Case Report: Preimplantation Genetic Testing and Pregnancy Outcomes in Women With Alport Syndrome

Shi, Weihui; Ye, Mujin; Chen, Song-Chang; Zhang, Junyu; Chen, Yiyao; Zhou, Zhiyang; Qin, Ning-Xin; Zhou, Xuanyou; Xu, Nai-Xin; Jiang, Zi-Ru; Lin, Jing; Huang, He‐Feng; Xu, Chenming

doi:10.3389/fgene.2021.633003

Cited by 7 publications

(9 citation statements)

References 47 publications

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“…There was a delay in the diagnosis and monitoring of this patient because she did not have routine follow up and care with a nephrologist. Second, she had multiple pregnancies, which in turn can accelerate CKD progression [ 23 ]. Aside from her disease course, patient 1 exhibited the most common symptoms associated with AS, hematuria and proteinuria.…”

Section: Discussion and Conclusionmentioning

confidence: 99%

COL4A4 variant recently identified: lessons learned in variant interpretation—a case report

et al. 2022

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Background Alport syndrome is a hereditary kidney disease characterized by hematuria and proteinuria. Although there have been reports of autosomal dominant COL4A4 variants, this is likely an underdiagnosed condition. Improved access to affordable genetic testing has increased the diagnosis of Alport syndrome. As genetic testing becomes ubiquitous, it is imperative that clinical nephrologists understand the benefits and challenges associated with clinical genetic testing. Case Presentation We present a family of Mexican descent with a heterozygous COL4A4 variant (c.5007delC, ClinVar accession numbers: SCV001580980.2, SCV001993731.1) not previously discussed in detail in the literature. The proband received a biopsy diagnosis suggestive of Fabry disease 18 years after she first developed hematuria and progressed to chronic kidney disease stage III. One year later, the proband was provisionally diagnosed with Alport syndrome after a variant of uncertain significance in the COL4A4 gene was identified following targeted family variant testing of her daughter. Upon review of the medical histories of the proband’s children and niece, all but one had the same variant. Of the four with the variant, three display clinical symptoms of hematuria, and/or proteinuria. The youngest of the four, only months old, has yet to exhibit clinical symptoms. Despite these findings there was a considerable delay in synthesizing this data, as patients were tested in different commercial genetic testing laboratories. Subsequently, understanding this family’s inheritance pattern, family history, and clinical symptoms, as well as the location of the COL4A4 variant resulted in the upgrade of the variant’s classification. Although the classification of this variant varied among different clinical genetic testing laboratories, the consensus was that this variant is likely pathogenic. Conclusions This COL4A4 variant (c.5007delC) not yet discussed in detail in the literature is associated with Alport syndrome. The inheritance pattern is suggestive of autosomal dominant inheritance. This report highlights the intricacies of variant interpretation and classification, the siloed nature of commercial genetic testing laboratories, and the importance of a thorough family history for proper variant interpretation. Additionally, the cases demonstrate the varied clinical presentations of Alport syndrome and suggest the utility of early screening, diagnosis, monitoring, and treatment.

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Section: Discussion and Conclusionmentioning

confidence: 99%

COL4A4 variant recently identified: lessons learned in variant interpretation—a case report

et al. 2022

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“…In our case, the affected mother (II-3) did not have clinically detectable abnormalities, except for microscopic hematuria, even after she had given birth to 2 full-term babies. To date, 33 pregnancies have been reported in 23 women with different types of AS [24-29]. Among the affected women, 22 received a genetic diagnosis of AS, which included 16 women with XLAS, 4 with ARAS, and 2 patients with ADAS.…”

Section: Discussionmentioning

confidence: 99%

“…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. While NGS has been used in clinical practice for PGT-M, to the best of our knowledge, its detailed use for AS has only been described recently [24].…”

Section: Discussionmentioning

confidence: 99%

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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“…Among the 64 couples who had identified the P/LP variants of known kidney disease, the main reasons for their ART requests included abnormal pregnancy (29, 45.3%), birth defect (27, 42.2%) with some overlaps of abnormal pregnancy (8). Only 17 (26.6%) couples had a positive family history of kidney disease (Table 1 and Supplementary Figure 1).…”

