Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental and epileptic encephalopathy to syndromic optic atrophy.

The endosomal sorting complex required for transport (ESCRT) machinery is essential for membrane remodeling and autophagy and it comprises three multi-subunit complexes (ESCRT I-III). We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile). In patient-derived fibroblasts, bi-allelic SNF8 variants cause loss of ESCRT-II subunits. Snf8 loss of function in zebrafish results in global developmental delay and altered embryo morphology, impaired optic nerve development, and reduced forebrain size. In vivo experiments corroborated the pathogenicity of the tested SNF8 variants and their variable impact on embryo development, validating the observed clinical heterogeneity. Taken together, we conclude that loss of ESCRT-II due to bi-allelic SNF8 variants is associated with a spectrum of neurodevelopmental/neurodegenerative phenotypes mediated likely via impairment of the autophagic flux.

Exploring the factors affecting classification and reporting of uncertain prenatal microarray findings, using a "virtual fetus" model-a pilot study.

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.

Detection of copy number variants associated with late-onset conditions in ~16 200 pregnancies: parameters for disclosure and pregnancy outcome.

BACKGROUND: Copy number variants (CNVs) associated with late-onset medical conditions are rare but important secondary findings in chromosomal microarray analysis (CMA) performed during pregnancy. Here, we critically review the cases at two tertiary centres to assess the criteria which guide the disclosure of such findings and develop a disclosure decision tool (DDT) aimed at facilitating disclosure decision. Parental decisions on receiving CNVs associated with risks for late-onset conditions were also recorded. METHODS: Prenatal CMAs in Hadassah and Shaare Zedek Medical Centers from November 2013 to October 2021 were reviewed for CNVs associated with late-onset conditions. The DDT proposed uses a five-parameter scoring system, which considers the severity, median age of onset, penetrance, understanding of genotype-phenotype correlation and actionability of the finding. RESULTS: Out of 16 238 prenatal CMAs, 16 (0.1%) harboured CNVs associated with late-onset conditions, 15 of which were disclosed. Outcome information was available on 13 of the 16 pregnancies, all of which continued to delivery. CONCLUSIONS: Our suggested DDT will help clinicians to quantitatively weigh the variables associated with CNVs of this type and arrive at a well thought out clinical decision regarding disclosure. Although the prevalence of late-onset conditions as a major finding in the prenatal setup is low, it is expected to rise with the increasing use of non-invasive CMA testing and whole exome and genome sequencing.

[THE DIFFERENTIAL DIAGNOSIS OF EXTREMELY HIGH MATERNAL SERUM ALPHA FETOPROTEIN - A CASE REPORT].

INTRODUCTION: A 34 years-old woman was referred to genetic counseling due to extremely high maternal serum alpha fetoprotein (MSAFP) of 58 MoM (541 IU/mL, 654 ng/mL) in the second trimester biochemical test. The couple has five healthy children, three of them were delivered by cesarean section. Current pregnancy follow-up was uneventful except for the demonstration of placenta percreta during anomaly scan. The test also ruled out neural tube or abdominal wall defect. AFP levels in amniotic fluid were normal thus fetal disease was ruled out as the etiology. Total body MRI ruled out space occupying lesion as a source of ectopic secretion of AFP. After exclusion of other ominous etiologies for this extremely high MSAFP, it was related to the placental pathology and probably to abnormal feto-maternal shunts. Fetal fraction in cell free DNA was 18%, considered relatively high, a hint for those speculated shunts. We reviewed the literature regarding the differential diagnosis of high MSAFP including fetal, maternal and placental sources.

Bi-allelic PAGR1 variants are associated with microcephaly and a severe neurodevelopmental disorder: Genetic evidence from two families.

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.

The many etiologies of nonimmune hydrops fetalis diagnosed by exome sequencing.

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.

Is it time for prenatal chromosomal-microarray analysis to all women? A review of the diagnostic yield in structurally normal fetuses.

