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

BackgroundAlport syndrome, a monogenic kidney disease, is characterized by progressive hemorrhagic nephritis, sensorineural hearing loss, and ocular abnormalities. Mutations in COL4A5 at Xq22 accounts for 80–85% of X-linked Alport syndrome patients. Three couples were referred to our reproductive genetics clinic for prenatal or preconception counseling.MethodsPrenatal diagnoses were performed by amplifying targeted regions of COL4A5. Targeted next-generation sequencing (NGS)-based haplotype analysis or karyomapping was performed in two patients. Pregnancy outcomes in the three patients were collected and analyzed. Published Alport syndrome cases were searched in Pubmed and Embase.ResultsPrenatal diagnoses in two cases showed one fetus harbored the same pathogenic mutation as the proband and the other was healthy. The couple with an affected fetus and the patient with a family history of Alport syndrome chose to take the preimplantation genetic testing (PGT) procedure. One unaffected embryo was transferred to the uterus, and a singleton pregnancy was achieved, respectively. Two patients presented non-nephrotic range proteinuria (<3 g/24 h) during pregnancy and the three cases all delivered at full-term. However, published Alport cases with chronic kidney disease or proteinuria during pregnancy were came with a high rate (75%) of adverse maternal and fetal outcomes.ConclusionThe PGT procedure performed in this study was proven to be practicable and might be expanded to be applied in other monogenic diseases. Moderate or severe renal impairments in Alport syndrome were strongly associated with adverse maternal and fetal outcomes, and baseline proteinuria was a potential predictor for pregnancy outcomes of Alport syndrome as other kidney diseases.

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FC 012PRIMARY KIDNEY DISEASE IMPACTS OUTCOME IN CKD PREGNANCIES: COMPLICATIONS IN COL4A3-5 RELATED DISEASE (ALPORT SYNDROME) VS OTHER CKD PREGNANCIES

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab131.002 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Rozemarijn Snoek ◽

Margriet Gosselink ◽

Liffert Vogt ◽

Margriet De Jong ◽

Agne Cerkauskaite ◽

...

Keyword(s):

Kidney Disease ◽

Pregnancy Outcomes ◽

Alport Syndrome ◽

Low Birthweight ◽

Kidney Diseases ◽

Related Disease ◽

Ckd Stage ◽

Before And After ◽

Stage 1 ◽

Italian Cohort

Abstract Background and Aims Chronic kidney disease (CKD) affects approximately 3% of pregnant women. CKD increases the risk of pregnancy complications such as prematurity, low birthweight and pre-eclampsia. Also, kidney function can deteriorate more quickly due to pregnancy. There is limited knowledge on pregnancy outcomes in specific kidney diseases. The aim of the ALPART network is to study pregnancy outcomes differentiated by CKD aetiology. We have started with COLA3-5 related disease (Alport syndrome), which is one of the most prevalent monogenic kidney diseases. Comparing outcomes in COLA3-5 related disease to pregnancies with other CKD aetiologies allows us to investigate whether this specific diagnosis impacts outcome in CKD pregnancies. Method The ALPART network is an international 15-center network, which aims to include ∼200 COLA3-5 related disease pregnancies. In this intermediary analysis, we present data on 109 pregnancies from 68 women with COLA3-5 related disease. We compared outcomes to a cohort of 457 CKD stage 1-2 patients (a similar CKD stage as our cohort) of diverse aetiology from a 2015 Italian study and 159,924 women from the general Dutch population. Results The main pregnancy and kidney outcomes are presented in Figure 1. Foetal outcomes were better in COLA3-5 pregnancies than in pregnancies of women with CKD stage 1-2 of diverse aetiology. We saw less prematurity (17% vs 36% respectively) and a higher mean birthweight of 3216 ± 663 gram compared to 2768 ± 680 in the Italian cohort. Maternal kidney outcomes should be interpreted with caution (>30% missing data): proteinuria (73%) and hypertension (30%) were more frequent in COLA3-5 pregnancies than the Italian cohort. In the ALPART cohort, 10% developed severe hypertension. Median eGFR was not impacted by pregnancy and decline of eGFR before and after pregnancy were not significantly different between groups. Conclusion Fetal outcomes in pregnancies with COLA3-5 related disease seem to be more favorable than in a cohort with mixed cause of CKD. In this intermediary analysis, proteinuria levels and frequency of new-onset hypertension in pregnancy are higher. There is no significant eGFR loss during pregnancy or increased eGFR deterioration in the long-term. The differences between COLA3-5 and general CKD pregnancies underscore the importance of investigating pregnancy outcomes in specific kidney disease phenotypes to ensure adequate (pre-) pregnancy counselling and care.

