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Objective: Significant discrepancy exists between laboratories in classification and reporting of copy number variants (CNVs). Studies exploring factors affecting prenatal CNV management are rare. Our "virtual fetus" pilot study examines these factors. Method: Ten prenatally diagnosed CNVs of uncertain significance (VUS) > 1Mb, encompassing OMIM‐morbid genes, inherited from healthy parents, were classified by 15 MD geneticists from laboratory, prenatal, and preimplantation genetic testing (PGT) units. Geneticists addressed factors affecting classification, obligation to report, and recommendation for invasive testing or PGT. Results: CNVs were classified likely benign (10.7%), VUS (74.7%), likely pathogenic (8.7%), or pathogenic (6.0%). Classification discrepancy was higher for losses versus gains. Classifying pathogenic/likely pathogenic was more common for losses (adjusted odds ratio [aOR] 10.9, 95% CI 1.55–76.9), and geneticists specializing in gynecology (aOR 4.9, 95% CI 1.03–23.3). 84.0% of respondents would report CNVs, depending on classification and family phenotype. Invasive testing in pregnancies was recommended for 29.3% of CNVs, depending on the classification and geneticist's specialization. PGT was recommended for 32.4%, depending on classification, experience years, and family's phenotype (38.0% for patients undergoing in vitro fertilization irrespectively, 26.7% otherwise). Conclusion: Factors affecting CNV classification/reporting are mainly dosage, family phenotype, geneticist specialization and experience. Understanding factors from our pilot study may facilitate developing an algorithm for clinical consensus and optimal management. Key points: What's already known about this topic?Chromosomal Microarray Analysis (CMA) currently constitutes the first‐tier test in genetic evaluation of fetuses. Although the utilization of CMA is well established, the clinical dilemmas it causes remain complex since the phenotype of many copy number variants (CNVs) cannot be accurately estimated prenatally. CNVs with scarce data and variants of uncertain significance (VUS) frequently cause patient stress. Despite constant guideline updates, significant inconsistency exists in CNV classification and reporting by different laboratories. What does this study add?In our "virtual fetus" model we found large variability in interpreting prenatal CMA results. Copy number losses versus gains, familial phenotype of variants, and clinician's background (medical field, years of experience) were found to have a major impact on how variants are interpreted and reported, and recommendations given for preimplantation/prenatal testing in subsequent pregnancies. Awareness of variation in interpretation and complexity in clinical decisions regarding CNVs may standardize optimal prenatal management. [ABSTRACT FROM AUTHOR]

Background: Chromosomal‐microarray‐analysis (CMA) may reveal susceptibility‐loci (SL) of varied penetrance for autism‐spectrum‐disorder (ASD) and other neurodevelopmental conditions. Attitudes of women/parents to disclosure of SL during pregnancy are understudied. Methods: A multiple‐choice questionnaire was distributed to postpartum women. Data were collected on women's interest to receive prenatal genetic information with various levels of penetrance. Results: Women's (n = 941) disclosure choices were dependent on the magnitude of risk: approximately 70% supported disclosure of either full or 40% penetrance, 53% supported disclosure at a 20% risk threshold, and 40% supported disclosure at 10% or less. Although most women supported, rejected or were indecisive about disclosure consistently across all risk levels, nearly one‐quarter (24%) varied their responses based on penetrance, and this was associated with religiosity, education, parity and concern about fetal health (p‐values <0.04). Among those who varied their choices, the risk threshold was lower among secular women (20%) than among ultraorthodox women (40%). In a multivariable analysis, ultraorthodox women were much less likely to vary their choices on ASD disclosure compared with secular women (aOR = 0.37, p < 0.001). Conclusion: Women's attitudes toward disclosure are influenced by the level of risk and their individual characteristics. We therefore encourage engaging women/couples in disclosure decisions regarding uncertain and probabilistic results from prenatal genomic tests. Key points: What's already known about this topic? Disclosure policy of susceptibility‐loci (SL) ranges from full disclosure via the disclosure of SLs with 20% and above penetrance to parental choice regarding low penetrance SL.When offered a choice, women tend to request maximum information on their fetuses. What does this study add? Women's attitudes toward the disclosure of genetic information are influenced not only by the severity of the condition but also by the level of risk.Choices are associated with women's cultural characteristics. [ABSTRACT FROM AUTHOR]

