Expanded targeted preconception screening panel in Israel: findings and insights.

BACKGROUND: We aimed to analyse the efficacy and added value of a targeted Israeli expanded carrier screening panel (IL-ECSP), beyond the first-tier test covered by the Israeli Ministry of Health (IMOH) and the second-tier covered by the Health Maintenance Organisations (HMOs). METHODS: A curated variant-based IL-ECSP, tailored to the uniquely diverse Israeli population, was offered at two tertiary hospitals and a major genetics laboratory. The panel includes 1487 variants in 357 autosomal recessive and X-linked genes. RESULTS: We analysed 10 115 Israeli samples during an 18-month period. Of these, 6036 (59.7%) were tested as couples and 4079 (40.3%) were singles. Carriers were most frequently identified with mutations in the following genes: GJB2/GJB6 (1:22 allele frequency), CFTR (1:28), GBA (1:34), TYR (1:39), PAH (1:50), SMN1 (1:52) and HEXA (1:56). Of 3018 couples tested, 753 (25%) had no findings, in 1464 (48.5%) only one partner was a carrier, and in 733 (24.3%) both were carriers of different diseases. We identified 79 (2.6%) at-risk couples, where both partners are carriers of the same autosomal recessive condition, or the female carries an X-linked disease. Importantly, 48.1% of these would not have been detected by ethnically-based screening tests currently provided by the IMOH and HMOs, for example, variants in GBA, TYR, PAH and GJB2/GJB6. CONCLUSION: This is the largest cohort of targeted ECSP testing, tailored to the diverse Israeli population. The IL-ECSP expands the identification of couples at risk and empowers their reproductive choices. We recommend endorsing an expanded targeted panel to the National Genetic Carrier Screening programme.

Amniocentesis in pregnancies at or beyond 24 weeks: An international multicenter study.

BACKGROUND: Amniocentesis for genetic diagnosis is most commonly done between 15 and 22 weeks of gestation, but can be performed at later gestational ages. The safety and genetic diagnostic accuracy of amniocentesis have been well-established through numerous large-scale, multicenter studies for procedures before 24 weeks, but comprehensive data on late amniocentesis remain sparse. OBJECTIVES: To evaluate the indications, diagnostic yield, safety, and maternal and fetal outcomes associated with amniocentesis performed at or beyond 24 weeks of gestation. STUDY DESIGN: We conducted an international, multicenter retrospective cohort study examining pregnant individuals who underwent amniocentesis for prenatal diagnostic testing at gestational ages between 24w0d and 36w6d. The study, spanning from 2011 to 2022, involved nine referral centers. We included singleton or twin pregnancies with documented outcomes, excluding cases where other invasive procedures were performed during pregnancy or if amniocentesis was conducted for obstetric indications. We analyzed indications for late amniocentesis, types of genetic tests performed, their results, and the diagnostic yield, along with pregnancy outcomes and post-procedure complications. RESULTS: Of the 752 pregnant individuals included in our study, late amniocentesis was primarily performed for the prenatal diagnosis of structural anomalies (91.6%), followed by suspected fetal infection (2.3%) and high-risk findings from cell-free DNA screening (1.9%). The median gestational age at the time of the procedure was 28w5d, and 98.3% of pregnant individuals received results of genetic testing before birth or pregnancy termination. The diagnostic yield was 22.9%, and a diagnosis was made 2.4 times more often for fetuses with anomalies in multiple organ systems (36.4%) compared to those with anomalies in a single organ system (15.3%). Additionally, the diagnostic yield varied depending on the specific organ system involved, with the highest yield for musculoskeletal anomalies (36.7%) and hydrops fetalis (36.4%) when a single organ system or entity was affected. The most prevalent genetic diagnoses were aneuploidies (46.8%), followed by copy number variants (26.3%) and monogenic disorders (22.2%). The median gestational age at delivery was 38w3d, with an average of 59 days between the procedure and delivery date. The overall complication rate within two weeks post-procedure was 1.2%. We found no significant difference in the rate of preterm delivery between pregnant individuals undergoing amniocentesis between 24-28 weeks and those between 28-32 weeks, reinforcing the procedure's safety across these gestational periods. CONCLUSIONS: Late amniocentesis, at or after 24 weeks gestation, especially for pregnancies complicated by multiple congenital anomalies, has a high diagnostic yield and a low complication rate, underscoring its clinical utility. It provides pregnant individuals and their providers with a comprehensive diagnostic evaluation and results before delivery, enabling informed counseling and optimized perinatal and neonatal care planning.