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Preimplantation Genetic Testing for Monogenic Kidney Disease

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.03550320 ◽

2020 ◽

Vol 15 (9) ◽

pp. 1279-1286 ◽

Cited By ~ 2

Author(s):

Rozemarijn Snoek ◽

Marijn F. Stokman ◽

Klaske D. Lichtenbelt ◽

Theodora C. van Tilborg ◽

Cindy E. Simcox ◽

...

Keyword(s):

Genetic Testing ◽

Kidney Disease ◽

Polycystic Kidney Disease ◽

Kidney Diseases ◽

Medical Center ◽

Live Birth Rate ◽

Genetic Diagnostics ◽

Adult Onset ◽

Polycystic Kidney ◽

Preimplantation Genetic Testing

Background and objectivesA genetic cause can be identified for an increasing number of pediatric and adult-onset kidney diseases. Preimplantation genetic testing (formerly known as preimplantation genetic diagnostics) is a reproductive technology that helps prospective parents to prevent passing on (a) disease-causing mutation(s) to their offspring. Here, we provide a clinical overview of 25 years of preimplantation genetic testing for monogenic kidney disease in The Netherlands.Design, setting, participants, & measurements This is a retrospective cohort study of couples counseled on preimplantation genetic testing for monogenic kidney disease in the national preimplantation genetic testing expert center (Maastricht University Medical Center+) from January 1995 to June 2019. Statistical analysis was performed through chi-squared tests.ResultsIn total, 98 couples were counseled regarding preimplantation genetic testing, of whom 53% opted for preimplantation genetic testing. The most frequent indications for referral were autosomal dominant polycystic kidney disease (38%), Alport syndrome (26%), and autosomal recessive polycystic kidney disease (9%). Of couples with at least one preimplantation genetic testing cycle with oocyte retrieval, 65% experienced one or more live births of an unaffected child. Of couples counseled, 38% declined preimplantation genetic testing for various personal and technical reasons.ConclusionsReferrals, including for adult-onset disease, have increased steadily over the past decade. Though some couples decline preimplantation genetic testing, in the couples who proceed with at least one preimplantation genetic testing cycle, almost two thirds experienced at least one live birth rate.

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GENETIC KIDNEY DISEASES AS AN UNDERECOGNIZED CAUSE OF CHRONIC KIDNEY DISEASE: THE KEY ROLE OF INTERNATIONAL REGISTRY REPORTS

Clinical Kidney Journal ◽

10.1093/ckj/sfab056 ◽

2021 ◽

Author(s):

Roser Torra ◽

Mónica Furlano ◽

Alberto Ortiz ◽

Elisabet Ars

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Kidney Diseases ◽

Unknown Etiology ◽

Correct Treatment ◽

Monogenic Diseases ◽

High Prevalence ◽

Incorrect Diagnosis ◽

Kidney Replacement Therapy

Abstract Inherited kidney diseases (IKDs) are among the leading causes of early-onset chronic kidney disease (CKD) and are responsible for at least 10–15% of cases of kidney replacement therapy (KRT) in adults. Pediatric nephrologists are very aware of the high prevalence of IKDs among their patients, but this is not the case for adult nephrologists. Recent publications have demonstrated that monogenic diseases account for a significant percentage of adult cases of CKD. A substantial number of these patients have received a non-specific/incorrect diagnosis or a diagnosis of CKD of unknown etiology, which precludes correct treatment, follow-up and genetic counseling. There are a number of reasons why genetic kidney diseases are difficult to diagnose in adulthood: a) adult nephrologists, in general, are not knowledgeable about IKDs, b) existence of atypical phenotypes, c) genetic testing is not universally available, d) family history is not always available or may be negative, e) lack of knowledge of various genotype–phenotype relationships, f) conflicting interpretation of the pathogenicity of many sequence variants.

