Utilizing ChatGPT to facilitate referrals for fetal echocardiography.

Introduction OpenAI's GPT-4 (Artificial intelligence (AI)) is being studied for its use as a medical decision support tool. This research examines its accuracy in refining referrals for fetal echocardiography (FE) to improve early detection and outcomes related to congenital heart defects. Methods Past FE data referred to our institution were evaluated separately by pediatric cardiologist, gynecologist ( human experts(experts) ), and AI, according to established guidelines. We compared experts and AI's agreement on referral necessity, with experts addressing discrepancies. Results Total of 59 FE cases were addressed retrospectively. Cardiologist, gynecologist, and AI recommended performing FE in 47.5%, 49.2%, and 59.0% of cases, respectively. Comparing AI recommendations to experts, indicated agreement of around 80.0% with both experts (p< 0.001). Notably, AI suggested more echocardiographies for minor CHD (64.7%) compared to experts (47.1%), and for major CHD, experts recommended performing FE in all cases(100%) while AI recommended in majority of cases(90.9%). Discrepancies between AI and experts are detailed and reviewed. Conclusions The evaluation found moderate agreement between AI and experts. Contextual misunderstandings and lack of specialized medical knowledge limits AI, necessitating clinical guidelines guidance. Despite shortcomings, AI's referrals comprised 65% of minor CHD cases VS experts 47%, suggesting its potential as a cautious decision aid for clinicians.

Vaccination in twin pregnancies: comparison between immunization before conception and during pregnancy.

To evaluate the development of neutralizing Anti-Spike Protein IgG (Anti-S-IgG) during twin pregnancies before conception vs. during pregnancy. In this prospective study, three blood samples were collected from pregnant women and subjected to anti-S-IgG immunodiagnostics. The patient's medical records, including vaccination and PCR test results, were collected from the hospital's electronic database. Age-matched non-pregnant women were used as a control group. We enrolled 83 women with twin pregnancies. 49 women were vaccinated before conception, 21 women were vaccinated during pregnancy, and 13 were not vaccinated. Of the 13 women who weren't vaccinated, three became positive during pregnancy, and all three were severely ill. By contrast, in women who were vaccinated during or before pregnancy, COVID-19 infection during pregnancy caused only mild symptoms. A ten-fold lower level of neutralizing Anti-S-IgG in the 3rd trimester was observed in healthy women who were vaccinated before conception and remained healthy until discharge from the hospital after delivery 1605 (IQR: 763-2410) compared to the healthy women who were vaccinated during pregnancy 152 AU/mL (IQR: 54-360). This difference was higher among women who were infected by COVID-19 (as verified by a positive PCR test). The third-trimester level of neutralizing Ant-S-IgG in the infected group was 4770 AU/mL (4760-6100) in infected women vaccinated before conception compared to those vaccinated during pregnancy who had 70 AU/mL (IQR: 20-170) (p < 0.001). In women vaccinated at 13-16 weeks gestation, neutralizing Anti-S-IgG at 20-22 weeks went up to 372 AU/mL (IQR: 120-1598) but rapidly dropped to 112 AU/mL (IQR: 54-357) at 28-30 weeks, (p < 0.001), a faster decline than in women vaccinated at a median 22 weeks before conception. Being infected by COVID-19 before conception was linked to having low Anti-S-IgG levels during pregnancy, whereas being infected by COVID-19 during pregnancy led to a very high response in the 3rd trimester. In twin pregnancies, significantly lower neutralizing Anti-S-IgG levels were observed in women vaccinated during pregnancy compared to those vaccinated before conception, whether infected or not infected by COVID-19. A full course of vaccination before conception is recommended.Trial registration. ClinicalTrials.gov Protocol Registration and Results System (PRS) Receipt Release Date: October 4, 2021. https://clinicaltrials.gov/ ID: NCT04595214.

[NUCHAL TRANSLUCENCY CONCURRENT WITH EARLY ANOMALY SCAN: TIME TO RECONSIDER].