Female fragile X premutation carriers are at increased risk for metabolic syndrome from early adulthood.

BACKGROUND AND AIMS: Women with primary ovarian insufficiency exhibit an unfavorable cardiovascular risk profile. A common cause for primary ovarian insufficiency is fragile X premutation (FXPC), and data on the cardiovascular risk factors in women with FXPC are scarce. We aimed to assess the prevalences of abnormal metabolic components among FXPC. METHODS AND RESULTS: Clinical, anthropometric and laboratory data were collected from 71 women with FXPC and compared to 78 women referred for counseling in an in-vitro fertilization clinic (control group). The mean ± SD ages of the FXPC and control groups were 33.5 ± 5.6 and 36.2 ± 5.3 years, respectively (p = 0.003). In a logistic regression analysis, the FXPC group had increased risks for hyperglycemia, hypertriglyceridemia, central obesity and low high-density lipoprotein cholesterol, of 21.8-fold (95% CI 2.7-175, p = 0.004), 6.9-fold (95% CI 2.5-18.7, p < 0.0001), 3.1-fold (95% CI 1.4-6.9, p = 0.005) and 2.4-fold (95% CI 1.1-5.2, p = 0.03), compared to the control group. The FXPC group had 2.7-fold higher prevalence of two abnormal metabolic components; 19% met the full criteria of MetS, compared to 3% of the control group. Neither CGG repeats nor ovarian reserve markers were associated with metabolic risk. CONCLUSIONS: Carriers of fragile X premutation are at increased metabolic risk from early adulthood; waist circumference, glucose and lipid levels are particularly elevated. We recommend metabolic screening for all women with FMR1 premutation, to enable early interventions for prevention of long-term cardiovascular comorbidities.

Ethnicity has a multiplex impact upon the risk of a full mutation expansion among female heterozygotes for FMR1 premutation.

PURPOSE: To evaluate whether ethnicity affects the risk of full mutation expansion among females heterozygous for FMR1 premutation. METHODS: Women who carry the FMR1 premutation alelle of Jewish origin who underwent fragile X prenatal diagnosis between 2011 and 2018 in two medical centers in Israel were included. The heterozygote women and fetuses were analyzed for the number of CGG repeats and AGG interruptions. RESULTS: Seven hundred sixty-six subjects were included. Parental ethnicity was fully concordant in 592 cases (Jewish, Ashkenazi, and non-Ashkenazi). Ashkenazi compared with non-Ashkenazi heterozygotes have a significantly higher mean number of CGG repeats (68 ± 8.7, 64 ± 6.4 respectively, P = 0.03) and a lower mean number of AGG interruptions (0.89 ± 0.83, 1.60 ± 1.18 respectively, p = 0.0001). Overall, 56/198 (28.2%) fetuses of Ashkenazi heterozygotes had an expansion to a full mutation compared with 6/98 among the non-Ashkenazi (6.1%) (p = 0.001). Multivariate analysis demonstrated that, in addition to CGG repeats and AGG interruptions (which contributed 68.3% of variance), ethnicity is an independent risk factor for a full mutation expansion (odds ratio [OR] = 2.04, p < 0.001) and accounted for 9% of the variation of a full mutation expansion. CONCLUSION: Apart from significant differences regarding the number of CGG repeats and AGG interruptions between Ashkenazi and non-Ashkenazi heterozygotes, ethnicity independently affects the risk of a full mutation.

Abnormal nuchal translucency followed by normal microarray analysis is associated with placental pathology-related complications.