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MO046NGS PANEL PERFORMANCE IN THE DIAGNOSIS OF HEREDITARY RENAL DISEASE IN SOUTHERN SPAIN

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab080.0018 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

María del Mar Del Águila García ◽

Antonio M Poyatos Andújar ◽

Ana Isabel Morales García ◽

Margarita Martínez Atienza ◽

Susana García Linares ◽

...

Keyword(s):

Kidney Disease ◽

Renal Disease ◽

Polycystic Kidney Disease ◽

Genetic Study ◽

Alport Syndrome ◽

Autosomal Dominant ◽

Kidney Diseases ◽

Polycystic Kidney ◽

Autosomal Dominant Polycystic Kidney ◽

Hereditary Renal Disease

Abstract Background and Aims Hereditary renal disease (HRD) is still underdiagnosed: although we know aspects related to autosomal dominant polycystic kidney disease (ADPKD), we know little about the incidence and prevalence of other entities such as Alport syndrome. Altogether, HRD can represent 15% of individuals undergoing renal replacement therapy (RRT) or could even be higher. The advancement of genetics at the healthcare level let to achieve accurate and early renal diagnoses, as well as the incorporation of genetic counseling to families, all of which will result in better management of the disease in its initial stages and the possibility of offering reproductive options that avoid transmission to offspring. Our objective is to know the performance offered by the implementation of the ERH panel through Next Generation Sequencing (NGS) in our healthcare area. Method Observational-descriptive study of 259 probands (141 men / 118 women), mean age of 46 years (30 pediatric / 123 over 50 years), with chronic kidney disease and suspected hereditary cause attended in the specialized consultation of our centers from October 2018 to October 2020. The DNA extracted from leukocytes obtained by venipuncture was processed with Nephropathies Solution version 3 panel (SOPHiA Genetics) according to the manufacturer's protocol. This panel covers the coding regions and splicing junctions of 44 HRD-related genes such as nephrotic syndromes, polycystic kidney diseases, Bartter syndromes, Alport syndrome, CAKUT or tubulopathies (table 1). The sequencing of the libraries was done in a MiSeq (Illumina Inc), the bioinformatic analysis of the data and annotation of variants was performed using the SOPHiA DDM 5.8.0.3 software, and the revision of variants by consulting the main databases (ClinVar, Exac, HGMD, NCBI, PKD Foundation, LOVD). Results The panel was informative (pathogenic or probably pathogenic) in 80/259 patients (31%) and 56/259 cases (21.66%) of variants of uncertain significance (VSI) were detected. Autosomal dominant polycystic kidney disease accounted for 76.2% of the variants identified (56.2% PKD1, 20% PKD2), following Alport syndrome with 15% and the alterations in the PKHD1 gene associated with renal polycystic disease in its recessive form with about 4% (Figure 1). We have also identified a case of autosomal dominant tubulointerstitial kidney disease associated with the UMOD gene that was not suspected until the genetic study was performed. We highlight that 45% (36/80) of the variants identified as responsible for the renal disease are not yet described. Overall, the most prevalent type of mutation is that which produces displacement in the reading frame or frameshift (Figure 2). Individually, frameshift is the most frequent alteration in PKD1, PKD2 and COL4A5, while for PKHD1, COL4A3 and COL4A4 it is missense. Conclusion Our NGS HRD panel a) offers an adequate diagnostic performance at the healthcare level, with definitive results in 1 out of 3 cases and has also allowed the performance of many carrier studies among family members b) is able of diagnosing the most frequent disease, ADPKD and Alport syndrome, as well as unresolved or poorly characterized cases, and c) opens the horizon for new diagnoses, all without increasing costs by outsourcing services. All this makes the genetic study of renal pathology a useful and efficient strategy. These results encourage us to enhance the resources in this area that we consider to be of strategic value.