INTRODUCTION: During the last decades, a major achievement was reported in detecting Down's syndrome in the first trimester of pregnancy. This is attributed to the use of high-resolution accurate ultrasound machine allowing the detection of a "nuchal translucency" in the back of the fetus during 11-14 weeks' gestation. This is considered to be a physiologic finding, but when increased, may alert for chromosomal abnormality (mainly Down's syndrome), cardiac and other organ anomalies and other genetic syndromes. Later additional sonographic findings were found, including nasal bone assessment, and Doppler flow studies of the ductus venosus and tricuspid regurgitation Technology advancement accompanied by sonographers' skills enhancement allows (at the time frame of the nuchal scan) a detailed anomaly scan. Additional screening for pregnancy complication was achieved using first trimester multi marker assessment, alerting for preeclamptic toxemia or placenta accreta. Currently, many national and international professional organizations recommend performing the nuchal scan concurrent with an early anomaly scan both at the same time of gestation. This approach is different than the one performed in Israel, whereas the nuchal scan is conducted separately and 2-3 weeks later an anomaly scan is offered. We call for reconsideration of the sequential approach and performing all the tests in a comprehensive first trimester clinic.

High sensitivity and specificity in fetal gender identification in the first trimester, using ultrasound and Noninvasive Prenatal Screening (NIPS) in twin pregnancies, a prospective study.

INTRODUCTION: Determination of the fetal gender in the first trimester is important in twin pregnancy cases of familial X-linked genetic syndromes and helps determine chorionicity. We assessed and compared the accuracy of first-trimester ultrasound scans, and cell-free fetal DNA (CfDNA) in determining fetal gender in the first trimester of twin pregnancies. METHODS: Women with twin pregnancies were recruited prospectively during the first trimester. Fetal gender was determined using both ultrasound scans and CfDNA screening. Both results were compared to the newborn gender after delivery. RESULTS: A total of 113 women with twin pregnancies were enrolled. There was 100% sensitivity and specificity in Y chromosome detection using CfDNA. Gender assignment using ultrasound in any first-trimester scans was 79.7%. Accuracy level increased from 54.2% in CRL 45-54 mm to 87.7% in CRL 55-67 mm and 91.5% in CRL 67-87 mm. Male fetuses had significantly higher chances of a gender assignment error compared to female fetuses, odds ratio = 23.574 (CI 7.346 - 75.656). CONCLUSIONS: CfDNA is highly sensitive and specific in determining the presence of the Y chromosome in twin pregnancies in the first trimester. Between CRL 55-87 mm, ultrasound scanning offers a highly accurate determination of fetal gender in twin pregnancies.

Pregnancy with Facial Cleft: 20 Years of Experience at a Single Center.

BACKGROUND: Fetal facial clefts are among the most common congenital anomalies detected prenatally. This finding may lead to termination of pregnancy in some cases. OBJECTIVES: To compare a cohort of fetuses with facial clefts in which the pregnancy was terminated to the cohort of cases that were born with facial clefts. To investigate risk factors for facial clefts. METHODS: We conducted a retrospective chart review of all women with prenatal and postnatal diagnosis of facial cleft that were managed in our institute. A telephone questionnaire was conducted regarding a positive family history and/or genetic predisposition for facial clefts abnormalities. RESULTS: The final cohort consisted of two group. One group included 54 cases of termination of pregnancy (TOP) that were performed due to cleft lip (CL) or cleft palate (CLP); 27 women answered the telephone questionnaire. The second group comprised 99 women who delivered children with facial cleft during the same period; 60 answered the questionnaire. Only seven cases were diagnosed prenatal. Among the two groups, no correlation to family history was discovered. Of note, there was one case of three consecutive fetuses with CL in one woman, without any significant genetic findings. CONCLUSIONS: To the best of our knowledge, this is the first study to describe an anatomical malformation posing an ethical dilemma before TOP. Primary prevention with folic acid and early sonographic detection of CL/CLP with multidisciplinary consultation should be considered.

Prenatally diagnosed isolated perimembranous ventricular septal defect: Genetic and clinical implications.

OBJECTIVE: To evaluate the incidence of chromosomal aberrations and the clinical outcomes following the prenatal diagnosis of isolated perimembranous ventricular septal defect (pVSD). METHODS: This retrospective study was composed of a cohort of pregnant women whose fetuses were diagnosed with isolated pVSD. Complete examinations of the fetal heart were performed, as well as a postnatal validation echocardiography follow-up at 1 year of age. The collected data included: spontaneous closure of the pVSD, need for intervention, chromosomal aberrations and postnatal outcome. RESULTS: Fifty-five pregnant women were included in the study. 34/55 (61.8%) of the fetuses underwent prenatal genetic workup which revealed no abnormal results. No dysmorphic features or abnormal neurological findings were detected postnatally in those who declined a prenatal genetic workup during the follow-up period of 2 years. In 25/55 of the cases (45.4%), the ventricular septal defects (VSD) closed spontaneously in utero, whereas in 17 cases of this group (30.9%) the VSD closed during the first year of life. None of the large 3 VSDs cases (>3 mm), closed spontaneously. CONCLUSION: Prenatally isolated perimembranous VSD has a favorable clinical outcome when classified as small-to-moderate size, children in our cohort born with such findings had no macroscopic chromosomal abnormalities.