This article discusses a rare form of early-onset parkinsonism called RAB39B-associated parkinsonism. The study focuses on a family with 13 siblings, four of whom developed parkinsonism along with mild and non-progressive intellectual disability. The article describes the clinical features, genetic analysis, and response to treatment in these affected individuals. The study also highlights the association between neurodevelopmental disorders and neurodegenerative disorders, suggesting that RAB39B-associated parkinsonism may serve as a model for this association. [Extracted from the article]

Bi‐allelic variants in COLEC11 and MASP1 have been associated with 3MC syndrome, a clinical entity made of up four rare autosomal recessive disorders: Carnevale, Mingarelli, Malpuech, and Michels syndromes, characterized by variable expression of facial dysmorphia, cleft lip/palate, postnatal growth deficiency, hearing loss, cognitive impairment, craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies. More recently, bi‐allelic variants in COLEC10 have been described to be associated with 3MC syndrome. Syndromic features seen in 3MC syndrome are thought to be due to disruption of the chemoattractant properties that influence neural crest cell migration. We identified nine individuals from five families of Ashkenazi Jewish descent with homozygosity of the c.311G > T (p.Gly104Val) variant in COLEC10 and phenotype consistent with 3MC syndrome. Carrier frequency was calculated among 52,278 individuals of Jewish descent. Testing revealed 400 carriers out of 39,750 individuals of Ashkenazi Jewish descent, giving a carrier frequency of 1 in 99 or 1.01%. Molecular protein modeling suggested that the p.Gly104Val substitution alters local conformation. The c.311G > T (p.Gly104Val) variant likely represents a founder variant, and homozygosity is associated with features of 3MC syndrome. 3MC syndrome should be in the differential diagnosis for individuals with short stature, radioulnar synostosis, cleft lip and cleft palate. [ABSTRACT FROM AUTHOR]

Waardenburg syndrome is a group of genetic conditions that can cause hearing loss and pigmentation deficiency of the hair, skin, and eyes. Klein‐Waardenburg syndrome (Waardenburg syndrome type 3) represents a distinct presentation of Waardenburg syndrome type 1 and includes musculoskeletal abnormalities in addition to dystopia canthorum hearing loss and pigmentary changes. Heterozygous or homozygous variants in the PAX3 gene cause Klein‐Waardenburg syndrome. Here we report on a new severely affected child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe), review the features of the syndrome, and propose a new classification. The designation of Waardenburg syndrome should be given only to patients with monoallelic pathogenic variants in PAX3 whether or not musculoskeletal abnormalities are present. Patients with biallelic PAX3 variants should be outlined as a distinct group and designated Klein syndrome. [ABSTRACT FROM AUTHOR]

Background: Advanced prenatal genomic technologies can identify risks for adult‐onset (AO) conditions in the fetus, challenging the traditional purpose of prenatal testing. Professional guidelines commonly support disclosure of high‐penetrance AO actionable conditions, yet attitudes of women/parents to these findings and factors affecting their attitudes are understudied. Methods: We explored 941 (77% response rate) postpartum women's attitudes towards receiving prenatal genetic information, and associations of sociodemographic, medical and psychological characteristics with their choices, focusing on AO conditions. Results: Women largely support the disclosure of actionable AO findings (58.4%), in line with professional guidelines. A third of the women also supported the disclosure of non‐actionable AO conditions. Stronger religious observance (p < 0.001) and higher psychological distress (p = 0.024) were associated with decreased interest in receiving actionable AO conditions, whereas higher concern for fetal health yielded increased interest (p = 0.032). Attitudes towards disclosure were strongly associated with women's perceived benefit of such information for their own, partner's, and future child's health. Termination of pregnancy based on such information received very little support. Conclusion: In‐light of the demonstrated understanding of nuanced genetic information and the observed diversity in attitudes, a culturally competent opt‐in/out policy could be considered. If full‐disclosure is practiced, support should be provided to those expressing higher levels of distress. Key points: What is known Advanced prenatal genomic technologies can identify risks for adult‐onset (AO) conditions.Professional guidelines support disclosure of high‐penetrance AO actionable conditions in pregnancy, yet attitudes of women/parents towards receiving this information are understudied. What this study adds Investigating the attitudes of nearly 1000 postpartum women demonstrates that women largely support the disclosure of actionable AO findings in pregnancy.Stronger religious observance and higher psychological distress predict decreased interest in receiving this information. [ABSTRACT FROM AUTHOR]