PURPOSE OF REVIEW: Chromosomal-microarray analysis (CMA) is the first-tier test in pregnancies with structural malformations. Accumulating data show that pathogenic copy number variants (CNVs) can also be identified in structurally normal fetuses. We set out to summarize the published data on the diagnostic yield of CMA in structurally normal fetuses. RECENT FINDINGS: Six studies summarize a total of 29,612 prenatal CMAs performed in structurally normal fetuses. The incidence of highly penetrant pathogenic/likely pathogenic CNVs is 0.4-2.5%. Variability was demonstrated in the timing of CMA testing and type of CNVs classified as pathogenic. The incidence of variants of uncertain significance is 0.4-5.4%. The prevalence of susceptibility loci is 0.3-0.7% when specified, and the incidence of CNVs associated with late onset disease is 0.1%. SUMMARY: With a frequency of abnormal CNVs of 1:40 to 1:250 in structurally normal fetuses, it is recommended that all pregnant women be informed of the possibility to have CMA performed, even in the absence of malformations. Information should also be provided about uncertain and secondary findings.

Chromosomal microarray should be performed for cases of fetal short long bones detected prenatally.

PURPOSE: To investigate the prevalence of pathogenic and likely-pathogenic variants detected by chromosomal microarray analysis (CMA), among pregnancies with fetal short long bones diagnosed by ultrasound. METHODS: The study cohort was based on cases of chromosomal microarray analyses performed nationwide for the indication of short long bones. RESULTS: CMA was performed in 66 cases of short long bones. There were 4 cases with a pathogenic/likely pathogenic result (6%). The rate of chromosomal abnormalities was significantly higher compared to the background risk for copy number variations (CNVs) in pregnancies with no sonographic anomalies (P < 0.001). The yield of CMA in our cohort was significantly higher for both isolated and non-isolated cases, for cases in which the lowest estimated bone length percentile was above the 3rd percentile (below 5th percentile), and for cases diagnosed with short long bones after 22 weeks but not for cases diagnosed after 24 weeks. CONCLUSION: The yield of CMA in cases with short long bones (both isolated and non-isolated) is significantly higher than the background risk for chromosomal anomalies in pregnancies with no sonographic anomalies. This suggests that CMA should be offered in pregnancies with a diagnosis of fetal short long bones.

The Yield of Chromosomal Microarray in Pregnancies Complicated with Fetal Growth Restriction Can Be Predicted According to Clinical Parameters.

INTRODUCTION: We evaluated the yield of chromosomal microarray analysis in pregnancies complicated with fetal growth restriction (FGR) according to specific clinical parameters. METHODS: The study was based on national records from the Israeli Ministry of Health. Chromosomal microarray analyses of amniocenteses performed nationwide for the indication of FGR, from January 2016 to March 2018, were included. The CMA yield was compared to 2 cohorts that reported the background risk. RESULTS: Of 174 tests performed for the indication of FGR, there were 11 cases with a pathogenic/likely pathogenic result (6.3%). The yield of CMA was significantly higher in cases with major structural findings (29.4 vs. 3.4%, p = 0.001), compared to isolated FGR but not for minor structural findings (6.1 vs. 3.4%, p = 0.5). The rate of chromosomal aberrations was significantly higher for all cases with FGR, when compared to the background risk of a cohort of normal pregnancies (odds ratio [OR] 4.7, 95% CI 2.5-9 and OR 6.09, 95% CI 3.2-11.4) but not for isolated cases or cases diagnosed after 24 weeks of pregnancy. CONCLUSIONS: Chromosomal microarray analysis should be performed for all pregnancies complicated with FGR diagnosed before 24 weeks and for cases with major structural anomalies.

Grandparental genotyping enhances exome variant interpretation.

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.

Prevalence and Characteristics of Postpartum Vulvovaginal Atrophy and Lack of Association With Postpartum Dyspareunia.