OBJECTIVE: Identify placental pathology-related complications, labor and neonatal outcomes in pregnancies complicated by pathological nuchal translucency (NT) with normal microarray analysis. METHODS: A retrospective study in which all women with singleton pregnancy who demonstrated NT above 3 mm and a normal microarray analysis were matched to women with normal NT and a normal microarray analysis (2013-2019) in a single tertiary academic center. The following placental pathology-related parameters were measured: preeclampsia, oligohydramnios, suspected intrauterine growth restriction, abnormal Doppler studies or small for gestational age (SGA) neonates. The primary outcome was defined as a composite of complications related to placental pathology including preeclampsia and SGA neonate. Secondary outcomes were labor complications and neonatal morbidity. RESULTS: A total of 185 women were included in the study: of them, 47 presented an abnormal NT (study group) and 138 presented normal NT (controls). Groups did not significantly differ in baseline characteristics. Regarding primary outcome, all placental-related complications frequencies were higher in the study group, with a composite rate of 17.02% versus 6.52% in controls (p = 0.042%). Secondary outcomes did not differ between groups. CONCLUSIONS: Abnormal NT measurement presented in pregnancies with normal fetal microarray analysis is associated with higher rates of placental-related complications.

Prenatal Diagnosis of Snijders Blok-Campeau Syndrome in a Fetus with Macrocephaly.

We present the prenatal imaging and whole exomics sequencing with the newly described Snijders Blok-Campeau macrocephaly syndrome.

Chromosomal Microarray Evaluation of Fetal Ventriculomegaly.

BACKGROUND: Fetal ventriculomegaly is one of the more common fetal anomalies detected during prenatal screening. OBJECTIVES: To assess the rate of genetic aberrations as the cause for ventriculomegaly in these fetuses. METHODS: A historic cohort study was conducted on 164 fetuses with sonographic diagnosis of ventriculomegaly. All cases were analyzed for karyotype and 41 cases were further analyzed by chromosomal microarray (CMA). The study group was subdivided by laterality, severity, and whether the ventriculomegaly was an isolated finding or not. Subgroups were compared and the study group was compared to a control group of 209 fetuses. RESULTS: Karyotype aberrations were more common among fetuses with ventriculomegaly (6.6%) compared to controls (0%, P < 0.001). CMA aberrations were more common in the non-isolated ventriculomegaly cases (24.1%) compared to controls (6.2%, P = 0.031). The rate of genetic aberrations was not associated with the degree of dilatation or laterality. CONCLUSIONS: It is equivocal whether CMA testing should be conducted on every amniotic fluid sample taken from fetuses with isolated ventriculomegaly. However, if more anomalies are detected during an anatomical survey, CMA analysis should be conducted to decrease oversights of genetic diagnoses.

Neurodevelopmental outcome following prenatal diagnosis of a short corpus callosum.

OBJECTIVE: Data regarding the neurodevelopmental outcome of fetal short corpus callosum (CC) diagnosed according to standard reference charts is scarce. The purpose of this study was to assess whether the finding is related to neurodevelopmental delay, and to examine reclassification to normal fetal CC length using CC length/EFW ratio. METHOD: Historical prospective cohort study including pregnant women who were referred for fetal neurosonogram due to abnormal CC. Short CC was defined below the 5th percentile according to reference charts. Twenty cases were included in the study group and compared with a control group of 59 normal cases. The patients in the study group were divided into two groups according to CC length/EFW ratio. Children's neurodevelopment was assessed using the Vineland Adaptive Behavior Scale (VABS). RESULTS: VABS scores were within normal range in 90% of the cases. There was no significant statistical difference between the study group and the control group. In addition, there was no statistically significant difference between fetuses reclassified as normal callosal length according to CC length/EFW ratio in comparison to the control group. CONCLUSION: The neurodevelopmental outcome of fetuses with diagnosed short CC did not differ from the neurodevelopment of normal fetuses in the control group.

Fetal pleural effusion: Contemporary methods of genetic evaluation.