Objective: To explain the importance of identifying an etiology for the pathological finding of nonimmune hydrops fetalis (NIHF) and to explore the impact of exome sequencing in recurrent NIHF. In addition, we present two cases of pregnancies affected with recurrent NIHF, in which genetic investigation was advantageous. Methods: Our study aimed to investigate the genetic background, if available, of all fetuses with NIHF referred to our tertiary medical center from January 2013 to August 2020. We summarized the etiology of NIHF if known, sonographic findings, genetic investigation and the pregnancies' outcomes. Results: We encountered 144 families with NIHF. Genetic investigation was performed by chromosomal microarray analysis (CMA) in 63 (63/144. 44%) fetuses. Seventeen of 63 (27%) had a positive CMA result. In the negative CMA group, 15 (15/46, 33%) opted for exome sequencing, of which seven exomes were positive (47%). Among these, there were four couples with recurrent pregnancies affected by hydrops. Among the remaining 11 exome investigations for non‐recurrent hydrops, another three were diagnostic. Conclusion: As identifying the etiology of the NIHF is an invaluable tool for the prognosis of the pregnancy, exome sequencing can provide further elucidation of the underlying pathogenesis of NIHF. Thus, genetic investigation should be recommended for cases of NIHF. Key points: What is already known about this topic? Exome sequencing has high diagnostic yield in detecting monogenic disordersA delineated monogenic etiology for the cause of a sonographic finding will help parents make informed decisions regarding family planningAdditionally, an inherited pathogenic variant of a dominant mode from a mildly affected parent to a severely affected fetus might be surprising but invaluable for the parents What does this study add? Exome sequencing is a powerful tool in the investigation of recurrent nonimmune hydrops fetalis (NIHF) and thus clinicians should consider embedding trio‐exome sequencing in the investigation of cases of unexplained NIHFWe describe seven monogenic etiologies for NIHF. The novel variants in the PIEZO1, GLDN and FOXC2 and DOK7 genes were identified in recurrent cases through exome sequencing and are related to the outlined clinical manifestations [ABSTRACT FROM AUTHOR]

Exome and genome sequencing were used to identify the genetic etiology of a severe neurodevelopmental disorder in two unrelated Ashkenazi Jewish families with three affected individuals. The clinical findings included a prenatal presentation of microcephaly, polyhydramnios and clenched hands while postnatal findings included microcephaly, severe developmental delay, dysmorphism, neurologic deficits, and death in infancy. A shared rare homozygous, missense variant (c.274A > G; p.Ser92Gly, NM_024516.4) was identified in PAGR1, a gene currently not associated with a Mendelian disease. PAGR1 encodes a component of the histone methyltransferase MLL2/MLL3 complex and may function in the DNA damage response pathway. Complete knockout of the murine Pagr1a is embryonic‐lethal. Given the available evidence, PAGR1 is a strong candidate gene for a novel autosomal recessive severe syndromic neurodevelopmental disorder. [ABSTRACT FROM AUTHOR]

ABSTRACT Hemoglobin City of Hope (Hb‐COH), NC_000011.9(NM_000518.5):c.208G > A; NP_000509.1:p.(Gly70Ser), has rarely been described. The presentation ranges from asymptomatic heterozygosity to significant anemia in patients carrying an additional pathogenic variant in β‐globin. To elucidate the clinical spectrum of Hb‐COH, we analyzed 31 individuals carrying the variant, including, for the first time, homozygous individuals. Seven patients who were compound heterozygous for Hb‐COH and an additional variant in β‐globin, presented with mild‐to‐severe microcytic anemia and elevated hemoglobin‐A2. Three (43%) of these also had elevated fetal hemoglobin, but none required blood transfusions. Seven patients coinherited Hb‐COH with an ‐α3.7‐deletion (NG_000006.1:g.34247_38050del), their presentation ranged from mild microcytic anemia to normal blood counts. Three homozygous and 14 heterozygous individuals for Hb‐COH had normal blood counts. Most Hb‐COH alleles whose origin was traceable were from Ashkenazi Jews (70.4%). To conclude, while isolated Hb‐COH appears asymptomatic even in the homozygous state, it may cause significant anemia when coinherited with an additional pathogenic variant in β‐globin. Understanding the full impact of Hb‐COH is crucial for optimal patient management and for genetic counseling. [ABSTRACT FROM AUTHOR]