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A Comparison of Pregnancy Outcomes in Patients Undergoing Donor Egg Single Embryo Transfers With and Without Preimplantation Genetic Testing

Reproductive Sciences ◽

10.1177/1933719118820474 ◽

2018 ◽

Vol 26 (12) ◽

pp. 1661-1665 ◽

Cited By ~ 6

Author(s):

Alexis K. Masbou ◽

Jenna B. Friedenthal ◽

David H. McCulloh ◽

Caroline McCaffrey ◽

M. Elizabeth Fino ◽

...

Keyword(s):

Genetic Testing ◽

Pregnancy Outcomes ◽

Implantation Rate ◽

Live Birth Rate ◽

Oocyte Donation ◽

Single Embryo Transfer ◽

Freezing Process ◽

Preimplantation Genetic Testing ◽

Comparison Groups ◽

Donor Egg

Two of the many milestone developments in the field of assisted reproduction have been oocyte donation and preimplantation genetic testing for aneuploidy (PGT-A). Because it has been demonstrated that even young women produce a meaningful proportion of aneuploid embryos, screening out such abnormalities could potentially increase the efficacy of donor egg (DE) cycles. In this retrospective cohort study, we investigated the effect of PGT-A on DE cycle outcomes, including implantation rate (IR), spontaneous abortion rate (SABR), and ongoing pregnancy/live birth rate. We used fresh and frozen donor cycles not using PGT-A as comparison groups; all cases involved single embryo transfer. Data analysis revealed that PGT-A did not improve pregnancy outcome metrics in DE cycles, although there was a trend toward decreasing the SABR. There was a significant increase in IR with fresh cycles outperforming all frozen cycles. Overall, these results suggest that the benefits of performing PGT-A on embryos derived from young DEs may be limited and that there is an effect of the freezing process on pregnancy outcomes. These findings may provide useful insights into the science and practice of PGT-A across all of its applications.

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Short Tandem Repeats Used in Preimplantation Genetic Testing of Β-Thalassemia: Genetic Polymorphisms For 15 Linked Loci in the Vietnamese Population

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2019.840 ◽

2019 ◽

Vol 7 (24) ◽

pp. 4383-4388

Author(s):

Dang Tien Truong ◽

Ngo Van Nhat Minh ◽

Dinh Phuong Nhung ◽

Hoang Van Luong ◽

Do Quyet ◽

...

Keyword(s):

At Risk ◽

Genetic Testing ◽

Tandem Repeats ◽

Drop Out ◽

Preimplantation Genetic Testing ◽

Thalassemia Patient ◽

Gene Assay ◽

Monogenic Diseases ◽

Vietnamese Population ◽

Short Tandem

BACKGROUND: β-thalassemia is one of the most common monogenic diseases worldwide. Preimplantation genetic testing (PGT) of β-thalassemia is performed to avoid affected pregnancies has become increasingly popular worldwide. In which, the indirect analysis using short tandem repeat (STRs) linking with HBB gene to detect different β-globin (HBB) gene mutation is a simple, accurate, economical and also provides additional control of contamination and allele-drop-out ADO. AIM: This study established microsatellite markers for PGT of Vietnamese β-thalassemia patient. METHODS: Fifteen (15) STRs gathered from 5 populations were identified by in silico tools within 1 Mb flanking the HBB gene. The multiplex PCR reaction was optimized and performed on 106 DNA samples from at-risk families. RESULTS: After estimating, PIC values were ≥ 0.7 for all markers, with expected heterozygosity and observed heterozygosity values ranged from 0.81 to 0.92 and 0.53 to 0.86, respectively. One hundred percent of individuals had at least seven heterozygous markers and were found to be heterozygous for at least two markers on either side of the HBB gene. The STRs panel was successfully performed on one at-risk family. CONCLUSION: In general, a pentadecaplex marker (all < 1 Mb from the HBB gene) assay was constituted for β-thalassemia PGT on Vietnamese population.