OBJECTIVE: To determine the contribution of chromosomal microarray (CMA) and other advanced genetic tests to the genetic evaluation of fetal pleural effusion (FPE) and to identify parameters that might assist in predicting genetic abnormality. METHODS: A retrospective study of FPE cases referred between 2013 and 2018 was conducted. Cases that underwent genetic evaluation were divided into two groups, chromosomally normal and genetically abnormal. The types and prevalence of genetic abnormalities were reported. Clinical and sonographic parameters were compared. Univariate and multivariate analyses were performed to determine an association between different parameters and genetic abnormality. RESULTS: Sixty-two cases were included in the study. Forty-eight cases were genetically assessed (karyotype, CMA, whole exome sequencing, Noonan panel, or a combination). A clinically significant genetic abnormality was detected in 29.17% (14/48) of cases. Aneuploidy and single gene disorders were found in 78.6% (11/14) and 21.4% (3/14) of abnormal cases. Four additional cases had microdeletion/duplications detected, yet none were of clinical significance. Multivariate analysis indicated that the presence of anomalies was statistically associated with genetic abnormality (95% CI, 1.144-168.2; 0.039). CONCLUSION: In our cohort, CMA did not demonstrate an additional clinical yield over karyotyping. The presence of anomalies was independently associated with underlying genetic abnormality.

LMOD3-Associated Nemaline Myopathy: Prenatal Ultrasonographic, Pathologic, and Molecular Findings.

To describe the prenatal presentation, including ultrasonographic, histologic, and molecular findings, in 2 fetuses affected with LMOD3-related nemaline myopathy. Prenatal ultrasonographic examinations and histopathologic studies were performed on 2 fetuses with evidence of nemaline myopathy. To establish a molecular diagnosis, whole-exome sequencing was pursued for the affected fetuses. Nemaline myopathy is a common form of congenital myopathy manifesting with nonprogressive generalized muscle weakness, hypotonia, and electron-dense protein inclusions in skeletal myofibers. Although clinically, nemaline myopathy can be viewed as a common pathway phenotype, its molecular basis is heterogeneous, with mutations in 11 identified genes implicated in its pathogenesis so far. Whole-exome sequencing revealed that the affected fetuses were compound heterozygous for 2 newly reported pathogenic variants in the LMOD3 gene, which encodes leiomodin 3. To our knowledge, this article is the first report of LMOD3-related nemaline myopathy since the original reported cohort. We provide a detailed description of the prenatal imaging of these affected fetuses, which we hope, in combination with next-generation sequencing, may contribute to further diagnosis in additional families.

Preimplantation genetic diagnosis versus prenatal diagnosis-decision-making among pregnant FMR1 premutation carriers.

PURPOSE: To detect which factors influence decision-making among pregnant FMR1 premutation carriers regarding the preferred mode of genetic diagnosis: IVF-PGT-M (in vitro fertilization with preimplantation genetic testing for monogenic gene diseases), or CVS (chorionic villus sampling), or AC (amniocentesis) after spontaneous conception. METHODS: In Israel FMR1 premutation preconception genetic screening is offered, free of charge, to every woman in her reproductive years. FMR1 premutation carriers with ≥ 70 CGG repeats, or a history of FXS offspring, are offered IVF-PGT-M. This is a historical cohort study including all pregnant FMR1 premutation carriers who underwent prenatal diagnosis between the years 2011 and 2016 at a tertiary medical center. Data were collected from electronic charts and through phone interviews. RESULTS: One hundred seventy-five women with high-risk pregnancies who were offered IVF-PGT-M were evaluated. In 37 pregnancies (21%), the women decided to undergo IVF-PGT-M. Using the generalized estimating equations (GEE) statistical method including seven parameters, we found that previous termination of pregnancy due to FXS and advanced woman's age were significantly associated with making the decision to undergo IVF-PGT-M. Previously failed IVF was the most significant parameter in a woman's decision not to undergo IVF-PGT-M. CONCLUSION: The most dominant factor affecting the decision of FMR1 premutation carriers to choose spontaneous conception with prenatal diagnosis versus IVF-PGT-M is a previous experience of failed IVF treatments. Women whose IVF treatments failed in the past tended to try to conceive naturally and later, during the course of the pregnancy, perform CVS or AC. Conversely, women who previously experienced a termination of pregnancy (TOP) due to an affected fetus, and older women, preferred to undergo IVF-PGT-M procedures.

Prenatal Ultrasonographic Diagnosis of Cataract: In Utero Manifestations of Cryptic Disease.