Objective: Israel is one of the first countries to incorporate chromosomal microarray analysis into routine prenatal care. We explored attitudes of Israeli healthcare professionals (HCPs) towards the disclosure of challenging findings: variants of uncertain clinical significance (VUS), susceptibility loci (SL) for neurodevelopmental disorders and variants associated with adult-onset (AO) conditions. Particularly, we sought their views on providing parental choice regarding the disclosure of these findings.Methods: Twenty-nine in-depth interviews were conducted with genetic counselors (n = 19), medical geneticists (n = 4), medical geneticists that are trained in and practice fetal medicine (n = 3), and fetal medicine experts (n = 3).Results: Most participants (n = 24) supported parental choice regarding uncertain genetic information. Engaging parents in disclosure decisions allows avoidance from potentially anxiety-provoking information, practicing parental autonomy, and better preparation in cases where uncertain findings are identified. HCPs believed that given appropriate preparation, parents can make informed decisions. Four participants believed that disclosure should be based on professional judgment and one supported full-disclosure. Unlike VUS or SL, all interviewees agreed that in cases of medically actionable AO conditions, the benefit of disclosure outweighs the damage.Conclusion: HCPs attitudes are largely in-line with the Israeli practice of involving parents in disclosure decisions regarding uncertain information. This may mitigate disclosure dilemmas and allow personalized disclosure based on parents' views. [ABSTRACT FROM AUTHOR]

Calpainopathies constitute a heterogeneous group of disorders resulting from deficiencies in calpains, calcium‐specific proteases that modulate substrates by limited proteolysis. Clinical manifestations depend on tissue‐specific expression of the defective calpain and substrate specificity. CAPN15, encoding the Drosophila small optic lobes (sol) homolog, was recently found to cause various eye defects in individuals carrying bi‐allelic missense variants. Here we report on two siblings with manifestations reminiscent of Johanson‐Blizzard syndrome including failure to thrive, microcephaly, global developmental delay, dysmorphic features, endocrine abnormalities and congenital malformations, in addition to eye abnormalities. Exome sequencing identified a homozygous 47 base‐pair deletion in a minimal intron of CAPN15, including the splice donor site. Sequencing of cDNA revealed single exon skipping, resulting in an out‐of‐frame deletion with a predicted premature termination codon. These findings expand the phenotypic spectrum associated with CAPN15 variants, and suggest that complete loss‐of‐function is associated with a recognizable syndrome of congenital malformations and developmental delay, overlapping Johanson‐Blizzard syndrome and the recently observed brain defects in Capn15 knockout (KO) mice. Moreover, the data highlight the unique opportunity for indel detection in minimal introns. [ABSTRACT FROM AUTHOR]

Trio exome sequencing is a powerful tool in the molecular investigation of monogenic disorders and provides an incremental diagnostic yield over proband‐only sequencing, mainly due to the rapid identification of de novo disease‐causing variants. However, heterozygous variants inherited from unaffected parents may be inadvertently dismissed, although multiple explanations are available for such scenarios including mosaicism in the parent, incomplete penetrance, imprinting, or skewed X‐inactivation. We report three probands, in which a pathogenic or likely pathogenic variant was identified upon exome sequencing, yet was inherited from an unaffected parent. Segregation of the variants (in NOTCH1, PHF6, and SOX10) in the grandparent generation revealed that the variant was de novo in each case. Additionally, one proband had skewed X‐inactivation. We discuss the possible genetic mechanism in each case, and urge caution in data interpretation of exome sequencing data. We illustrate the utility of expanding segregation studies to the grandparent generation and demonstrate the impact on exome interpretation strategies, by showing that objective genotype data can overcome subjective parental report of lack of symptoms. [ABSTRACT FROM AUTHOR]