Managing patients with suspected postpartum retained products of conception using a novel sonographic classification.

BACKGROUND: Suspicion of retained products of conception (RPOC) often arises after delivery and still poses a diagnostic and management challenge. PURPOSE: To prospectively evaluate a sonographic classification for the management of patients with suspected RPOC after delivery. MATERIAL AND METHODS: Based on grayscale and Doppler ultrasound parameters, patients were classified into high, moderate, or low probability of RPOC. For the low and moderate probability groups, an ultrasound follow-up at the end of the puerperium was recommended. For the high probability group, a follow-up examination was conducted 10-14 days after the first ultrasound, and patients with persistent high probability findings were referred for surgical intervention. RESULTS: The sample was composed of 215 patients at risk of RPOC. Of these, 100, 93, and 22 patients were classified as having a low, moderate, or high probability of RPOC, respectively. Rates of RPOC were 55%, 2%, and 2% in the high, moderate, and low probability categories, respectively. When the categorization was based on the most recent ultrasound obtained during the puerperium, the adjusted RPOC prevalence rates were 71% in the high, 6% in the moderate, and 0% in the low probability groups. CONCLUSION: This study confirms the effectiveness of our sonographic classification for managing patients with suspected RPOC after delivery. In all three categories, it is recommended to adhere to a conservative management protocol in clinically stable women until the end of the puerperium. This approach provides good predictability for RPOC and can reduce unnecessary surgical interventions.

Analgesic efficacy of virtual reality for acute pain in amniocentesis: A randomized controlled trial.

BACKGROUND: To evaluate the efficacy of virtual reality (VR) as a distraction technique in the management of acute pain and anxiety during amniocentesis. STUDY DESIGN: A randomized controlled trial was conducted between September 2020 and October 2020 involving 60 women undergoing mid-trimester amniocentesis. Thirty women were assigned randomly to the VR intervention (immersive video content as a distraction method) group and 30 to the standard care group using a predetermined randomization code. The primary outcome measure was the visual analog scale (VAS) pain score, along with the women's ratings of their extent of anxiety experienced during the procedure. The VAS consisted of a 10 cm line ranging from 0 to 10 (anchored by 0 = no pain and 10=very severe pain). Anxiety was assessed on Spielberger's state-trait anxiety inventory (STAI) questionnaire. RESULTS: The patients' characteristics and obstetric data were similar in both groups. The ratings on the VAS indicated that the VR intervention was associated with significantly less pain than the ratings in the standard of care group; namely, 2.5 ± 1.5 vs. 3.8 ± 1.7, respectively (95 % CI 0.44-2.13; p = 0.003). There were no significant differences in maternal anxiety levels before and after amniocentesis. CONCLUSION: The VR intervention as a distractive technique emerged as effective in reducing pain during amniocentesis. It is easy to use, relatively inexpensive, has the advantage of no serious side effects, and may decrease the fear of pain that can affect patients' experiences and compliance with this procedure.

A fetal reduction from twin to singleton based on sonography and cell-free fetal DNA testing: A sequential approach to old pitfalls.

OBJECTIVE: We examined the potential value of combining ultrasound and non-invasive prenatal screening (NIPS) of maternal blood to screen for major aneuploidies as an early approach before selective fetal reduction from twin pregnancy to singleton. STUDY DESIGN: The sample was composed of pregnant women with di-chorionic di-amniotic twins who chose to undergo fetal reduction to singleton at 12-24 weeks of gestation. These women were asked to provide a blood sample for cell-free fetal DNA (cffDNA) testing prior to fetal reduction. RESULTS: A total of 24 pregnant women with a twin pregnancy prior to fetal reduction to singleton were enrolled. There were 8 cases with structural anomalies (33.3%) in one twin that dictated fetal reduction. The proportion of patients who underwent selective fetal reduction for fetal abnormalities was larger than in several other studies. The NIPS identified 1 case of Trisomy 13 (4.2%). The other 15 cases (62.5%) had no structural or chromosomal anomalies. The decision to undergo elective reduction of twin pregnancy to singleton was made for social reasons or upon the parents' request. Given the 33% of structural anomalies in the cohort, a cost analysis indicated that this procedure was 6.6-fold less expensive (vs. 4.6-fold with 4% structural anomalies in other publications) than conducting invasive procedures for the entire cohort. CONCLUSION: The findings suggest that an early anatomical scan and cffDNA can increase the overall safety margin and reduce interventional procedures before elective reduction of twin pregnancy to singleton. However, a larger cohort is needed to confirm these results.

