Region (eyaHR) was identified, where missense pathogenic variants significantly affect protein stability, indicating a crucial area associated with the severity of phenotypic expression in EYA1 gene-associated disorders. CONCLUSION: This study enhances the understanding of the genetic landscape of BOR spectrum disorders and suggests that certain phenotypic markers and genetic regions may be pivotal in improving prenatal screening and diagnosis for EYA1-related diseases.

[Prenatal diagnosis of a fetus with Rubinstein-Taybi syndrome].

OBJECTIVE: To explore the clinical characteristics and variant of CREBBP gene in a fetus with Rubinstein-Taybi syndrome (RSTS). METHODS: A fetus with RSTS diagnosed at the Third Affiliated Hospital of Zhengzhou University in August 2022 was selected as the study subject. Clinical data, amniotic fluid sample of the fetus and peripheral blood samples of its parents were collected for whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: Foot malformation, cerebellar vermis agenesis, brain agenesis, polysyndactyly of the big toes and other phenotypes were found by prenatal ultrasound. WES revealed that the fetus has harbored a heterozygous c.4684G>T (p.E1562*) variant in exon 28 of the CREBBP gene (NM_004380.3), which was de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic (PVS1+PS2_Moderate+PM2_Supporting). After genetic counseling, the couple had opted to terminate the pregnancy and refused autopsy of the fetus. CONCLUSION: The c.4684G>T (p.E1562*) variant of the CREBBP gene probably underlay the RSTS in this fetus. The newly discovered variant has enriched the mutational spectrum of the CREBBP gene and illustrated that WES is an efficient tool for the prenatal diagnosis of RSTS.

[Prenatal ultrasonographic manifestations and genetic diagnosis of nine fetuses with 7q11.23 duplication syndrome].

OBJECTIVE: To analyze ultrasonographic manifestations and genetic etiology of nine fetuses with 7q11.23 duplication syndrome. METHODS: Ultrasonographic finding, pregnancy outcome and follow-up of nine fetuses detected at the Prenatal Diagnosis Center of the Third Affiliated Hospital of Zhengzhou University from January 2017 to December 2021 were retrospectively analyzed. RESULTS: The fetuses were found to harbor a duplication in the 7q11.23 region by chromosomal microarray analysis (CMA). Among these, five had shown ventriculomegaly, including four syndromic and one non-syndromic. For the remainders, one had ventricular septal defect and mild tricuspid regurgitation, one had echogenic intracardiac focus, whilst another two were normal. Five couples had accepted parental verification, and the results confirmed that the 7q11.23 duplication carried by their fetuses were de novo in origin. Following genetic counseling, seven couples had opted to terminate their pregnancies. Two fetuses were delivered at full term, and follow-up had found no abnormalities. CONCLUSION: Prenatal ultrasonographic manifestations of fetuses with 7q11.23 duplication syndrome are variable. CMA can provide assistance for their diagnosis and genetic counseling.

Genetic variability of human papillomavirus type 51 E6, E7, L1 and L2 genes in Southwest China.

Genetic variations among HR-HPV types lead to altered biological functions with possible clinical significance in different geographical locations. To explore intratype genetic variations of HPV51 E6, E7, L1 and L2 genes originating from Southwest China, a total of 5204 cervical scraped cell samples were collected for DNA extraction and HPV typing. And then the E6, E7, L1 and L2 genes of HPV51 (n = 79) were sequenced and compared to the reference sequence (M62877). The ConSurf server was used for identification of conserved structural and functional amino acids of the E6 and E7 oncogenes, and the changes of the secondary structure were analyzed by PSIPred software. Phylogenetic trees were constructed by the maximum likelihood method implemented in IQ-TREE. The selection pressure acting on the E6, E7, L1 and L2 genes was estimated by Datamonkey web server. 13 nucleotide polymorphism sites were observed in E6-E7 gene and the most common mutation sites were C395T (S100L), C756T (S66L), C796T, A832G. 36 nucleotide polymorphism sites were identified in full length L1 gene and the non-synonymous mutations T6311G, A6312T (V264G), G6313A (G265S) A5674C (I52L), A6335C (N272T), A6586C (T354P) and synonymous mutations A5649T, C6147T, A6435G, G6570A, A6651G, T6774C, A6784C, A6882G, C6918A, and G6984A were the most common mutations. 53 nucleotide variation sites were identified in full-length L2 gene including four insertion sites (4418A, 4670G, 4693A, 4694C) and one deletion site (A4430). Besides, the non-synonymous mutations G4227A (V32I), A4407G (I92V), G4945A (D271N), C4985A (T284K), T5260G (L376V), A5335C (T401P) and the synonymous mutations A4166G, G4229A, G4283A, T4453C, C4566A, T4596C, C4695T, C4830T, G4839A, A5160C, and T5286G were the most common mutations. Specially, a triallelic mutation site (G4461C/A) in L2 was identified, with 26% G4461C (E109D) being non-synonymous mutation. Selective pressure analysis showed that only codon site 66 in E7 and 52 in L1 were the positively selected sites and codon sites 72, 107, 342, 412, 427 were negatively selected sites in L2 gene. Our investigation also suggests that A2 and A4 were the most frequent HPV51 lineage in Southwest China.

Genetic variability and lineage phylogeny of human papillomavirus type 45 based on E6 and E7 genes in Southwest China.

The current study investigated nucleotide variability and phylogeny in high-risk HPV45 collected from Chinese women. Fifty-one samples positive for single infections of HPV45 were collected for DNA extraction and HPV typing. The E6 and E7 genes of HPV45 were sequenced, and then the phylogenetic tree was reconstructed by the maximum likelihood method implemented in IQ-TREE under the HKY nucleotide substitution model. The selection pressures of the E6 and E7 genes were estimated using PAML software. Eleven nucleotide polymorphism sites were observed in the HPV45 E6 sequences, with 6 synonymous (C134T, T163C, A284C, T341C, T482C, A497G) and 5 non-synonymous (A124C, C157T, T162A, G259T, G487A) mutations. Six nucleotide polymorphism sites were observed in the E7 sequences, with 5 non-synonymous (G600A, A603C, A769C, G808T, G832T) and 1 synonymous (A718C) mutation. Our investigation suggests that B2 was the most frequent HPV45 sublineage in Southwest China, followed by A2; no A1 or A3 variants were detected. Selective pressure analysis showed that these mutations could reflect positive selection in HPV45 E6 and E7 genes.

[Idiopathic teratozoospermia is not correlated with c.144delC polymorphism in the AURKC gene in Sichuan].

OBJECTIVE: To investigate the association of a very common mutation of c.144delC in the aurora kinase C (AURKC) gene with idiopathic teratozoospermia in Chinese infertile men in Sichuan. METHODS: Using polymerase chain reaction (PCR) and next-generation sequencing, we analyzed the correlation between c.144delC polymorphism of the AURKC gene and male infertility in 98 idiopathic teratozoospermia patients in comparison with 162 normal fertile men. RESULTS: Neither c.144delC mutation nor other meaningful mutations were detected in the AURKC gene in the 98 idiopathic teratozoospermia patients or the 162 normal controls. CONCLUSIONS: Teratozoospermia is not correlated with c.144delC mutation in the AURKC gene in the men of the Sichuan area. Therefore, large-scale genotyping of the AURKC gene may not be necessary clinically among Chinese patients with idiopathic teratozoospermia.