OBJECTIVE: Breastfeeding-related hypoestrogenic state has been reported as a possible risk factor for postpartum dyspareunia. This study aimed to evaluate the prevalence and characteristics of postpartum vulvovaginal atrophy according to 3 different diagnostic methods and to estimate its association with postpartum dyspareunia and daily vulvovaginal symptoms. METHODS: This is a prospective cohort study of puerperal women attending a routine postpartum checkup. Participants completed a questionnaire and underwent a gynecological examination. Atrophy was diagnosed separately according to gynecologist impression, vaginal pH measurement (≥5.1), and cytologic vaginal maturation index. Patients were followed up with a telephone survey 2-3 months later, inquiring about symptoms possibly associated with atrophy. RESULTS: Of 117 participants, vaginal atrophy was diagnosed in 48% by gynecological examination, 62% by a pH level of 5.1 or greater, and 40.2% had cytological atrophy. Of the 35.9% of women who had resumed sexual intercourse (42/117), 69% reported dyspareunia. No significant association was found between dyspareunia and atrophy parameters. There was no difference in the rates of dyspareunia among women who were exclusively breastfeeding (21/27 = 78%), partially breastfeeding (4/7 = 57%), or not breastfeeding (4/8, 50%). Atrophy was more common in breastfeeding women according to the 3 criteria (gynecological examination: 57.6% vs 16.7%, p = .006; pH: 70% vs 22%, p < .001; vaginal maturation index: 51.1% vs 0%, p < .001). Of the 117 participants, 47% reported daily vulvovaginal symptoms. Those with daily symptoms reported more dyspareunia as compared with those without daily symptoms (85% vs 52%, p = .025). CONCLUSIONS: A high prevalence of atrophy was observed in puerperal women in association with breastfeeding. There was no significant association between atrophy and dyspareunia or daily vulvovaginal symptoms.

Ultrasound findings provide clues to investigate founder mutations expressed as runs of homozygosity in chromosomal microarray studies.

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.

Third- or Fourth-Degree Intrapartum Anal Sphincter Tears Are Associated With Levator Ani Avulsion in Primiparas.

OBJECTIVES: We evaluated primiparous women with clinically diagnosed third- and fourth-degree and anal sphincter tears, to evaluate the rate of levator ani muscle injury compared to primiparous women without sphincter tears. METHODS: Primiparous women delivering in our maternity ward with intrapartum diagnoses of third- or fourth-degree anal sphincter tears, repaired by the overlapping technique, were recruited to undergo 3-dimensional transperineal sonography of the pelvic floor anatomy, including the anterior and posterior compartments. Primiparas with uncomplicated vaginal deliveries were recruited as a comparison group. Patient files were examined, and maternal backgrounds and delivery and neonatal details were extracted for all patients. RESULTS: Ninety-four women with tears were recruited to the study group, and 464 women with normal vaginal deliveries constituted the comparison group. The groups differed significantly in the rates of levator ani defects: 38 of 94 women (40.4%) in the study group versus 75 of 464 (16.2%) in the comparison group (P < .001; odds ratio, 3.53; 95% confidence interval, 2.18­5.7). Neonatal head circumference differed significantly between the study and comparison groups: (mean ・} SD, 34.5 ・} 1.3 cm in the study group versus 33.9 ・} 1.3 cm in the comparison group; P= .005), as did birth weight (3322 ・} 430 g in the study group versus 3169 ・} 458 g in the comparison group; P= .007). The groups did not differ in maternal age, gestational age at delivery, length of second stage of labor, and rates of epidural anesthesia, episiotomy, and vacuum extraction. CONCLUSIONS: Third- and fourth-degree intrapartum sphincter tears are associated with levator ani avulsion. Knowledge of complex pelvic floor damage may allow for prompt referral to secondary preventive measures for pelvic floor disorders.

Third- or Fourth-Degree Intrapartum Anal Sphincter Tears Are Associated With Levator Ani Avulsion in Primiparas.

