Clinical Actionability of Genetic Findings in Cerebral Palsy: A Systematic Review and Meta-Analysis.

Importance: Single gene variants can cause cerebral palsy (CP) phenotypes, yet the impact of genetic diagnosis on CP clinical management has not been systematically evaluated.

Objective: To evaluate how frequently genetic testing results would prompt changes in care for individuals with CP and the clinical utility of precision medicine therapies.

Data Sources: Published pathogenic or likely pathogenic variants in OMIM genes identified with exome sequencing in clinical (n = 1345) or research (n = 496) cohorts of CP were analyzed.

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.

SHaploseek is a sequencing-only, high-resolution method for comprehensive preimplantation genetic testing.

Recent advances in genomic technologies expand the scope and efficiency of preimplantation genetic testing (PGT). We previously developed Haploseek, a clinically-validated, variant-agnostic comprehensive PGT solution. Haploseek is based on microarray genotyping of the embryo's parents and relatives, combined with low-pass sequencing of the embryos.

Intellectual disability syndrome associated with a homozygous founder variant in in Ashkenazi Jews.

Background: Neurodevelopmental disorders (NDDs) impact both the development and functioning of the brain and exhibit clinical and genetic variability. RAP and RAB proteins, belonging to the RAS superfamily, are identified as established contributors to NDDs. However, the involvement of SGSM (small G protein signalling modulator), another member of the RAS family, in NDDs has not been previously documented.

Clinical actionability of genetic findings in cerebral palsy.

Background And Objectives: Single gene mutations are increasingly recognized as causes of cerebral palsy (CP) phenotypes, yet there is currently no standardized framework for measuring their clinical impact. We evaluated Pathogenic/Likely Pathogenic (P/LP) variants identified in individuals with CP to determine how frequently genetic testing results would prompt changes in care.

Methods: We analyzed published P/LP variants in OMIM genes identified in clinical (n = 1,345 individuals) or research (n = 496) cohorts using exome sequencing of CP patients.

Angular Correlations in the β Decay of ^{8}B: First Tensor-Current Limits from a Mirror-Nucleus Pair.

We present the first measurement of the α-β-ν angular correlation in the Gamow-Teller β^{+} decay of ^{8}B. This was accomplished using the Beta-decay Paul Trap, expanding on our previous work on the β^{-} decay of ^{8}Li. The ^{8}B result is consistent with the V-A electroweak interaction of the standard model and, on its own, provides a limit on the exotic right-handed tensor current relative to the axial-vector current of |C_{T}/C_{A}|^{2}<0.

Clinically Complex LRBA Deficiency Due to a Founder Allele in the Georgian Jewish Population.

Pathogenic variants in LRBA, encoding the LPS Responsive Beige-Like Anchor (LRBA) protein, are responsible for recessive, early-onset hypogammaglobulinemia, severe multi-organ autoimmunity, and lymphoproliferation, with increased risk for malignancy. LRBA deficiency has a wide clinical spectrum with variable age of onset and disease severity. Three apparently unrelated patients with LRBA deficiency, of Georgian Jewish descent, were homozygous for LRBA c.

Carrier screening for Krabbe disease in an isolated inbred community.

Infantile Krabbe disease (OMIM 245200) is a severe, fatal autosomal recessive neurodegenerative disorder that is relatively frequent in two Muslims villages within Jerusalem. After the characterization of the founder mutation, a population carrier screening for Krabbe disease became a component of the Israeli program for the detection and the prevention of birth defects. Between 2010 and 2018, 3366 individuals were tested and among them 247 carriers for Krabbe disease were identified (7.

Improved Limit on Tensor Currents in the Weak Interaction from ^{8}Li β Decay.

The electroweak interaction in the standard model is described by a pure vector-axial-vector structure, though any Lorentz-invariant component could contribute. In this Letter, we present the most precise measurement of tensor currents in the low-energy regime by examining the β-ν[over ¯] correlation of trapped ^{8}Li ions with the Beta-decay Paul Trap. We find a_{βν}=-0.

Combining cytogenetic and genomic technologies for deciphering challenging complex chromosomal rearrangements.

Complex chromosomal rearrangements (CCRs), a class of structural variants (SVs) involving more than two chromosome breaks, were classically thought to be extremely rare. As advanced technologies become more available, it has become apparent that CCRs are more common than formerly thought, and are a substantial cause of genetic disorders. We attempted a novel approach for solving the mechanism of challenging CCRs, which involve repetitive sequences, by precisely identifying sequence-level changes and their order.

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.

Diagnostic yield of chromosomal microarray and trio whole exome sequencing in cryptogenic cerebral palsy.

Objective: To determine the yield of genetic diagnoses using chromosomal microarray (CMA) and trio whole exome sequencing (WES), separately and combined, among patients with cryptogenic cerebral palsy (CP).

Methods: Trio WES of patients with prior CMA analysis for cryptogenic CP, defined as disabling, non-progressive motor symptoms beginning before the age of 3 years without known cause.

Results: Given both CMA analysis and trio WES, clinically significant genetic findings were identified for 58% of patients (26 of 45).

The yield of chromosomal microarray in pregnancies with congenital cardiac defects and normal noninvasive prenatal screening.

Background: Evidence comparing the yield of chromosomal microarray analysis to noninvasive prenatal screening in pregnancies with congenital heart anomalies is currently limited.

Objective: This study aimed to examine the residual risk of clinically significant chromosomal microarray analysis results in fetuses with congenital heart defects by its various subtypes following a normal noninvasive prenatal screening.

