OBJECTIVES:To describe a cohort of fetuses with abnormal prenatal findings in whom exome sequencing (ES) identified genetic diagnoses that refined prognostic assessment and reduced prognostic uncertainty. METHODS:We retrospectively reviewed all fetal ES studies performed at our center between 2017 and 2025 for structural or biochemical abnormalities. Cases with a definitive molecular diagnosis were identified, and those with predicted mild, isolated, transient, or treatable phenotypes were classified as having comparatively favorable prognostic implications. Clinical findings and expected postnatal outcomes were analyzed. RESULTS:Among 1692 fetuses undergoing ES, a molecular diagnosis was identified in 291 (17%). Of these, five cases (∼2%) were considered reassuring: isolated postaxial polydactyly due to a GLI1 variant; X-linked ichthyosis (STS) in a fetus with low estriol; isolated situs inversus; CFAP52-related situs inversus totalis; and MAGED2-associated transient antenatal Bartter syndrome. In all cases, ES refined prognosis and reduced the likelihood of severe syndromic conditions, enabling clearer counseling. CONCLUSIONS:Beyond detecting severe disorders, ES may help distinguish mild or manageable conditions from complex syndromes. In selected cases, it provides meaningful reassurance, reduces uncertainty, and supports informed prenatal decision-making.

We investigated an atypical form of limb-girdle muscular dystrophy type R3 (LGMDR3) associated with a homozygous synonymous variant in SGCA that significantly expands the recognized clinical phenotype to include prominent cardiac involvement. While LGMDR3, caused by pathogenic variants in SGCA, typically presents as progressive muscle weakness with relatively limited cardiac manifestations, the individuals in our study developed substantial left ventricular dysfunction, arrhythmias, and even life-threatening ventricular tachyarrhythmias. Five consanguineous families, initially evaluated through exome sequencing, showed no conclusive results until a focused genotype-phenotype correlation reanalysis pinpointed a single homozygous synonymous SGCA variant. Despite its location distant from canonical splice sites, this variant disrupted normal mRNA splicing, leading to aberrant transcripts and, presumably, a nonfunctional or structurally altered α-sarcoglycan protein. Cardiac assessments, including echocardiography, Holter monitoring, and cardiac magnetic resonance imaging, revealed a spectrum of findings from mild asymptomatic dysfunction to severe dilated cardiomyopathy and malignant arrhythmias requiring implantable cardioverter-defibrillators. This case broadens current understanding of LGMDR3 and its molecular underpinnings, ultimately guiding more personalized management strategies for affected individuals. It illustrates that thorough and ongoing variant interpretation is crucial, particularly in consanguineous populations where seemingly benign alterations may confer significant phenotypic consequences. By integrating carefully curated genomic data with clinical insights, clinicians can better identify patients at risk, tailor surveillance protocols, and implement timely interventions. In doing so, this discovery not only refines our appreciation of the intricate interplay between genetic variants and their phenotypic manifestations, but also underscores the importance of precision medicine approaches in the evolving landscape of inherited cardiomyopathies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics Committee/IRB of Hadassah Hebrew University Medical Center (approval number 0151-20-HMO) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Limb-girdle muscular dystrophy type R3 (LGMDR3) is caused by pathogenic SGCA variants and typically presents as progressive muscle weakness with limited cardiac manifestations. We investigated five consanguineous families with substantial left ventricular dysfunction, arrhythmias, and life-threatening ventricular tachyarrhythmias. Cardiac assessments, including echocardiography, Holter monitoring, and cardiac magnetic resonance imaging, revealed a spectrum of findings from mild asymptomatic dysfunction to severe dilated cardiomyopathy and malignant arrhythmia requiring implantable cardioverter-defibrillators. Initial evaluation with exome sequencing showed no conclusive results until a genotype-phenotype correlation reanalysis pinpointed a single homozygous synonymous SGCA variant shared by all affected individuals. Despite being distant from canonical splice sites, this variant disrupted normal mRNA splicing, leading to aberrant transcripts and a presumably nonfunctional or structurally altered α-sarcoglycan protein. This study broadens the recognized clinical spectrum of LGMDR3 by revealing significant cardiac involvement and exemplifies how a splice-disrupting synonymous variant, initially classified as likely benign, can underlie a severe cardiac phenotype and merit reclassification. Our findings highlight the importance of integrating genotype-phenotype correlation with functional studies to improve diagnostic accuracy, particularly in underrepresented populations.