OBJECTIVES: We evaluated primiparous women with clinically diagnosed third- and fourth-degree and anal sphincter tears, to evaluate the rate of levator ani muscle injury compared to primiparous women without sphincter tears. METHODS: Primiparous women delivering in our maternity ward with intrapartum diagnoses of third- or fourth-degree anal sphincter tears, repaired by the overlapping technique, were recruited to undergo 3-dimensional transperineal sonography of the pelvic floor anatomy, including the anterior and posterior compartments. Primiparas with uncomplicated vaginal deliveries were recruited as a comparison group. Patient files were examined, and maternal backgrounds and delivery and neonatal details were extracted for all patients. RESULTS: Ninety-four women with tears were recruited to the study group, and 464 women with normal vaginal deliveries constituted the comparison group. The groups differed significantly in the rates of levator ani defects: 38 of 94 women (40.4%) in the study group versus 75 of 464 (16.2%) in the comparison group (P < .001; odds ratio, 3.53; 95% confidence interval, 2.18-5.7). Neonatal head circumference differed significantly between the study and comparison groups: (mean ± SD, 34.5 ± 1.3 cm in the study group versus 33.9 ± 1.3 cm in the comparison group; P= .005), as did birth weight (3322 ± 430 g in the study group versus 3169 ± 458 g in the comparison group; P = .007). The groups did not differ in maternal age, gestational age at delivery, length of second stage of labor, and rates of epidural anesthesia, episiotomy, and vacuum extraction. CONCLUSIONS: Third- and fourth-degree intrapartum sphincter tears are associated with levator ani avulsion. Knowledge of complex pelvic floor damage may allow for prompt referral to secondary preventive measures for pelvic floor disorders.

Detailed transabdominal fetal anatomic scanning in the late first trimester versus the early second trimester of pregnancy.

OBJECTIVES: To compare visualization rates for early targeted organ scanning at gestational ages ranging from 11 weeks 3 days to 13 weeks 2 days versus 14 weeks 3 days to 16 weeks 2 days. METHODS: We conducted a prospective longitudinal study of patients who presented for nuchal translucency (NT) screening and targeted organ scanning. Extended targeted organ scanning, including the central nervous system, face and neck, chest, heart (including complete echocardiography), digestive system, abdominal wall, urinary system, skeleton, and umbilical cord with its insertion and placenta, was performed on gravidas in 2 age ranges. Uterine artery Doppler mapping was performed during the second scan. All cases were examined twice: once at NT screening (up to 13 weeks 2 days) and again in the early second trimester. RESULTS: A total of 408 women were recruited and scanned twice. Three abnormalities were diagnosed in the second scan that were not seen in the first: dysplastic long bones, tricuspid stenosis, and cleft lip (without palate involvement). None had chromosomal anomalies. Successful visualization rates in all organ systems exceeded 94% in the second trimester. At the first-trimester scan, some systems had high success rates, whereas others were very low; eg, in the brain, the cerebellum and posterior fossa were visualized successfully approximately 50% of the time and the upper lip only approximately 10%. On fetal echocardiography, the 4-chamber view and outflow tracts were imaged successfully approximately 40% of the time, and the kidneys approximately 35%. Uterine artery Doppler mapping was possible in all patients on at least one side. On third-trimester follow-up, we diagnosed 1 mild pulmonary stenosis, 1 autosomal recessive polycystic kidney disease, and 1 ventricular septal defect. CONCLUSIONS: The early second-trimester scan was much more productive than targeted organ scanning performed during the NT window. When counseling women regarding the optimal time for early transabdominal targeted organ scanning, successful visualization rates for various organ systems should be considered.

A Case Report of Familial Mayer-Rokitansky-Küster-Hauser Syndrome as Part of the Phenotypic Spectrum of the 2q37 Deletion.