Biallelic variants in ETV2 in a family with congenital heart defects, vertebral abnormalities and preaxial polydactyly.

The combination of congenital heart defects and vertebral anomalies with or without additional abnormalities has been reported in many genetic disorders. We describe a family in which four consecutive pregnancies were characterized by the combination of fetal congenital heart malformations and vertebral anomalies. In addition, preaxial polydactyly was detected in one of the fetuses. Reanalysis of the non-diagnostic clinical exome data revealed compound heterozygous variants c.350del, p.(Gly117AlafsTer90) and c.757G > T, p.(Asp253Tyr) in ETV2 which have previously not been known to be associated with a phenotype in humans. In mice, Etv2 encodes an obligatory transcription factor involved in the generation of hematopoietic and endothelial cells. Its homozygous disruption results in embryonic lethality due to severe blood and vessel defects. The Etv2 promoter may be bound by Nkx2-5, a key transcription factor in heart development. Pathogenic variants in the NKx2-5 homolog in humans (NKX2-5) are related to congenital heart defects. The identification of additional fetuses or live-born individuals with biallelic pathogenic variants in ETV2 will shed further light on this presumably novel gene-phenotype association and on the full phenotypic spectrum.

Clinical Observation: Effect of a Second Transpositioned Variant in a Family with Autosomal Dominant Ryanodine Receptor-1-Related Disease.

Mutations in the ryanodine receptor-1 ( RYR1 ) may cause disorders inherited in an autosomal dominant/recessive fashion. Sequencing of RYR1 in an infant of Ashkenazi Jewish descent with severe hypotonia, dislocation of hip, torticollis and scoliosis, and paternal family history of autosomal dominant mild disease. The child was compound heterozygote for a missense variant c.7042G > A inherited from her father associated with autosomal dominant disease, and a missense variant of unknown significance c.5309C > T inherited from an asymptomatic mother. This case raises the possibility of a dominant disease complicated by a second variant in the other allele serving as a modifier.

Indications for genetic testing leading to termination of pregnancy.

PURPOSE: In this study, we aimed to assess the distribution of genetic abnormalities leading to termination of pregnancy and its fluctuation during the past 8 years in light of those technical advances. METHODS: Our cohort consisted of all pregnant women who underwent termination of pregnancy because of genetic aberrations in their fetuses from January 2010 through April 2018 in our medical center. The information that was gathered included: maternal age, results of the nuchal scan, results of the first- and second-trimester biochemical screening, ultrasonographic findings, reasons for conducting a genetic evaluation, gestational age at which termination of pregnancy was carried out, and the type of genetic aberration. RESULTS: 816 women underwent termination of pregnancy at our institution due to genetic aberrations, most of them because of positive biochemical screening (n = 297, 36%) or because of maternal anxiety (n = 283, 35%). Findings in chromosomal microarray led to termination of pregnancy in 100 women (100/816, 12%). Chromosomal microarray had been performed due to maternal choice and not because of accepted medical indications among most of the women who underwent termination of pregnancy due to findings on chromosomal microarray (69/100, 69%). CONCLUSION: Performing chromosomal microarray on a structurally normal fetus and identifying abnormal copy number variants may give the parents enough information for deciding on the further course of the pregnancy.

The genetic and clinical outcome of isolated fetal muscular ventricular septal defect (VSD).

Introduction: Our objective was to evaluate the incidence of chromosomal aberration (both microscopic and submicroscopic) and the clinical outcome of fetuses with isolated muscular ventricular septal defect (VSD). Material and methods: The study included 40 pregnant women whose fetuses were diagnosed with isolated muscular ventricular septal defect (mVSD). Of these, 30 patients underwent amniocentesis and 10 declined. All samples were tested by chromosomal microarray analysis (CMA). Of the 40 women in the study, 32 gave birth and the clinical outcome of the children was retrieved from the patients' medical records. Results: Of the 30 patients who underwent amniocentesis, one was detected with mosaic Klinefelter syndrome and one was detected with a pathogenic copy number variant unrelated to the VSD. Clinical follow-up was performed on 26 children after birth. The first postnatal echocardiography did not detect a VSD in 13 (50%) of the followed-up children. Spontaneous closure occurred in another eight (30.8%) children during the postnatal follow-up period. In only five children (19.2%) VSD was still detected by echocardiography after the first year of life. Discussion: Isolated muscular VSD diagnosed prenatally does not appear to be a significant risk factor for chromosomal abnormalities and has a favorable clinical outcome.

