Maya I.,The Raphael Recanati Genetics Institute |
Maya I.,Tel Aviv University |
Kahana S.,The Raphael Recanati Genetics Institute |
Yeshaya J.,The Raphael Recanati Genetics Institute |
And 13 more authors.
Ultrasound in Obstetrics and Gynecology | Year: 2017
Objective: To evaluate the association between aberrant right subclavian artery (ARSA), with or without additional risk factors for aneuploidy or ultrasound abnormality, and results of chromosomal microarray analysis (CMA). Methods: This was a multicenter study of fetuses diagnosed with ARSA that underwent genetic analysis by CMA, all samples being analyzed in the same laboratory. Clinical investigation included nuchal translucency measurement, first- and second-trimester maternal serum screening, early and late second-trimester fetal anatomy scans and fetal echocardiography. Comparative genomic hybridization microarray analysis or single-nucleotide polymorphism array technology was used for CMA of DNA samples obtained from amniotic fluid. Results: CMA results were available for 63 fetuses with ARSA. In 36 fetuses, ARSA was an isolated finding, and no pathogenic variant was found. Additional ultrasound findings and/or risk factors for aneuploidy were present in 27 fetuses, five of which had pathogenic CMA results. Of these five, trisomy 21 was detected in a fetus with echogenic intracardiac focus (EIF), 22q11 deletion was detected in a fetus with EIF and an increased risk of trisomy 21 of 1:230 from maternal serum screening, 22q11 duplication was detected in a fetus with hypoplastic right kidney and choroid plexus cyst and 22q11 deletion was detected in a fetus with right aortic arch and clubfoot. The fifth fetus had increased nuchal translucency thickness (4 mm) and a ventricular septal defect, and CMA identified both 22q11 deletion and 1q21 duplication. Conclusions: In fetuses with isolated ARSA, an invasive procedure for CMA is not indicated. However, CMA is recommended when additional ultrasound abnormalities or risk factors for aneuploidy are observed. The chromosomal findings in four of the five cases with an abnormal CMA result in our study would not have been detected by standard fetal chromosomal testing. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.
Lee J.Y.W.,King's College London |
Hsu C.-K.,National Cheng Kung University |
Michael M.,King's College London |
Nanda A.,Al Sabah Hospital |
And 30 more authors.
American Journal of Human Genetics | Year: 2017
SPG23 is an autosomal-recessive neurodegenerative subtype of lower limb spastic paraparesis with additional diffuse skin and hair dyspigmentation at birth followed by further patchy pigment loss during childhood. Previously, genome-wide linkage in an Arab-Israeli pedigree mapped the gene to an approximately 25 cM locus on chromosome 1q24–q32. By using whole-exome sequencing in a further Palestinian-Jordanian SPG23 pedigree, we identified a complex homozygous 4-kb deletion/20-bp insertion in DSTYK (dual serine-threonine and tyrosine protein kinase) in all four affected family members. DSTYK is located within the established linkage region and we also found the same mutation in the previously reported pedigree and another Israeli pedigree (total of ten affected individuals from three different families). The mutation removes the last two exons and part of the 3′ UTR of DSTYK. Skin biopsies revealed reduced DSTYK protein levels along with focal loss of melanocytes. Ultrastructurally, swollen mitochondria and cytoplasmic vacuoles were also noted in remaining melanocytes and some keratinocytes and fibroblasts. Cultured keratinocytes and fibroblasts from an affected individual, as well as knockdown of Dstyk in mouse melanocytes, keratinocytes, and fibroblasts, were associated with increased cell death after ultraviolet irradiation. Keratinocytes from an affected individual showed loss of kinase activity upon stimulation with fibroblast growth factor. Previously, dominant mutations in DSTYK were implicated in congenital urological developmental disorders, but our study identifies different phenotypic consequences for a recurrent autosomal-recessive deletion mutation in revealing the genetic basis of SPG23. © 2017 American Society of Human Genetics
Smirin-Yosef P.,Ariel University |
Smirin-Yosef P.,Felsenstein Medical Research Center |
Zuckerman-Levin N.,Clalit Health Services |
Zuckerman-Levin N.,Rambam Medical Center |
And 15 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2017