Study Design: Using a population-based, countrywide computerized database, we retrieved the reports of all pregnancies undergoing chromosomal microarray analysis because of congenital heart defects through the years 2013-2019.

Expanded clinical validation of Haploseek for comprehensive preimplantation genetic testing.

Purpose: We previously developed Haploseek, a method for comprehensive preimplantation genetic testing (PGT). However, some key features were missing, and the method has not yet been systematically validated.

Methods: We extended Haploseek to incorporate DNA from embryo grandparents and to allow testing of variants on chromosome X or in regions where parents share common haplotypes.

Preimplantation genetic testing (PGT) for copy number variants of uncertain significance (CNV- VUS) in the genomic era: to do or not to do?

Purpose: To review cases of couples presented to our PGT-unit with copy number variants (CNVs) classified as variants of uncertain significance (VUS) in order to better understand their needs.

Methods: Retrospective cohort study conducted in a tertiary medical-center, 2014-2019. We reviewed files of all couples applying for genetic counseling with CNVs classified as VUS.

The role of orotic acid measurement in routine newborn screening for urea cycle disorders.

Urea cycle disorders (UCDs), including OTC deficiency (OTCD), are life-threatening diseases with a broad clinical spectrum. Early diagnosis and initiation of treatment based on a newborn screening (NBS) test for OTCD with high specificity and sensitivity may contribute to reduction of the significant complications and high mortality. The efficacy of incorporating orotic acid determination into routine NBS was evaluated.

A defect in GPI synthesis as a suggested mechanism for the role of ARV1 in intellectual disability and seizures.

Deficiency of the endoplasmic reticulum transmembrane protein ARV1 leads to epileptic encephalopathy in humans and in mice. ARV1 is highly conserved, but its function in human cells is unknown. Studies of yeast arv1 null mutants indicate that it is involved in a number of biochemical processes including the synthesis of sphingolipids and glycosylphosphatidylinositol (GPI), a glycolipid anchor that is attached to the C-termini of many membrane bound proteins.

Cold-sensitive phenotypes of a yeast null mutant of ARV1 support its role as a GPI flippase.

Glycosylphosphatidylinositol (GPI) is synthesized in the endoplasmic reticulum (ER) and added onto proteins to form GPI-anchored proteins. Among the many proteins involved in this process, ACAT-related enzyme-2 required for viability 1 (Arv1) is a candidate, functioning as a flippase that translocates GPI intermediates from the cytoplasmic side into the luminal side of the ER membranes. Here, we show that the deletion of the ARV1 gene in yeast leads to cold-sensitive defects in cell growth and GPI anchor synthesis.

The novel founder homozygous V225M mutation in the HSD17B3 gene causes aberrant splicing and XY-DSD.

Purpose: Mutations in the gene HSD17B3 encoding the 17-beta hydroxysteroid dehydrogenase 3 enzyme cause testosterone insufficiency leading to XY disorders of sex development. In this study the clinical and molecular characteristics of three patients from consanguineous families are elucidated.

Methods: We identified three patients from two unrelated families with XY DSD and a novel homozygous HSD17B3:c.

Haploseek: a 24-hour all-in-one method for preimplantation genetic diagnosis (PGD) of monogenic disease and aneuploidy.

Purpose: To develop an economical, user-friendly, and accurate all-in-one next-generation sequencing (NGS)-based workflow for single-cell gene variant detection combined with comprehensive chromosome screening in a 24-hour workflow protocol.

Methods: We subjected single lymphoblast cells or blastomere/blastocyst biopsies from four different families to low coverage (0.3×-1.

Chromosomal Microarray Analysis Results From Pregnancies With Various Ultrasonographic Anomalies.

Objective: To examine chromosomal microarray analysis results in pregnancies with various ultrasonographic anomalies and to characterize the copy number variants in diverse fetal phenotypes.

Methods: We retrospectively examined chromosomal microarray analyses of amniocenteses performed nationwide as a result of fetal ultrasonographic anomalies (structural defects, fetal growth restriction, and polyhydramnios) between January 2013 and September 2017. The rate of abnormal chromosomal microarray findings was compared between the different phenotypes and with a previously described control population of 15,225 pregnancies with normal ultrasonographic findings.

An immune tolerance approach using transient low-dose methotrexate in the ERT-naïve setting of patients treated with a therapeutic protein: experience in infantile-onset Pompe disease.

Purpose: To investigate immune tolerance induction with transient low-dose methotrexate (TLD-MTX) initiated with recombinant human acid α-glucosidase (rhGAA), in treatment-naïve cross-reactive immunologic material (CRIM)-positive infantile-onset Pompe disease (IOPD) patients.

Methods: Newly diagnosed IOPD patients received subcutaneous or oral 0.4 mg/kg TLD-MTX for 3 cycles (3 doses/cycle) with the first 3 rhGAA infusions.

Essential Role of BRCA2 in Ovarian Development and Function.

The causes of ovarian dysgenesis remain incompletely understood. Two sisters with XX ovarian dysgenesis carried compound heterozygous truncating mutations in the BRCA2 gene that led to reduced BRCA2 protein levels and an impaired response to DNA damage, which resulted in chromosomal breakage and the failure of RAD51 to be recruited to double-stranded DNA breaks. The sisters also had microcephaly, and one sister was in long-term remission from leukemia, which had been diagnosed when she was 5 years old.