Background Neurodevelopmental disorders (NDDs) impact both the development and functioning of the brain and exhibit clinical and genetic variability. RAP and RAB proteins, belonging to the RAS superfamily, are identified as established contributors to NDDs. However, the involvement of SGSM (small G protein signalling modulator), another member of the RAS family, in NDDs has not been previously documented. Methods Proband-only or trio exome sequencing was performed on DNA samples obtained from affected individuals and available family members. The variant prioritisation process focused on identifying rare deleterious variants. International collaboration aided in the identification of additional affected individuals. Results We identified 13 patients from 8 families of Ashkenazi Jewish origin who all carried the same homozygous frameshift variant in SGSM3 gene. The variant was predicted to cause a loss of function, potentially leading to impaired protein structure or function. The variant co-segregated with the disease in all available family members. The affected individuals displayed mild global developmental delay and mild to moderate intellectual disability. Additional prevalent phenotypes observed included hypotonia, behavioural challenges and short stature. Conclusions An Ashkenazi Jewish homozygous founder variant in SGSM3 was discovered in individuals with NDDs and short stature. This finding establishes a connection between another member of the RAS family and NDDs. Additional research is needed to uncover the specific molecular mechanisms by which SGSM3 influences neurodevelopmental processes and the regulation of growth.

PURPOSE:Bilateral pediatric cataract (BPC) is one of the most common causes of childhood visual impairment and blindness worldwide. A significant percentage of pediatric cataracts are caused by genetic alterations. We aim to characterize the set of genes and variants that cause BPC in the Israeli and Palestinian populations and to assess genotype-phenotype correlation. METHODS:Retrospective study in a multidisciplinary center for visual impairment, located in a tertiary medical center. Medical charts of families who underwent genetic counseling because of BPC in a family member were reviewed. Clinical characteristics and genetic tests results were obtained from medical records of affected subjects. RESULTS:Twenty-two families (47 patients) underwent genetic counseling and completed genetic testing. Causative variants were identified in 18/22 (81.8%) of the families, including 3 novel variants. Genetic testing used included mainly panel for congenital cataracts and whole exome sequencing. Eleven families performed genetic testing with the intention of future pregnancy planning. Main causative genes identified were crystalline genes followed by transcription factor genes. BCOR gene variants were associated with persistent fetal vasculature (PFV) cataract in two of three families. CONCLUSIONS:Combined molecular techniques are useful in identifying variants causing pediatric cataracts and showed a high detection rate in our population. BCOR gene variants might be associated with PFV type of cataracts. The study of pathogenic variants may aid in family planning and prevention of pediatric cataracts in future pregnancies. Additionally, in certain cases, it assists in diagnosing non-suspected syndromic types of pediatric cataracts.

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of diseases which cause visual loss due to Mendelian mutations in over 250 genes, making genetic diagnosis challenging and time-consuming. Here, we developed a new tool, CDIP (Cost-effective Deep-sequencing IRD Panel) in which a simultaneous sequencing of common mutations is performed. CDIP is based on simultaneous amplification of 47 amplicons harboring common mutations followed by next-generation sequencing (NGS). Following five rounds of calibration of NGS-based steps, CDIP was used in 740 IRD samples. The analysis revealed 151 mutations in 131 index cases. In 54 (7%) of these cases, CDIP identified the genetic cause of disease (the remaining were single-heterozygous recessive mutations). These include a patient that was clinically diagnosed with retinoschisis and found to be homozygous for NR2E3-c.932G>A (p.R311Q), and a patient with RP who is hemizygous for an RPGR variant, c.292C>A (p.H98N), which was not included in the analysis but is located in proximity to one of these mutations. CDIP is a cost-effective deep sequencing panel for simultaneous detection of common founder mutations. This protocol can be implemented for additional populations as well as additional inherited diseases, and mainly in populations with strong founder effects.