We performed a genetic investigation into the case of an inherited Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Our patients were an adolescent and her mother, both with MRKH syndrome. The delivery of a biological offspring was achieved via a gestational carrier. Karyotype and exome sequencing were used to complete a three-generation genetic analysis of the family. Both the mother and her daughter harbored a deletion of 4 Mb at the locus of 2q37, a syndrome rarely described in association with MRKH. No pathogenic single-nucleotide variant relevant to the phenotype was found. The deletion was not inherited from either parent of the mother. In addition, some physical findings suggesting 2q37 deletion syndrome were found in our patients. We conclude that when combined with the use of a gestational carrier or uterine transplantation, the identification of a genetic cause for MRKH may enable the application of preimplantation genetic testing on embryos, thus potentially averting the transmission of the genetic anomaly to subsequent generations.

Tumor STAT3 tyrosine phosphorylation status, as a predictor of benefit from adjuvant chemotherapy for breast cancer.

Signal transducer and activator of transcription 3 (STAT3) is a point of convergence for numerous oncogenic signaling pathways. In breast cancer cell lines and xenograft models activated STAT3 participates in breast tumorigenesis, while studies in humans have demonstrated that phosphorylated (tyrosine705)-STAT3 is a marker of good prognosis in breast cancer. In order to resolve this paradox we hypothesized that in clinic, phospho-STAT3 has a predictive role of benefit from adjuvant chemotherapy; therefore the goal of this study was to determine the usefulness of phospho-STAT3 status as a predictor of benefit from adjuvant chemotherapy in breast cancer patients. Immunohistochemical analysis of phospho-STAT3 was performed on a tissue microarray of breast cancer specimens. The expression pattern of phospho-STAT3 was retrospectively correlated with pathological parameters and overall survival in patients who were or were not treated with adjuvant chemotherapy. Of 375 tissue specimens interpretable for phospho-STAT3, 134 (36 %) exhibited positive phospho-STAT3 nuclear expression. Among 234 patients who received adjuvant therapy, those with tumors displaying positive phospho-STAT3 nuclear expression had a better ten-year rate of overall survival than patients with tumors displaying negative phospho-STAT3 nuclear expression (P = 0.001). Among patients who did not received adjuvant chemotherapy, positive phospho-STAT3 nuclear status was not correlated with increased overall survival (P = 0.54). Positive phospho-STAT3 was correlated with improved overall survival only among patients who received adjuvant chemotherapy in a multivariate analysis adjusted for stage, grade, hormonal status, Her2 status, and age, irrespective of the chemotherapy regimen received (hazard ratio for death, 0.35 [95 % CI 0.188-0.667]; P = 0.001). These findings support the role of phospho-STAT3 as a marker of favorable outcome in breast cancer patients treated with adjuvant chemotherapy. Whether phospho-STAT3 has a predictive role of benefit from adjuvant chemotherapy has to be validated on prospective, randomized, controlled studies.

Prenatal diagnosis of lanosterol synthase deficiency: Fetal ultrasound findings as a window on family genetics.

Cholesterol is essential in the brain from the earliest stages of embryonic development. Disruption of cholesterol synthesis pathways that leads to cholesterol deficiency underlies a few syndromes, including desmosterolosis and Smith-Lemli-Opitz syndrome. In both syndromes, brain anomalies can occur. The LSS gene encodes lanosterol synthase (LSS), an important enzyme in the cholesterol biosynthesis pathway. Biallelic pathogenic variants in this gene cause alopecia-intellectual disability type 4 syndrome (APMR4, MIM 618840), a rare autosomal recessive disorder. Here, we describe two new LSS variants (c.1016C > T; p. Ser339Leu and c.1522G > C; p. Gly508Arg) found in a compound heterozygous fetus diagnosed prenatally with brain abnormalities by ultrasound scanning. Two of his siblings from the same parents also harbored these variants. Both siblings had alopecia, mild intellectual disability, autism spectrum disorder, and cataracts. To the best of our knowledge, this case represents the first prenatal diagnosis of APMR4 first suspected by ultrasound. In addition, the phenotypic features of the siblings are extensive compared with those described in previous reports and include abnormal corpus callosum, cataracts, alopecia, and developmental delay.