[PRE-ECLAMPSIA: A NEW TEST FOR AN OLD DISEASE].

INTRODUCTION: In the western world, pre-eclampsia, diagnosed in 3-5% of pregnant women, is a major cause of maternal and fetal morbidity and mortality. Once pre-eclampsia is diagnosed, the only effective treatment is delivery. There are known historical risk factors for the development of pre-eclampsia, however only 30% of the women who will develop pre-eclampsia are identified based on their presence. Recently, new first trimester algorithms for the prediction of pre-eclampsia were developed, based on the observation that pregnant women who develop pre-eclampsia have imbalanced placental angiogenic factors and that failure of the trophoblastic migration may change the flow in the uterine arteries. These algorithms include maternal history and demographics, biochemical and clinical markers (mean arterial pressure, uterine artery flow PLGF, PAPP-A, PP-13). The combination of early diagnosis of a high risk group together with promising evidence that simple preventive measures, such as low-dose aspirin and calcium supplements may prevent pre-eclampsia or change its appearance leads to the idea that we are on the verge of a new era regarding detection and prevention of pre-eclampsia.

Termination of pregnancy due to fetal abnormalities performed after 32 weeks' gestation: survey of 57 fetuses from a single medical center.

OBJECTIVE: To assess fetal abnormalities leading to very late termination of pregnancy (VLTOP) performed after 32 weeks' gestation. METHOD: The study population included all pregnant women with singleton pregnancy that underwent VLTOP in our institute because of fetal indications between the years 1998 and 2015. RESULTS: Fifty-seven cases (2.0%) were at ≥32 weeks' gestation and are the subjects of the current study. Our VLTOP cases were subdivided into four categories according to the sequence of events that led to the decision for VLTOP: (1) No routine prenatal screening with an incidental fetal finding discovered after 32 weeks' gestation (9 fetuses ∼16%); (2) Routine early prenatal care raised suspicion of abnormalities, and the final diagnosis was established by additional tests (8 fetuses, ∼14%); (3) Developmental findings detected during the third trimester (21 fetuses; ∼37%), and (4) fetal abnormalities that could have been detected earlier during pregnancy (19 fetuses; ∼33%). CONCLUSIONS: The two categories in which the pregnant women did not underwent any fetal evaluation (i.e. group 1) or those that could have been detected earlier (i.e. group 4) consists ∼49% from our cohort in which VLTOP could have been avoided.

Dilemmas in genetic counseling for low-penetrance neuro-susceptibility loci detected on prenatal chromosomal microarray analysis.

BACKGROUND: Chromosomal microarray analysis is standard of care in fetuses with malformations, detecting clinically significant copy number variants in 5-7% of cases over conventional karyotyping. However, it also detects variants of uncertain significance in 1.6-4.2% of the cases, some of which are low-penetrance neuro-susceptibility loci. The interpretation of these variants in pregnancy is particularly challenging because the significance is often unclear and the clinical implications may be difficult to predict. OBJECTIVE: The purpose of this study was to describe counseling dilemmas regarding low-penetrance neuro-susceptibility loci that are detected by prenatal chromosomal microarray analysis. STUDY DESIGN: During the study period (January 2014 to December 2015), 700 prenatal chromosomal microarray analyses were performed. Cases were categorized as "indicated" (n=375) if there were abnormal sonographic findings or suggestive medical history and "patient choice" (n=325) in the presence of a structurally normal fetus with no other particular indication. The laboratory reported on copy number variants ≥400 Kb in size in loci known to be associated with genetic syndromes and ≥1 Mb in other areas of genome. Results were classified as gross aneuploidy, copy number variants, and normal. Copy number variants were categorized according to the American College of Medical Genetics standards and guidelines: pathogenic, variants of uncertain significance, or benign. Variants of uncertain significance were further subdivided into categories of likely pathogenic, variants of uncertain significance with no subclassification, and likely benign. Statistical analysis was performed with the use of Chi square test and Fisher's exact test to compare intergroup differences in incidence of the different result categories and demographic data. RESULTS: Patient choice cases became more prevalent with time (35.5% in the beginning of the study, compared with 48.4% at the end of the study period). Clinically significant copy number variants were found in 14 of 375 (3.7%) of indicated cases vs only 2 of 325 (0.6%) of patient choice cases (P=.009). All "likely benign" variants consisted of low-penetrance neuro-susceptibility loci. The incidence thereof was similar between the indicated and patient choice groups (3.7% vs 3.4%; P=.85). In the indicated group, some variants of uncertain significance may have contributed to the abnormal anatomic findings. Conversely, in the patient choice group, the finding of low-penetrance neuro-susceptibility loci was often unexpected and confounding for prospective parents. CONCLUSION: Prenatal chromosomal microarray analysis added clinically significant information in both groups. However, it also detected low-penetrance neuro-susceptibility loci in approximately 3.5% of the cases. This fact should be conveyed during pretest counseling to allow patients to make informed choices, particularly when chromosomal microarray is to be performed for patient choice.