The yield of chromosomal microarray analysis (CMA) is well established in structurally normal fetuses (0.4–1.4%). We aimed to determine the incremental yield of exome sequencing (ES) in this population. From February 2017 to April 2022, 1,526 fetuses were subjected to ES; 482 of them were structurally normal (31.6%). Only pathogenic and likely pathogenic (P/LP) variants, per the American College of Medical Genetics and Genomics (ACMG) classification, were reported. Additionally, ACMG secondary findings relevant to childhood were reported. Four fetuses (4/482; 0.8%) had P/LP variants indicating a moderate to severe disease in ATP7B, NR2E3 , SPRED1 and FGFR3 , causing Wilson disease, Enhanced S-cone syndrome, Legius and Muenke syndromes, respectively. Two fetuses had secondary findings, in RET and DSP . Our data suggest that offering only CMA for structurally normal fetuses may provide false reassurance. Prenatal ES mandates restrictive analysis and careful management combined with pre and post-test genetic counseling.

Inherited eye diseases (IED) are among the most common causes for childhood and young adulthood blindness in developed countries. Genetic counseling and testing have become an essential part of caregiving for families affected by one of these severe ocular pathologies. The objective of our study is to describe our experience during the 2020 (COVID-19) pandemic, following a practice protocol of safe genetic counseling for inherited ophthalmic diseases. We conducted a review of the genetic counseling practices from January until December 2020 in a multidisciplinary clinic for patients with visual impairment, in a tertiary hospital. The new protocol covered patient screening, required personal protective equipment, and the implementation of telemedicine. One hundred and eighty-three counseling sessions were done in this period of time; 33/183 were telemedicine counseling. The results of this study indicate that the practice of genetic counseling in regard to inherited eye diseases in the era of COVID-19 is effective and safe. Despite the high risk of infectivity that threatened healthcare professionals, safety measures adopted to reduce the risk of infection allowed us to prevent the cancelation of routine counseling, while keeping patient care our priority. The use of telemedicine was a very useful tool for providing counseling during lockdown periods in 2020.

OBJECTIVE:To examine the choices of women with both high-risk and low-risk pregnancies who are undergoing prenatal chromosomal microarray analysis in a clinical setting regarding three challenging types of findings: variants of uncertain clinical significance, susceptibility loci for neurodevelopmental disorders, and copy number variants associated with risks for adult-onset conditions. We assessed whether women's choices were associated with indications for testing or with one-on-one pretest genetic counseling.METHODS:In this cross-sectional study, medical records of women who underwent invasive prenatal chromosomal microarray analysis testing (N=1,070) at Hadassah Medical Center between June 2017 and February 2018 were examined for testing indications, choices regarding chromosomal microarray analysis findings, and type of pretest genetic counseling. Multivariable analyses to assess associations with testing indication and prior genetic counseling were carried out using logistic regression models.RESULTS:In total, 56% of women (n=593) chose to be informed of all three types of findings and 20% (n=218) chose not to be informed of any of the findings beyond high-penetrance childhood-onset pathogenic findings. Variants of uncertain clinical significance as a single choice was the least-selected finding (2.5%, n=27). Low-risk pregnancies (ie, those with normal biochemical screening and fetal ultrasound examinations) were associated with increased interest in receiving genetic information about adult-onset conditions (adjusted odds ratio [aOR] 1.7; 95% CI 1.18-2.33) and susceptibility loci (aOR 1.5; 95% CI 1.08-2.10).CONCLUSION:Women with both high-risk and low-risk pregnancies were generally more likely to choose to receive additional genetic information, albeit differences in preferences depend on testing indication and type of pretest counseling.