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Do donor oocyte recipients benefit from preimplantation genetic testing for aneuploidy(PGT-A) to improve pregnancy outcomes?

Fertility and Sterility ◽

10.1016/j.fertnstert.2018.07.219 ◽

2018 ◽

Vol 110 (4) ◽

pp. e72-e73

Author(s):

N. Doyle ◽

M. Gainty ◽

J.O. Doyle ◽

M. Levy ◽

A.H. DeCherney ◽

...

Keyword(s):

Genetic Testing ◽

Pregnancy Outcomes ◽

Preimplantation Genetic Testing ◽

Donor Oocyte

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Clinical Genetic Screening in Adult Patients with Kidney Disease

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.15141219 ◽

2020 ◽

Vol 15 (10) ◽

pp. 1497-1510 ◽

Cited By ~ 2

Author(s):

Enrico Cocchi ◽

Jordan Gabriela Nestor ◽

Ali G. Gharavi

Keyword(s):

Genetic Testing ◽

Kidney Disease ◽

Massively Parallel Sequencing ◽

Kidney Diseases ◽

Chromosomal Microarray ◽

Ethical Considerations ◽

Clinical Genetic ◽

Genetic Sequencing ◽

Sequencing Technologies ◽

Potential Benefits

Expanded accessibility of genetic sequencing technologies, such as chromosomal microarray and massively parallel sequencing approaches, is changing the management of hereditary kidney diseases. Genetic causes account for a substantial proportion of pediatric kidney disease cases, and with increased utilization of diagnostic genetic testing in nephrology, they are now also detected at appreciable frequencies in adult populations. Establishing a molecular diagnosis can have many potential benefits for patient care, such as guiding treatment, familial testing, and providing deeper insights on the molecular pathogenesis of kidney diseases. Today, with wider clinical use of genetic testing as part of the diagnostic evaluation, nephrologists have the challenging task of selecting the most suitable genetic test for each patient, and then applying the results into the appropriate clinical contexts. This review is intended to familiarize nephrologists with the various technical, logistical, and ethical considerations accompanying the increasing utilization of genetic testing in nephrology care.

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P0066KIDNEYCODE: A GENETIC TESTING PROGRAM FOR PATIENTS WITH CHRONIC KIDNEY DISEASE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0066 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Prasad Devarajan ◽

Geoffrey Block ◽

Keisha Gibson ◽

Jim McKay ◽

Colin Meyer ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Genetic Testing ◽

