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.

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.

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.

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

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.

Exome sequencing for structurally normal fetuses-yields and ethical issues.

The yield of chromosomal microarray analysis (CMA) is well established in structurally normal fetuses (0.4-1.4%).

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.

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.

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.

Fanconi Anemia Gene Variants in Patients with Gonadal Dysfunction.

Fanconi anemia (FA) is a multisystem disease, characterized by the triad of physical abnormalities, bone marrow failure, and increased risk for malignancy. In the past few years, data has accumulated regarding fertility issues in FA patients, mostly due to gonadal dysfunction, which is prevalent in FA patients reaching puberty. It seems that attenuated FA phenotype lacking the classical manifestations often is presented with POI or azoospermia.

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.

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.

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.

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.

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.

Information Women Choose to Receive About Prenatal Chromosomal Microarray Analysis.

Objective: To examine the choices of women with both high-risk and low-risk pregnancies who are undergoing prenatal chromosomal microarray analysis in a clinical setting regarding three challenging types of findings: variants of uncertain clinical significance, susceptibility loci for neurodevelopmental disorders, and copy number variants associated with risks for adult-onset conditions. We assessed whether women's choices were associated with indications for testing or with one-on-one pretest genetic counseling.

Methods: In this cross-sectional study, medical records of women who underwent invasive prenatal chromosomal microarray analysis testing (N=1,070) at Hadassah Medical Center between June 2017 and February 2018 were examined for testing indications, choices regarding chromosomal microarray analysis findings, and type of pretest genetic counseling.

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.

BRCA mutations and reproduction.

Deleterious mutations in BRCA1 or BRCA2 genes have long been recognized as independent risk factors, mostly for breast and ovarian cancer. Numerous studies have evaluated the molecular processes involving these genes, the pathophysiology of BRCAness, follow up options and modes of prophylaxis. The fertility of BRCA carriers, however, has not been widely investigated.

Failure to Thrive in the Context of Carney Complex.

Background/aims: Carney complex (CNC) is a rare syndrome associated with multiple tumors and several other unique manifestations. We describe the clinical, genetic, and laboratory findings in a cohort of patients with CNC and failure to thrive (FTT).

Methods: A retrospective case series of pediatric patients with CNC presenting with FTT.

Autosomal dominant gain of function STAT1 mutation and severe bronchiectasis.

Background: In a substantial number of patients with non-cystic fibrosis (CF) bronchiectasis an etiology cannot be found. Various complex immunodeficiency syndromes account for a significant portion of these patients but the mechanism elucidating the predisposition for suppurative lung disease often remains unknown.

Objective: To investigate the cause and mechanism predisposing a patient to severe bronchiectasis.