ABSTRACTObjectiveChromosomal microarray analysis (CMA) is the modality of choice for prenatal diagnosis in pregnancy with fetal malformation, as it has a high diagnostic yield for microdeletion/duplication syndromes. The aim of this study was to demonstrate the additional utility of single‐nucleotide polymorphism (SNP)‐based CMA in diagnosing monogenic diseases, imprinting disorders and uniparental disomy (UPD).MethodsCMA was performed using Affymetrix CytoScan array, for all indications in 6995 pregnancies, at a tertiary referral hospital from November 2013 to June 2018. We describe four cases that had a CMA result that provided a more comprehensive understanding of the complex genetic mechanisms underlying the clinical presentation.ResultsIn the first fetus, CMA was performed due to intrauterine growth restriction and revealed a 75 kbp maternally inherited microdeletion encompassing the Bloom syndrome gene (BLM). A diagnosis of Bloom syndrome was made upon identifying a paternally inherited common Ashkenazi founder mutation. In the second case, CMA was performed due to severely abnormal maternal serum analytes and revealed a deletion in 14q32.2q32.31 on the maternally inherited copy, leading to a diagnosis of Kagami–Ogata syndrome, which is an imprinting disorder. In the third case, amniocentesis was performed because of late‐onset fetal macrosomia and mild polyhydramnios. CMA detected a deletion encompassing the locus of Prader–Willi/Angelman syndrome. In the fourth case, amniocentesis was performed due to maternal cytomegalovirus seroconversion. Maternal UPD of the entire long arm of chromosome 11 was detected.ConclusionPrenatal CMA, based on oligo and SNP platforms, increases the diagnostic yield and enables a wider spectrum of disorders to be detected through the identification of complex genetic etiologies beyond only copy number variants. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

ABSTRACTObjectiveTo explore the indications for and diagnostic outcomes of fetal exome sequencing in a tertiary referral center.MethodsBetween 2012 and 2017, 77 unrelated fetal samples from pregnancies referred to our center underwent exome sequencing. The cohort included 37 fetuses, 36 products of conception (from cases of pregnancy termination or intrauterine fetal death), one case with DNA from both the fetus and a previous termination of pregnancy, and three cases with DNA of unknown origin. Exome sequencing was performed on DNA extracted from amniocytes or fetal tissue and, in some cases, from parental peripheral blood. Indications, turnaround time, diagnostic rates and pregnancy outcomes were investigated. Diagnostic yield was analyzed according to consanguinity (yes or no), sample type (proband only, or trio or other) and referral indication (malformation or isolated nuchal translucency (NT)).ResultsThe most common indication for fetal exome sequencing was multiple malformations (21/77, 27%), followed by isolated brain malformation (15/77, 19%). Twelve (16%) fetuses were referred for isolated increased NT. Exome analysis was diagnostic for 16 fetuses (21%); when subclassified into fetal malformations vs isolated increased NT it became clear that exome analysis did not reveal any known or probable pathogenic variants in cases referred for isolated increased NT, whereas, among the remaining fetuses, a molecular diagnosis was reached in 16/65 (25%). Proband‐only cases received a diagnosis more often than did cases that had trio exome sequencing.ConclusionsExome sequencing has the potential to provide molecular diagnoses in cases in which conventional prenatal cytogenetic testing is negative. Referral bias of consanguineous cases could account for the high diagnostic rate of proband‐only sequencing. Syndrome‐specific prognostic information enables parents to make informed decisions, whereas challenges include time limitations and variant interpretation in the setting of non‐specific fetal findings. As we report only established disease–gene associations, further segregation and functional studies in a research setting are expected to increase significantly the diagnostic yield. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

The traditional timing for amniocentesis is between 17-23 weeks of pregnancy. This timing enables decisions related to the pregnancy to be made before viability. Less frequently, third trimester amniocentesis is performed. Advanced genomic technologies introduce far more detailed information about the fetus compared to traditional G-banded chromosomal analysis. Not much is known about the indications, safety and CMA yield of this procedure. We aimed to assess the indications for late amniocentesis, safety, genetic test results (especially chromosomal microarray) and pregnancy outcome. The medical records regarding all late amniocentesis procedures performed at gestational age 24+0 to 38+6 weeks, during the period June 2013 to March 2017, were included. The indications for the procedure, any complications, CMA results and pregnancy outcome were recorded and analysed. 291 women (303 fetuses, 277 singleton pregnancies, 10 twin pregnancies) underwent late amniocentesis during the study period. CMA was performed for all indications. Main indication was abnormal sonographic finding/s (204/303 fetuses, 67%). Preterm delivery rate was 2% and 5.3% within one week and one month from the procedure, respectively. Nine fetuses were diagnosed with aneuploidy (3%) and another nine had a pathogenic copy number variation (3%) suggesting that CMA doubled the diagnostic yield of chromosomal analysis. Maximal diagnostic yield (17.5%) was achieved for the sub-group of fetuses with sonographic findings in two or more organ systems. Variants of uncertain significance and copy number variations of susceptibility loci were found in another 10 (3.3%) fetuses. The increased detection rates and shorter turnaround time of CMA may make late amniocentesis a helpful tool for detecting abnormalities or reassuring parents following late appearing abnormal sonographic findings. However, CMA may also create uncertainties for which the couple should be prepared. The procedure appears to be safe. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