PURPOSE: To report and review our experience with antenatal evaluation for fetuses diagnosed with congenital cataract. MATERIALS AND METHODS: We retrospectively identified pregnancies diagnosed with fetal cataract during antenatal ultrasound. Evaluation of fetal eyes included intraocular anatomy and biometry. Data on fetal malformations, serology and fetal karyotype were collected. RESULTS: 8 cases, identified over the course of 10 years, were reviewed. Week 15 was the mean time for diagnosis (range 11 - 34). Extraocular anomalies were demonstrated in 6 cases (central nervous system, cardiac and renal systems). Additional intraocular abnormalities were detected in two cases: one fetus had persistent hyperplastic primary vitreous and another had bilateral retinal detachment. All cases but one involved cataracts in both eyes. The unilateral case was associated with microphthalmic aphakia. All cases had negative serology for TORCHs. 7 out of the 8 fetuses were terminated. The only one who survived developed in utero cataracts secondary to maternal steroid therapy. He underwent bilateral cataract extraction during the first weeks of life and ophthalmologic evaluation at 2 years of age was unremarkable, without any visual impairment. CONCLUSION: In most cases, fetal cataract was associated with additional abnormalities, both intra- and extra-ocular. In instances when cataracts are isolated, we suggest conducting a detailed and thorough in utero ophthalmic examination in order to improve antenatal parental counselling.

[FROM GENETICS OF FRAGILE X SYNDROME TO DEVELOPMENT OF TARGETED AND PERSONALIZED DRUG THERAPY].

INTRODUCTION: At the end of the last century Fragile X syndrome was identified, and the main syndrome characteristics were discovered. The syndrome is caused from a flaw in the number of nucleotide repeats that encodes for a regulatory protein which is critical for neural connectivity and normal brain development. The syndrome is characterized by neurodevelopmental and intellectual disabilities, autism spectrum features and other clinical features associated with the same gene aberration. The number of trinucleotide repeats have a direct effect on the outcome and the need for genetic counseling. We advocate performing genetic tests for every child with developmental delay, learning disabilities, autism spectrum disorders and especially, intellectual impairment. It is also advisable to check the number of nucleotide repeats of the gene, in every woman suffering from infertility or early menopause. In addition, genetic testing should be performed on older adults manifesting early symptoms of Parkinson's disease, balance instability, tremor or cognitive dysfunction with unknown etiology. Due to the tremendous progress in understanding the biological mechanisms of the syndrome, new molecules/drugs have been proposed and are tested, in order to find a way to bypass the defect mechanism underlying the disorder. We will review the most commonly used drugs in the treatment of Fragile X syndrome and many medications that are currently under investigation as a more targeted treatment.

[FMR1 PREMUTATION CARRIERS - ARE THEY REALLY ASYMPTOMATIC?]

INTRODUCTION: Fragile X Syndrome (FXS), the most common form of inherited mental retardation, is caused by a trinucleotide repeat expansion (CGG) in the 5'-untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene located at Xq27.3. Patients with fragile X -related mental retardation, carry the full mutation CGG-repeat expansions (>200 CGG repeats), which are generally accompanied by hypermethylation of the promoter region, with the consequent transcriptional silencing of the FMR1 gene and absence of the encoded FMR1 protein (FMRP). Expansion of the CGG triplet number above the normal range (n=5-54) towards the so-called premutation status (n=55-199) is associated with increased risk for Fragile X-Associated Premature Ovarian Insufficiency (FXPOI) in females and Fragile X-Associated Tremor/ Ataxia Syndrome (FXTAS) predominantly in males. In addition, premutation women carriers are at increased risk for learning disabilities, as well as psychologic, endocrine, autoimmune and metabolic disorders. The observation that premutation carriers, both males and females, have increased FMR1 transcript levels, led researchers to suggest a similar molecular pathogenesis in both FXPOI and FXTAS. Two models have been proposed as the culprits of FXTAS and FXPOI: The toxic RNA gain-of-function model and the Repeat Associated Non-AUG initiated (RAN) translation protein toxicity model. The Fragile X Multidisciplinary Center in Sheba Medical Center, at Tel Hashomer includes a team of geneticists, fertility specialists, endocrinologists, psychologists and neurologists who work together in order to provide early detection of FMR1 premutation carriers and offer FMR1 premutation carriers and their families adequate multidisciplinary medical consultation, follow-up and care.