Context: Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle dysfunction, characterized by amenorrhea with elevated gonadotropin levels. The disorder presents as absence of normal progression of puberty. Objective: To elucidate the cause of ovarian dysfunction in a family with POI. Design: We performed whole-exome sequencing in 2 affected individuals. To evaluate whether DNA double-strand break (DSB) repair activities are altered in biallelic mutation carriers, we applied an enhanced green fluorescent protein-based assay for the detection of specific DSB repair pathways in blood-derived cells. Setting: Diagnoses were made at the Pediatric Endocrine Clinic, Clalit Health Services, Sharon-Shomron District, Israel. Genetic counseling and sample collection were performed at the Pediatric Genetics Unit, Schneider Children's Medical Center Israel, Petah Tikva, Israel. Patients and Intervention: Two sisters born to consanguineous parents of IsraeliMuslim Arab ancestry presented with a lack of normal progression of puberty, high gonadotropin levels, and hypoplastic or absent ovaries on ultrasound. Blood samples forDNAextractionwere obtained from all familymembers. Main Outcome Measure: Exome analysis to elucidate the cause of POI in 2 affected sisters. Results: Analysis revealed a stop-gain homozygous mutation in the SPIDR gene (KIAA0146) c.839G.A, p.W280∗. This mutation altered SPIDR activity in homologous recombination, resulting in the accumulation of 53BP1-labeled DSBs postionizing radiation and gH2AX-labeled damage during unperturbed growth. Conclusions: SPIDR is important for ovarian function in humans. A biallelic mutation in this gene may be associated with ovarian dysgenesis in cases of autosomal recessive inheritance. © 2017 by the Endocrine Society.
Basel-Vanagaite L.,Raphael Recanati Genetic Institute |
Basel-Vanagaite L.,Tel Aviv University |
Basel-Vanagaite L.,Felsenstein Medical Research Center |
Basel-Vanagaite L.,Pediatric Genetics Unit |
And 23 more authors.
American Journal of Human Genetics | Year: 2013
Epileptic encephalopathies are genetically heterogeneous severe disorders in which epileptic activity contributes to neurological deterioration. We studied two unrelated children presenting with a distinctive early-onset epileptic encephalopathy characterized by refractory epilepsy and absent developmental milestones, as well as thick and short corpus callosum and persistent cavum septum pellucidum on brain MRI. Using whole-exome sequencing, we identified biallelic mutations in seizure threshold 2 (SZT2) in both affected children. The causative mutations include a homozygous nonsense mutation and a nonsense mutation together with an exonic splice-site mutation in a compound-heterozygous state. The latter mutation leads to exon skipping and premature termination of translation, as shown by RT-PCR in blood RNA of the affected boy. Thus, all three mutations are predicted to result in nonsense-mediated mRNA decay and/or premature protein truncation and thereby loss of SZT2 function. Although the molecular role of the peroxisomal protein SZT2 in neuronal excitability and brain development remains to be defined, Szt2 has been shown to influence seizure threshold and epileptogenesis in mice, consistent with our findings in humans. We conclude that mutations in SZT2 cause a severe type of autosomal-recessive infantile encephalopathy with intractable seizures and distinct neuroradiological anomalies. © 2013 The American Society of Human Genetics.
PubMed | University of Groningen, University of Cincinnati, Alberta Health Services, Baylor College of Medicine and 61 more.
Type: Journal Article | Journal: Nature genetics | Year: 2016
Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.
PubMed | Pediatric Genetics Unit, CNR Institute of Neuroscience, Felsenstein Medical Research Center, Raphael Recanati Genetic Institute and 3 more.
Type: | Journal: Clinical genetics | Year: 2016
Mutations of several genes have been implicated in autosomal recessive osteopetrosis (OP), a disease caused by impaired function and differentiation of osteoclasts. Severe combined immune deficiencies (SCID) can likewise result from different genetic mutations. We report two siblings with SCID and an atypical phenotype of OP. A biallelic microdeletion encompassing the 5 region of TRAF6, RAG1 and RAG2 genes was identified. TRAF6, a tumor necrosis factor receptor-associated family member, plays an important role in T-cell signaling and in RANKL-dependent osteoclast differentiation and activation but its role in human OP has not been previously reported. The RAG proteins are essential for recombination of B and T cell receptors, and for the survival and differentiation of these cells. This is the first study to report a homozygous deletion of TRAF6 as a cause of human disease.