Kidney Disease ◽

Exome Sequencing ◽

Polycystic Kidney Disease ◽

Whole Exome Sequencing ◽

Alport Syndrome ◽

Polycystic Kidney ◽

Accuracy And Precision ◽

Whole Exome

Abstract Background and Aims Knowledge about genetic causes of chronic kidney disease (CKD) is one of the key gaps in global kidney research and recent International Society of Nephrology recommendations encourage the adoption of genetic testing to enable a goal of providing precision medicine based on individual risk (1). A recent whole-exome sequencing study showed that genetic inheritance may be responsible for up to 10% of CKD diagnoses, many of which may be previously undiagnosed or mis-diagnosed (2). Continued advances in DNA sequencing technology have made genetic testing, even whole-exome sequencing, applicable to routine clinical diagnoses. In order to test the hypothesis that genetic testing can provide valuable information to increase the accuracy and precision of diagnosis in CKD, we designed a gene panel to prospectively provide genetic testing in a subset of patients with CKD defined by a specific set of inclusion criteria. Method Reata Pharmaceuticals is partnering with Invitae on a program called KidneyCode, which provides no-charge genetic testing to enable diagnosis of three specific rare monogenic causes of CKD: Alport syndrome (AS), autosomal dominant polycystic kidney disease (ADPKD) due to PKD2 mutations, and focal segmental glomerulosclerosis (FSGS), as well as detection of variants in one of the autosomal recessive polycystic kidney disease gene, PKHD1. Invitae’s renal disease panel includes 17 genes (ACTN4, ANLN, CD2AP, COL4A3, COL4A4, COL4A5, CRB2, HNF1A, INF2, LMX1B, MYO1E, NPHS1, NPHS2, PAX2, PKD2, PKHD1, and TRPC6), and its assay includes both full-gene sequencing and intragenic deletion/duplication analysis using next-generation sequencing (NGS). The assay targets the coding exons and flanking 10bp of intronic sequences. Invitae’s method of variant classification uses a systematic process for assessing evidence based on guidelines published by the American College of Medical Genetics (3). Patients in the US at risk for hereditary CKD (eGFR ≤ 90 mL/min/1.73m2 plus hematuria or a family history of CKD) or with a known diagnosis of AS or FSGS are eligible. Family members of those with suspected or known AS or FSGS are also eligible. All participants in the KidneyCode program have access to genetic counseling follow-up at no additional charge. Results In the first five months of the KidneyCode program, 152 genetic tests have been completed. A genetic variant was reported in 87 patients. Of those 87 patients, 67 patients had 75 variants in COL4A3, 4, or 5 genes (34 Pathogenic/Likely Pathogenic (P/LP), 41 Variants of Uncertain Significance (VUS)), 20 patients had 24 variants in genes associated with FSGS (3 P/LP, 21 VUS), 15 patients had 20 variants in PKHD1 (1 P/LP, 19 VUS), and 2 patients had variants in PKD2 (1 P/LP, 1 VUS). Of the 34 patients with Pathogenic or Likely Pathogenic COL4A variants, 19 reported a previous diagnosis of Alport syndrome. Other diagnoses in patients with COL4A mutations included FSGS, thin basement membrane disease, and familial hematuria. Extra-renal manifestations such as hearing loss and eye disease were reported in 7 of the 34 patients with COL4A variants. Conclusion Initial results with the KidneyCode panel demonstrate the utility of NGS and support the hypothesis that combining genetic testing with clinical presentation and medical history can significantly improve accuracy and precision of diagnosis in patients with hereditary CKD.

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In Vitro Fertilisation (IVF) Associated with Preimplantation Genetic Testing for Monogenic Diseases (PGT-M) in a Romanian Carrier Couple for Congenital Disorder of Glycosylation Type Ia (CDG-Ia): A Case Report

Genes ◽

10.3390/genes11060697 ◽

2020 ◽

Vol 11 (6) ◽

pp. 697

Author(s):

Bogdan Doroftei ◽

Loredana Nemtanu ◽

Ovidiu-Dumitru Ilie ◽

Gabriela Simionescu ◽

Iuliu Ivanov ◽

...

Keyword(s):

Genetic Testing ◽

Congenital Disorder ◽

In Vitro Fertilisation ◽

Comparative Genomic Hybridisation ◽

Comparative Genomic ◽

Preimplantation Genetic Testing ◽

Congenital Disorder Of Glycosylation ◽

Monogenic Diseases ◽

Type Ia

Background: Congenital disorder of glycosylation (CDG) is a severe morphogenic and metabolic disorder that affects all of the systems of organs and is caused by a mutation of the gene PMM2, having a mortality rate of 20% during the first months of life. Results: Here we report the outcome of an in vitro fertilisation (IVF) cycle associated with preimplantation genetic testing for monogenic diseases (PGT-M) in a Romanian carrier couple for CDG type Ia with distinct mutations of the PMM2 gene. The embryonic biopsy was performed on day five of the blastocyst stage for six embryos. The amplification of the whole genome had been realized by using the PicoPLEX WGA kit. Using the Array Comparative Genomic Hybridisation technique, we detected both euploid and aneuploid embryos. The identification of the PMM2 mutation on exon 5 and exon 6 was performed for the euploid embryos through Sanger Sequencing with specific primers on ABI 3500. Of the six embryos tested, only three were euploid. One had compound heterozygosity and the remaining two were simple heterozygotes. Conclusion: PGT-M should be strongly considered for optimising embryo selection in partners with single-gene mutations in order to prevent transmission to the offspring.

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