Objective: To investigate the genetic basis of the recessive form of primary familial brain calcification and study pathways linking a novel gene with known dominant genes that cause the disease. Methods: Whole exome sequencing and Sanger‐based segregation analysis were used to identify possible disease causing mutations. Mutation pathogenicity was validated by structural protein modeling. Functional associations between the candidate gene, MYORG, and genes previously implicated in the disease were examined through phylogenetic profiling. Results: We studied nine affected individuals from two unrelated families of Middle Eastern origin. The median age of symptom onset was 29.5 years (range 21–57 years) and dysarthria was the most common presenting symptom. We identified in the MYORG gene, a homozygous c.1233delC mutation in one family and c.1060_1062delGAC mutation in another. The first mutation results in protein truncation and the second in deletion of a highly conserved aspartic acid that is likely to disrupt binding of the protein with its substrate. Phylogenetic profiling analysis of the MYORG protein sequence suggests co‐evolution with a number of calcium channels as well as other proteins related to regulation of anion transmembrane transport (False Discovery Rate, FDR < 10−8) and with PDCD6IP, a protein interacting with PDGFRβ which is known to be involved in the disease. Interpretation: MYORG mutations are linked to a recessive form of primary familial brain calcification. This association was recently described in patients of Chinese ancestry. We suggest the possibility that MYORG mutations lead to calcification in a PDGFRβ‐related pathway. [ABSTRACT FROM AUTHOR]

Objectives: Chromosomal microarray analysis is effectively applied prenatally to detect copy number changes. Single nucleotide polymorphism (SNP) probes included in the microarray platform can detect regions of excessive homozygosity and identical-by-descent genomic stretches. The utility of the latter as part of prenatal diagnosis is not well established. Recessive founder mutations are well recognized within distinct ethnic groups. Combining these data with prenatal sonography provides accurate focused molecular diagnoses quickly. We aimed to evaluate the application of this approach in expectant families presenting to our unit.Methods: Three unrelated gravidae presenting with specific fetal sonographic findings: (1) ventriculomegaly with encephalocele; (2) severe polyhydramnion; and (3) enlarged echogenic kidneys, underwent amniocentesis for chromosomal microarray analysis, and genome-wide human SNP array was used to analyze DNA from amniocytes. The Genomic Oligoarray and SNP array evaluation tool v3.0© was used to detect recessive loci associated with the reported clinical findings. Candidate genes were further interrogated using the Israeli National Genetic Database (INGD) and specifically searching and identifying a corresponding founder mutation within the defined ethnic group.Results: Three fetuses from 3 distinct nuclear families in which the parents shared a similar ethnicity (either Ashkenazi or Bukharan Jews) albeit no reported consanguinity were assessed. We found no copy number changes; however, by evaluating regions of homozygosity, we were able to reveal relevant candidate gene for the specific phenotype for each fetus. Using the INGD led to targeted testing of a specific homozygous fetal mutation for which parents were found to be carriers. In the fetus with ventriculomegaly with encephalocele c.1167dupA mutation in the FKTN gene, in the fetus with severe polyhydramnion c.167ins6[TTTCCC] mutation in the BSND gene, and in the fetus with enlarged echogenic kidneys, c.3761_3762delCCinsG in the PKHD1 gene were identified.Conclusions: A tripartite approach integrating sonographic pathology with regions of excessive homozygosity data and INGD-based founder mutation repository yields a comprehensive streamlined approach to provide accurate genetic diagnosis and counselling within the time constraints of an ongoing pregnancy. [ABSTRACT FROM AUTHOR]

Lissencephaly is a severe malformation of cortical development, most often attributed to abnormalities in neuronal migration. It is associated with a severe prognosis including developmental delay, intellectual disability, and seizures. Lissencephaly can be reliably diagnosed during late gestation by neurosonography or fetal magnetic resonance imaging (MRI). We report two sibling male fetuses who were diagnosed with delayed cortical sulcation highly suggestive of lissencephaly during late pregnancy. After receiving genetic counseling, the parents elected to terminate the pregnancies based on the neuroradiological findings and the associated severe prognosis. Whole exome sequencing (WES) of an affected fetus, and subsequent Sanger sequencing of the second fetus, revealed a homozygous frameshift variant in CRADD, which encodes an adaptor protein that interacts with PIDD and caspase-2 to initiate apoptosis. Biallelic variants in this gene have been recently reported to cause 'thin' lissencephaly and intellectual disability. Interestingly, the allegedly healthy father was also found to be homozygous for the variant, prompting evaluation by brain MRI which revealed hypogyration. This study underscores the phenotypic variability of pathogenic variants in CRADD and the challenges of prenatal genetic counseling. [ABSTRACT FROM AUTHOR]