Nonobstructive Diffuse Dilated Bowel Loops: Prenatal Diagnosis, Fetal Characteristics and Neonatal Outcomes.

OBJECTIVES: The purpose of this study was to describe the characteristics and outcomes of fetuses with a diagnosis of nonobstructive diffuse dilated bowel loops. METHODS: We conducted a retrospective study of all pregnancies with fetal diagnosis of nonobstructive diffuse dilated bowel loops over 14 years in a large tertiary referral center. Fetomaternal and neonatal characteristics and outcomes were assessed. RESULTS: Seven fetuses had sonograms showing diffuse dilated bowel loops; none of them had intestinal obstruction after labor. The median gestational age at diagnosis was 33 weeks 1 day (range, 27 weeks-34 weeks 1 day). The median gestational age at delivery was 34 weeks 1 day (range, 32 weeks 4 days-39 weeks 1 day). Four cases had premature rupture of membranes beyond 32 weeks. Four among the 7 had gastrointestinal manifestations. Three cases presented with hematochezia, which resolved with conservative treatment. One fetus had intractable diarrhea, had a diagnosis of rare microvillus inclusion disease, and died of sepsis after 92 days. Not a single case of Hirschsprung disease was observed in our group. CONCLUSIONS: Nonobstructive diffuse dilated bowel loops diagnosed in the second half of pregnancy are associated with premature rupture of membranes and premature labor. As neonatal gastrointestinal complications may be anticipated, prenatal parental counseling with a neonatologist and pediatric gastroenterologist should be conducted.

Fragile X Premutation Carrier Epidemiology and Symptomatology in Israel-Results from a Tertiary Child Developmental Center.

Fragile X syndrome (FXS) is the most prevalent known genetically inherited cause for autism and intellectual disability. Premutation state can cause several clinical disorders as well. We aimed to perform a nesting approach to acquire data with regard to first degree relatives of index fragile X cases at the largest child development center in Israel in order to map characteristics of Israeli FXS permutation women carriers. Seventy-nine women were referred due to a related fragile X syndrome patient, mainly an offspring or sibling. General information regarding demographics, ethnicity, and associated medical conditions were collected using interviews and structured questionnaires. Thirteen (17 %) of the women who were referred as "carrier" were proven to be actually full mutation. The mean years of education were 14 (±1.51, range 12-17). Twenty-one women (27 %) originated from Tunisia (mainly from the island of Djerba). Ten women (13 %) reported delivery of their affected offspring beyond 41 gestational weeks. Twenty-two percent of women with premutation reported symptoms consistent with learning difficulties, mainly dyscalculia, and 14 % reported ADHD symptoms. Awareness about clinical disorders of the carriers was existent only in 25 % of the patients. Increased awareness and knowledge dissemination concerning premutation symptomatology and associated medical conditions are warranted. We suggest a national registry to be installed in different countries in order to identify fragile X premutation carriers at increased risk for various medical complications.

Prenatal sonographic features of triploidy at 12-16 weeks.

OBJECTIVE: The purpose of our study was to describe the sonographic appearance of triploidy in early pregnancy. METHODS: We report the sonographic characteristics of a cohort of fetal triploid cases detected at targeted ultrasonographic vaginal examinations between 12 and 16 weeks of gestation from 2008 to 2014. Indications for fetal karyotype following ultrasound were maternal request, advanced maternal age, increased nuchal translucency, and/or fetal abnormalities. RESULTS: Triploidy was detected in 25 cases during the 6 years of the study period with an estimated incidence of ~1 in 5000 pregnancies. Four cases had molar changes in the placenta. Among the remaining 21 cases, a consistent sonographic pattern was noted, which included the combination of asymmetric growth restriction with abdominal circumference lagging 2 weeks behind head circumference in 21/21, oligohydramnios in 20/21, abnormal posterior fossa or enlarged fourth ventricle in 20/21, and absent gall bladder in 17/21. Other findings present in more than 50% of cases included cardiac (70%) and renal (55%) abnormalities, clenched hands (55%), and hypoplastic lungs (67%). CONCLUSION: Fetal triploidy can manifest at 12-16 weeks with molar changes in the placenta or with a cluster of unusual sonographic findings whose presence should prompt appropriate testing for diagnosis in early pregnancy. © 2016 John Wiley & Sons, Ltd.

