Preimplantation genetic testing for a family with usher syndrome through targeted sequencing and haplotype analysis

Luo, Haining; Chen, Chao; Yang, Yun; Zhang, Yinfeng; Yuan, Yuan; Wang, Wanyang; Wu, Renhua; Peng, Zhiyu; Han, Yingyan; Jiang, Lu; Yao, Ruqiang; An, Xiaoying; Zhang, Weiwei; Le, Yanqun; Xiang, Jiale; Yi, Na; Huang, Hui; Li, Wei; Zhang, Yunshan; Sun, Jun

doi:10.1186/s12920-019-0600-x

Cited by 6 publications

(4 citation statements)

References 25 publications

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“…To avoid a misdiagnosis by PGT, prenatal genetic testing or postnatal confirmation has been recommended to confirm the diagnosis by PGT [37, 38]. In our study, prenatal diagnosis of a DNA sample from the amniotic fluid of the pregnancy was consistent with the PGT-M results, and a healthy baby boy was born at 38 gestational weeks.…”

Section: Discussionsupporting

confidence: 71%

Preimplantation Genetic Testing Prevented Intergenerational Transmission of X-Linked Alport Syndrome

Zhang

Yuan

et al. 2021

Kidney Dis

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Background: Alport syndrome (AS) is a hereditary renal basement membrane disease that can lead to end-stage renal disease in young adults. It can be diagnosed by genetic analysis, being mostly caused by mutations in COL4A3, COL4A4, and COL4A5. To date, there is no radical cure for this disease. Objectives: The aim of this study was to avoid the transmission of AS within an affected family by selecting healthy embryos for uterine transfer. The embryos were identified by preimplantation genetic testing for monogenic disorders (PGT-M). Methods: We used next-generation sequencing (NGS) to identify mutations in the proband and his parents. The results of NGS were confirmed by Sanger sequencing. Targeted NGS combined with targeted single-nucleotide polymorphism haplotyping was used for the in vitro identification of COL4A5 mutations in human embryos to prevent their intergenerational transmission. Results: The c.349_359delGGACCTCAAGG and c.360_361insTGC mutations in COL4A5 were identified in a family affected by X-linked AS. Whole-genome sequencing by NGS with targeted haplotyping was performed on biopsied trophectoderm cells. A healthy baby was born after transfer of a single freeze-thawed blastocyst. Conclusions: The use of targeted NGS for identifying diagnostic markers combined with targeted haplotyping is an easy and efficient PGT-M method for preventing intergenerational transmission of AS.

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Section: Discussionsupporting

confidence: 71%

Preimplantation Genetic Testing Prevented Intergenerational Transmission of X-Linked Alport Syndrome

Zhang

Yuan

et al. 2021

Kidney Dis

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“…Sequencing of fetal DNA obtained from amniotic fluid for prenatal diagnosis will be beneficial for this family, as hearing and visual loss in USH1F might not be detected by ultrasonography. Currently, preimplantation genetic testing for monogenic defects (PGT‐M) is available in clinical practice, and embryos diagnosed as free of identified P/LP variants through a customized capture probe targeting the PCDH15 gene and flanking region can be transferred (Luo et al, 2019 ). We believe that WGS‐based PGT‐M will be a reliable and effective diagnostic method in the future (Chen et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Case report: Compound heterozygous nonsense PCDH15 variant and a novel deep‐intronic variant in a Chinese child with profound hearing loss

Yang

Huang

Wei

et al. 2023

Molec Gen & Gen Med

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Background Usher syndrome is a condition characterized by partial or total hearing loss and progressive pigmentary retinopathy. Usher syndrome type 1F is caused by biallelic loss‐of‐function variants in Protocadherin 15 (PCDH15), which encodes the PCDH15 protein that plays an important role in the morphogenesis and cohesion of stereocilium bundles and retinal photoreceptor cell maintenance and function. Methods We report a child with bilateral nonsyndromic sensorineural hearing loss who received an inconclusive diagnosis based on clinical gene panel testing, which identified a paternal heterozygous nonsense variant (NM_033056.4: c.733C>T, p.R245*) in PCDH15. This variant has been described as a founder variant in the Ashkenazi Jewish population. Results A novel deep‐intronic variant (NM_033056.4: c.705+3767_705+3768del) inherited from the patient's mother was identified by trio‐based whole‐genome sequencing (WGS). A minigene splicing assay revealed that c.705+3767_705+3768del results in aberrant retention of 50 or 68 bp of intron 7. Conclusion Our genetic test results provided precise genetic counseling and prenatal diagnosis for this family, and our findings highlight the power of WGS for detecting deep‐intronic variants in patients with undiagnosed rare diseases. Additionally, this case expands the variant spectrum of the PCDH15 gene and our results support the extremely low carrier frequency of c.733C>T in the Chinese population.

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“…However, attitudes towards PND and PGT for non-lethal disorders such as HL vary greatly depending upon the culture, financial status, and religion of the at-risk individuals, as well as government policies. These factors, combined with the complex technical processes, have resulted in fewer PGT cases with HL being reported (Table S1) [9][10][11][12][13][14][15][16][17] than are in cases of another monogenic disease such as Huntington disease, cystic fibrosis, and neurofibromatosis.…”

Section: Introductionmentioning

confidence: 99%

Preimplantation genetic testing for hereditary hearing loss in Chinese population

Huang

Wang

et al. 2023

J Assist Reprod Genet

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Purpose To evaluate the clinical validity of preimplantation genetic testing (PGT) to prevent hereditary hearing loss (HL) in Chinese population. Methods A PGT procedure combining multiple annealing and looping-based amplification cycles (MALBAC) and single-nucleotide polymorphisms (SNPs) linkage analyses with a single low-depth next-generation sequencing run was implemented. Forty-three couples carried pathogenic variants in autosomal recessive non-syndromic HL genes, GJB2 and SLC26A4, and four couples carried pathogenic variants in rare HL genes: KCNQ4, PTPN11, PAX3, and USH2A were enrolled. Results Fifty-four in vitro fertilization (IVF) cycles were implemented, 340 blastocysts were cultured, and 303 (89.1%) of these received a definite diagnosis of a disease-causing variant testing, linkage analysis and chromosome screening. A clinical pregnancy of 38 implanted was achieved, and 34 babies were born with normal hearing. The live birth rate was 61.1%. Conclusions and relevance In both the HL population and in hearing individuals at risk of giving birth to offspring with HL in China, there is a practical need for PGT. The whole genome amplification combined with NGS can simplify the PGT process, and the efficiency of PGT process can be improved by establishing a universal SNP bank of common disease-causing gene in particular regions and nationalities. This PGT procedure was demonstrated to be effective and lead to satisfactory clinical outcomes.

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Preimplantation genetic testing for a family with usher syndrome through targeted sequencing and haplotype analysis

Cited by 6 publications

References 25 publications

Preimplantation Genetic Testing Prevented Intergenerational Transmission of X-Linked Alport Syndrome

Preimplantation Genetic Testing Prevented Intergenerational Transmission of X-Linked Alport Syndrome

Case report: Compound heterozygous nonsense PCDH15 variant and a novel deep‐intronic variant in a Chinese child with profound hearing loss

Preimplantation genetic testing for hereditary hearing loss in Chinese population

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