An emerging class of mitochondrial disorders is caused by mutations in nuclear genes affecting mitochondrial dynamics and function. One of these is the DNM1L gene encoding the dynamin-related protein 1 (DRP1), which is pivotal in the mitochondrial fission process. Here, we describe a patient with a novel dominant-negative, de novo DNM1L mutation, which expands the clinical spectrum. The patient reported here exhibits a chronic neurological disorder, characterized by postnatal microcephaly, developmental delay, and pain insensitivity. Muscle biopsy disclosed decreased respiratory chain complex IV activity. Exome sequencing showed a de novo heterozygous c.1084G>A (p.G362S) mutation. Subsequent studies of patient skin fibroblasts showed markedly impaired mitochondrial fission and a partial respiratory chain defect while peroxisomal morphology remained intact. Human foreskin fibroblasts over-expressing the mutant DNM1L gene displayed aberrant mitochondrial morphology. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objective. Gestational diabetes mellitus (GDM) influences fetal development and offspring's metabolic risk. We evaluated this association in 17-year-old offspring adjusting for birth weight (BW) and prepregnancy maternal BMI (mBMI). Study Design. The JPS birth cohort contains extensive data on 92,408 births from 1964 to 1976. Offspring's BMI and blood pressure (BP) were obtained from military records. For a subcohort born between 1974 and 1976, prepregnancy mBMI was available. Offspring were classified as born to mothers with GDM (n = 293) or born to mothers without recorded GDM (n = 59,499). Results. GDM offspring had higher mean BMI and systolic and diastolic BP compared to no-recorded-GDM offspring. After adjusting for BW, GDM remained significantly associated with offspring BMI and diastolic BP (β = 1.169 and 1.520, resp.). In the subcohort, when prepregnancy mBMI was entered to the models, it markedly attenuated the associations with GDM. Conclusions. Maternal characteristics have long-term effects on cardiometabolic outcomes of their offspring aged 17 years. [ABSTRACT FROM AUTHOR]

In Israel, Krabbe disease is frequent in two Moslem Arab villages in the Jerusalem area. In this paper we present our experience of almost four decades with diagnosis of Krabbe disease, carrier screening and prenatal diagnosis. The screening program is well accepted by the community, and there is a clear trend towards premarital testing. The screening program and prenatal diagnosis have led to a decrease in the incidence of Krabbe disease from 1.6 per 1,000 live births to 0.82 per 1,000. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

This study estimated the genetic and environmental determinants of plasma leptin and insulin levels and of obesity-related phenotypes. Included in this analysis were family members from 80 families living in kibbutz settlements, who participated in two examinations 8–10 years apart. We estimated that polygenes explained 30–50% of the adjusted leptin and insulin levels and 30–70% of the anthropometric phenotypes. This study demonstrated a significant genetic influence on longitudinal changes in leptin and BMI (h2 = 0.45) and small-to-moderate heritability estimates for changes in insulin and other obesity-related phenotypes. In bivariate genetic analyses, we observed positive genetic correlations between leptin and anthropometric phenotypes, suggesting that shared effects of the same sets of loci account for 20–30% of the additive genetic variance in these pairs of variables. Shared genetic factors also account for 20–25% of the additive genetic variance in insulin—anthropometric pairs of variables.Obesity (2009) 17 7, 1458–1460. doi:10.1038/oby.2008.672 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Niemann-Pick type C (NPC) disease is a lysosomal neurovisceral storage disease. The spectrum of the clinical presentation as well as the severity of the disease and the age of presentation may be highly variable. Fetal presentation is rarely described in the literature. Here, we report on seven new cases of fetal onset NPC of whom two were diagnosed in utero and five postnatally. The fetal clinical presentation, included, in utero splenomegaly (6/7), in utero hepatomegaly (5/7), in utero ascites (4/7), intra uterine growth retardation (IUGR) (2/7), and oligohydramnios (2/7). Placentomegaly was present in two of the three pregnancies examined. Congenital thrombocytopenia (4/4), congenital anemia (2/4), and petechial rash (2/5) were diagnosed immediately after birth. Three patients were born preterm. Pregnancy and postnatal outcome were remarkably poor with one case of intrauterine fetal death, one elective termination of pregnancy, and four patients who died within the first months of life from a rapidly fatal neonatal cholestatic disease. NPC1 gene mutation analysis identified all of the mutant alleles including three novel mutations. Splenomegaly, hepatomegaly, and ascites were the most consistent prenatal ultrasonographic findings of the NPC fetuses. We suggest that once identified these findings, should raise the suspicion of fetal NPC. Our study further expands the antenatal clinical spectrum of NPC and provides clues to its prenatal diagnosis., (2009 Wiley-Liss, Inc.)