Prenatal diagnosis of 17q12 deletion syndrome: from fetal hyperechogenic kidneys to high risk for autism.

OBJECTIVE: The linkage between 17q12 microdeletions, renal anomalies, and higher risk for neurodevelopmental disorders is well described in the literature. The current study presents prenatal diagnosis of normal-sized fetal hyperechogenic kidneys leading to the diagnosis of 17q12 deletion syndrome and autism spectrum disorder. METHODS: Over a period of 9 years in a single referral center, seven fetuses were diagnosed with hyperechogenic renal parenchyma and were followed up prospectively. Amniocentesis for molecular diagnosis was performed in all cases, and subsequently, five fetuses were found to harbor a 17q12 deletion by chromosomal microarray analysis. Postnatal evaluation was carried out by a developmental neurologist. RESULTS: Five of the seven fetuses had molecular diagnosis of 17q12 deletion. One patient elected termination of pregnancy. On long-term follow-up, all of the four children showed symptoms consistent with neurodevelopmental disorders. The two fetuses with no deletion have a normal follow-up with regression of the renal hyperechogenicity. CONCLUSIONS: We report a strikingly high correlation between prenatal hyperechogenic kidneys, 17q12 microdeletion, and autism spectrum disorder with the advantage of optimal prenatal counseling as well as early diagnosis and intervention. © 2016 John Wiley & Sons, Ltd.

Patients' Attitudes Towards Disclosure of Genetic Test Results to Family Members: The Impact of Patients' Sociodemographic Background and Counseling Experience.

Many factors predict the intention to disclose genetic information to relatives. The article examines the impact of patients' socio-demographic factors on their intention to disclose genetic testing results to their relatives. Data were collected in eight genetic clinics in Israel. Patients were requested to fill in a questionnaire after counseling. A convenience sample of 564 participants who visited these clinics was collected for a response rate of 85 %. Of them, 282 participants came for susceptibility testing for hereditary cancers (cancer group), and 282 for genetic screening tests (prenatal group). In the cancer group, being secular and having more years of education correlated positively with the intention to disclose test results to relatives. In the prenatal group, being married and female correlated positively with the intention to disclose. In the cancer group, being religious and with less years of education correlated positively with the view that the clinician should deliver the results to the family. In the prenatal group, being male and unmarried correlated positively with this belief. In both groups, being of young age correlated with the perception that genetic information is private. Varied sociodemographic factors affect the intention to inform family members. Thus, knowing the social background of patients will shed light on people's attitudes to genetic information and will help clinicians provide effective counseling in discussions with patients about the implications of test results for relatives.

Three-dimensional ultrasound demonstration of the fetal palate in high-risk patients: the accuracy of prenatal visualization.

OBJECTIVE: The aim of this research was to evaluate the ability of three-dimensional (3D) ultrasound for demonstrating the palate of fetuses at high risk for cleft palate. METHOD: Fifty-seven fetuses at high risk for cleft palate were referred for specialist ultrasound at 12-40 weeks' gestation. A detailed assessment of palate was made using both two-dimensional and 3D ultrasounds on the axial plane. Antenatal diagnoses were compared with postnatal findings. RESULTS: Cleft palate was suspected in 13 (22.8%); a normal palate was demonstrated in 38 (67%), and in six (10.2%), the palate view could not be obtained. Mean gestational age at the first visit was 27 weeks 6 days (range of 12-40 weeks 3 days). Examination after delivery revealed that one of the 38 fetuses with presumed normal palate had a cleft hard palate, and one had a cleft soft palate (false negative 5%). Among the 13 fetuses with suspected cleft palate, three had an intact palate (false-positive 23%). Sensitivity, specificity, positive predictive value, and negative predictive value of detection of palatal clefts were 71.4%, 91.9%, 62.5%, and 94.4%, respectively. CONCLUSION: Using 3D technology, we diagnosed a cleft palate in 83% of high-risk cases, with 5% false negative. 3D technology might produce some technical artifacts resulting in a 23% false-positive rate.