Section: Clinical Characteristicsmentioning

confidence: 99%

“…This approach thereby greatly reduces the chance of having a pregnancy affected with the genetic disease. Since the initial practice of PGT in the monogenetic disorders in 1990s (5), it has been extensively employed in the diagnosis of monogenic disease, X-linked disorders, aneuploidy, and chromosomal rearrangements (3,(6)(7)(8)(9)(10). Carrier screening is becoming standard practice for egg and sperm donors and couples seeking assisted reproduction, due to the introduction of target panels that screen for multiple variants in low risk Abbreviations: AD, autosomal dominant; AR, autosomal recessive; ART, assisted reproductive technology; ACMG, the American College of Medical Genetics and Genomics; BPR, biochemical pregnancy rate; CAKUT, congenital anomalies of the kidney and the urinary tract; CKD, chronic kidney disease; CNV, copy number variations; COH, controlled ovarian hyperstimulation; CSA, clinical sequence analyser; E2, estradiol; ECS, expanded carrier screening; ESRD, endstage renal disease; FHB, fetal heartbeat; FETs, frozenembryo transfers; GnRH, gonadotrophic releasing hormone; HGVS, human genome variation society; hCG, human chorionic gonadotropin; ICSI, intracytoplasmic sperm injection; IR, implantation rate; IVF, in vitro fertilization; MII, metaphase II stage; NGS, next-generation sequencing; NS, nephrotic syndrome; NPHP, nephronophthisis; OP/LBR, ongoing pregnancy/live birth rate; PGT, preimplantation genetic testing; PGT-A, PGT for aneuploidies; PGT-SR, PGT for structural rearrangements; PGT-M, preimplantation genetic testing for monogenic disease; PHCG, positive-human chorionic gonadotropin; PKD, polycystic kidney disease; PND, invasive prenatal diagnosis; TE, trophectoderm; SAB, spontaneous abortion; SNP, single nucleotide polymorphism; WES, whole exome sequencing; WGS, whole genome sequencing.…”

Section: Introductionmentioning

confidence: 99%

Combined Preimplantation Genetic Testing for Genetic Kidney Disease: Genetic Risk Identification, Assisted Reproductive Cycle, and Pregnancy Outcome Analysis

Xiao

Shi²,

Rao³

et al. 2022

Front. Med.

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BackgroundGenetic kidney disease is a major cause of morbidity and mortality in neonates and end-stage renal disease (ESRD) in children and adolescents. Genetic diagnosis provides key information for early identification of congenital kidney disease and reproductive risk counseling. Preimplantation genetic testing for monogenic disease (PGT-M) as a reproductive technology helps prospective parents to prevent passing on disease-causing mutations to their offspring.Materials and MethodsA retrospective cohort of couples counseled on PGT who had a risk to given birth to a child with genetic kidney disease or had a history of prenatal fetal kidney and urinary system development abnormalities from 2011 to 2021. Through a combination of simultaneously screening for aneuploidy and monogenic kidney disease, we achieved reproductive genetic intervention.ResultsA total of 64 couples counseled on PGT for monogenic kidney disease in a single reproductive center during the past 10 years, of whom 38 different genetic kidney diseases were identified. The most frequent indications for referral were autosomal recessive disease (54.7%), then autosomal dominant disease (29.7%), and X-linked disease (15.6%). Polycystic kidney disease was the most common diseases counted for 34.4%. After oocyte-retrieval in all of 64 females, a total of 339 embryos were diagnosed and 63 embryos were transferred in succession. Among 61 cycles of frozen-embryo transfer (FET), ongoing pregnancy/live birth rate (OP/LBR) reached 57.38%. The cumulative OP/LBR in our cohort for the 64 couples was 54.69%. In addition, we have carried out expanded carrier screening (ECS) in all the in vitro fertilization (IVF) couples performed PGT covering 7,311 individuals. The carrier frequency of the candidate genes for monogenic kidney diseases accounted for 12.19%.ConclusionOverall, the customization PGT-M plan in our IVF center is pivotal to decreasing the morbidity and implementing reproductive genetic intervention of genetic kidney disease.

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Case Report: Preimplantation Genetic Testing and Pregnancy Outcomes in Women With Alport Syndrome

Cited by 7 publications

References 47 publications

COL4A4 variant recently identified: lessons learned in variant interpretation—a case report

COL4A4 variant recently identified: lessons learned in variant interpretation—a case report

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

Combined Preimplantation Genetic Testing for Genetic Kidney Disease: Genetic Risk Identification, Assisted Reproductive Cycle, and Pregnancy Outcome Analysis

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