Outcomes of conception subsequent to methotrexate treatment for an unruptured ectopic pregnancy.

OBJECTIVE: To assess the risk of adverse pregnancy outcomes in subsequent pregnancies among women treated with methotrexate for ectopic pregnancy. METHODS: In a retrospective single-center study, data were assessed for women treated with methotrexate for ectopic pregnancy at Asaf Harofe Medical Center, Zerifin, Israel, between May 2004 and May 2014. RESULTS: Overall, 226 women were treated with methotrexate for ectopic pregnancy and subsequently conceived. The median time from treatment to conception was 10 months (range 1-120 months), and 127 women conceived within 12 months of treatment. Except for early missed abortion-which affected 23 (10.2%) pregnancies-adverse pregnancy outcomes such as fetal malformations were rare. The frequency of early abortion was lowest for women who conceived within 6 months of treatment with methotrexate (3/93, 3.2%), increased between 6 and 23 months (15/83, 18.1%), and remained high thereafter (7/50, 14.0%; P=0.006). CONCLUSION: The frequency of fetal malformation in a subsequent pregnancy was low among women treated with methotrexate for ectopic pregnancy. The frequency of early missed abortion was lowest during the first 6 months after treatment with methotrexate.

Association of aberrant right subclavian artery with abnormal karyotype and microarray results.

OBJECTIVES: The objective of this study is to evaluate the incidence of chromosomal aberration (both microscopic and sub-microscopic) in fetuses with an aberrant right subclavian artery (ARSA) detected by ultrasonographic anomaly scan. METHODS: The study included 62 pregnant women whose fetuses were diagnosed with ARSA who were referred for genetic counseling. Of these, 55 patients underwent amniocentesis and 7 declined invasive testing. All 55 amniocentesis samples were tested by standard G-banding and chromosomal microarray, except for 2 samples for which only karyotype and fluorescence in situ hybridization for 22q11.2 deletions were performed. RESULTS: Of the 55 women who underwent amniocentesis, 5 were detected with trisomy 21 (9.1%), all of whom had additional ultrasound findings. Among the 14 fetuses with ARSA and additional ultrasound findings, the incidence of trisomy 21 was 35.7%. In fetuses with isolated ARSA, no chromosomal aberrations were detected by standard cytogenetic analysis and only one (1.9%) deleterious copy number variants (CNV) was detected by chromosomal microarray. CONCLUSION: Aberrant right subclavian artery with additional ultrasound findings constitute a strong predictor for aneuploidy. However, when ARSA is found in isolation, it confers no increased risk for aneuploidy or pathogenic CNVs. © 2017 John Wiley & Sons, Ltd.

Rare familial TSC2 gene mutation associated with atypical phenotype presentation of Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a neurocutaneous disorder that results from mutations within either the TSC1 gene or the TSC2 gene. Diagnosis is based on well-established clinical criteria or genetic criteria. We describe an 18-month-old boy who presented with seizures and a single hypopigmented macule. He did not meet consensus criteria for the clinical diagnosis of TSC. Exome sequencing revealed a heterozygous TSC2 mutation (c.5138G>A (p.Arg1713His)) in the patient. This heterozygous alteration was detected in his mother as well as several other maternal family members. The mother and other family members with the mutation were asymptomatic except for the presence of hypopigmented macules. The phenotypic characteristics of the individuals in this family were not suggestive of a TSC2 mutation as none satisfied the clinical criteria for even a diagnosis of possible TSC. This case provides evidence for a unique TSC2 mutation that resulted in an atypical clinical presentation and indicates potential shortcomings of the current diagnostic criteria for TSC. These findings may have implications for genetic counseling and screening. © 2017 Wiley Periodicals, Inc.