To explore the indications and diagnostic outcomes of fetal exome sequencing analyses performed in a single referral centre. 77 unrelated fetal samples underwent exome sequencing between 2012 and 2017. Indications, turnaround time, diagnostic rates, and pregnancy outcomes were analysed. The pregnant women were assessed at average gestational age of 23.6 ± 2.9 (range 14-36) weeks. Average time from sample submission to initial result decreased with time, and in 2017 averaged 25.8 ± 7.2 days. The most common indication for fetal exome sequencing was multiple malformations (21/77, 27%), followed by isolated brain malformations (15/77, 19%). Twelve fetuses (15%) were referred for isolated increased nuchal translucency (IINT). Exome analysis was diagnostic for 16 fetuses. A comparison of cases of fetal malformations vs. IINT showed that exome analysis did not reveal any known or probable pathogenic variants in IINT cases, whereas among fetuses with anatomic malformation, a molecular diagnosis was reached in 16/65 (25%). Proband-only cases received a diagnosis more often than trio exomes. Exome sequencing has the potential to provide molecular diagnoses in cases where conventional prenatal cytogenetic testing is negative. A referral bias of consanguineous cases could account for the high diagnostic rate for proband-only sequencing. Syndrome-specific prognostic information enables parents to make informed decisions, whereas challenges include time limitations and variant interpretation in the setting of non-specific fetal findings. As we report only established disease-gene associations, further segregation and functional studies in a research setting are expected to significantly increase the diagnostic yield.

Hereditary cancer comprises more than 10% of all breast cancer cases. Identification of germinal mutations enables the initiation of a preventive program that can include early detection or preventive treatment and may also have a major impact on cancer therapy. Several recurrent mutations were identified in the BRCA1/2 genes in Jewish populations however, in other ethnic groups in Israel, no recurrent mutations were identified to date. Our group established panel sequencing in cancer patients to identify recurrent, founder, and new mutations in the heterogeneous and diverse populations in Israel, We evaluated five breast cancer patients of Arab descent diagnosed with cancer before the age of 50 years and identified the previously described TP53 mutation, c.541C>T, R181C (rs587782596), in two women from unrelated Arab families. The two probands were diagnosed with breast cancer at a young age (27 and 34 years) and had significant family history spanning a wide range of tumors (breast cancer (BC), papillary thyroid cancer, glioblastoma multiform (GBM), colon cancer and leukemia). The R181C variant is expected to disrupt p53 at the ASPP2 binding domain but not the DNA binding domain and is defined by Clinvar as likely pathogenic and in HGMD as disease mutation. We further tested 85 unrelated Arab cancer patients and father of a BC carrier patient for TP53 c.541C>T using a real time polymerase chain reaction (RT-PCR) approach and identified four additional carriers, two with BC one with lung cancer, and the father of a BC carrier patient, diagnosed with GBM. Another carrier suffering from BC was identified using a Myriad panel, suggesting a recurrent mutation in this population with a frequency of 5/42 (11.9%) of our selected BC patients. We suggest testing Arab women with a breast cancer at a young age, Arab patients with multiple malignancies, or with suggestive family history for TP53 c.541C>T.

What's Already Known About This Topic? Zellweger syndrome is a severe autosomal recessive disease rarely diagnosed prenatally. What Does This Study Add? This is the first report of nystagmus diagnosed on prenatal ultrasound and the first report on fetal ocular abnormalities associated with Zellweger syndrome.

Retinoblastoma (Rb) is a childhood tumor (~1 in 20,000 live births) developing in the retina due to mutations in the RB1 gene. Identification of the oncogenic mutations in the RB1 gene is important for the clinical management and for genetic counseling to families with a child or a parent affected with the tumor. Here we present our experience in detecting the pathogenic mutations in blood samples, from 150 unrelated Rb patients and highlight the relevant counseling issues. Mutation screening in the RB1 gene was based on Sanger sequencing, mosaicism of recurrent CpG transition mutations was detected by allele specific PCR and multiplex ligation dependent probe amplification for detecting of large deletions/duplications. The overall detection rate of mutations in our cohort was 55 % (82/150). In the familial cases it was 100 % (17/17), in bilateral and unilateral-multifocal sporadic cases 91 % (50/55), and in the unilateral sporadic cases 19 % (15/78). Nonsense mutations and small deletions or insertions that results in transcripts with premature termination codons that are subject to nonsense mediated decay were the most frequent, detected in 50/82 (61 %) of the patients. The rest were large deletions detected in 14/82 (17 %), splice site mutations detected in 11/82 (13 %), missense mutations in four patients and mutations in the promoter sequence in three patients. Mutation mosaicism ranging from 10 to 30 % was detected by allele specific PCR in ten patients, 9 % (5/55) of patients with bilateral tumor and 33 % (5/15) of the patients with unilateral tumor. In three patients rare variants were detected as the only finding which was also detected in other healthy family members. Allele specific amplification of recurrent mutations raises in our cohort the identification rate from 82 to 91 % in the sporadic bilateral cases and from 13 to 19 % in the unilateral sporadic cases. Most mosaic cases could not be identified by Sanger sequencing and therefore screening for recurrent CpG transition mutations by allele specific amplification is of utmost importance. Molecular screening is important for the genetic counseling regarding the risk for tumor development and the relevance for prenatal diagnosis but in several families is accompanied by detecting rare variants that might be rare polymorphisms or low penetrant mutations.

Founder mutations in BRCA1/2 genes have been detected in several Jewish communities in Israel, including in Ashkenazi Jews and Jews who immigrated to Israel from Iraq, Yemen, Iran and Afghanistan. We analyzed DNA samples of patients of Sephardic origin (descendents of Jews from the Iberian Peninsula) with breast cancer (BC) and/or ovarian cancer (OC) and additional family history of these cancers. In this study we identified 2 mutations: p.A1708E in BRCA1 and c.67 + 1G > A (IVS2 + 1G > A) in BRCA2, each in 3 unrelated patients. The frequency of the two mutations was 26–31% among Sephardic high risk families and about 3% among the full cohort of 177 patients of this origin who were tested in our center. Based on haplotype analysis we concluded that these mutations are most probably founder mutations in Sephardic Jews. We recommend testing the two mutations in women of Sephardic origin who apply for BRCA testing because of personal and/or family history of BC and/or OC. Furthermore, we suggest adding them to the 5 mutations included in “The Jewish panel” of BRCA1/2 mutations that are being tested in Israel.

Objective To describe our 2-year experience with preimplantation genetic diagnosis (PGD) for carriers of mutations in the genes BRCA1 and BRCA2, the dilemmas incurred and the lessons learned.Methods We collected data on those carriers of BRCA1/2 mutations who applied for PGD counseling and who decided to proceed. We describe the PGD procedures that were conducted and their outcome.Results Tell carriers of BRCA1/2 Mutations applied for PGD counseling. seven were healthy, and three were BC survivors. Eight women needed in vitro fertilization (IVF) because of coexisting infertility. After counseling, six opted for the procedure and five Of them underwent PGD for the BRCA Mutation. In one of these PGD, fluorescence in situ hybridization (FISH) analysis for chromosomes 21, X and Y was also performed. Three women conceived, each in the first treatment attempt. One of them gave birth to twins. the second to a singleton and the third is currently pregnant. During the pregnancies, dilemmas concerning PGD confirmation were discussed.Conclusions PGD is an acceptable reproductive Option for BRCA Mutation carriers, especially for those who require IVF due to fertility problems. Discussion of this option should be carried out with sensitivity, taking into account the age of the woman, her health, fertility status and emotional state. Confirmatory prenatal diagnosis may not always he encouraged. Copyright (C) 2009 John Wiley & Sons, Ltd.