Publications by authors named "Alina Kurolap"

28 Publications

  • Page 1 of 1

Pathogenic variants in , a chromatin remodeler, cause a range of syndromic neurodevelopmental features.

Sci Adv 2021 May 12;7(20). Epub 2021 May 12.

Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ, USA.

Intellectual disability encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for more than 50% of the patients remains elusive. We describe pathogenic variants in , encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a previously unidentified neurodevelopmental disorder, identifying 12 individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 ortholog led to smaller body size, reduced sensory dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology, and abnormal locomotor function. loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abf2066DOI Listing
May 2021

A recurring pathogenic variant causes a mitochondrial disorder with variable intra-familial patient outcomes.

Mol Genet Metab Rep 2021 Mar 30;26:100699. Epub 2020 Dec 30.

The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.

Iron‑sulfur clusters (FeSCs) are vital components of a variety of essential proteins, most prominently within mitochondrial respiratory chain complexes I-III; Fe-S assembly and distribution is performed multi-step pathways. Variants affecting several proteins in these pathways have been described in genetic disorders, including severe mitochondrial disease. Here we describe a Christian Arab kindred with two infants that died due to mitochondrial disorder involving Fe-S containing respiratory chain complexes and a third sibling who survived the initial crisis. A homozygous missense variant in : c.215G>A; p.Arg72Gln was detected by whole exome sequencing. The gene encodes a cysteine desulfurase, which, in complex with ISD11 and ACP, initiates the first step of Fe-S formation. Arginine at position 72 plays a role in NFS1-ISD11 complex formation; therefore, its substitution with glutamine is expected to affect complex stability and function. Interestingly, this is the only pathogenic variant ever reported in the gene, previously described once in an Old Order Mennonite family presenting a similar phenotype with intra-familial variability in patient outcomes. Analysis of datasets from both populations did not show a common haplotype, suggesting this variant is a recurrent variant. Our report of the second case of NFS1-related mitochondrial disease corroborates the pathogenicity of this recurring variant and implicates it as a hot-spot variant. While the genetic resolution allows for prenatal diagnosis for the family, it also raises critical clinical questions regarding follow-up and possible treatment options of severely affected and healthy homozygous individuals with mitochondrial co-factor therapy or cysteine supplementation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgmr.2020.100699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797929PMC
March 2021

Eculizumab-Responsive Adult Onset Protein Losing Enteropathy, Caused by Germline CD55-Deficiency and Complicated by Aggressive Angiosarcoma.

J Clin Immunol 2021 Feb 19;41(2):477-481. Epub 2020 Nov 19.

Institute of Thrombosis and Hemostasis, Sheba Medical Center, and Sackler Faculty of Medicine, University of Tel Aviv, Tel Aviv, Israel.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-020-00910-7DOI Listing
February 2021

A novel mutation in MYCN gene causing congenital absence of the flexor pollicis longus tendon as an unusual presentation of Feingold syndrome 1.

Clin Dysmorphol 2021 Apr;30(2):71-75

The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology.

Feingold syndrome 1 (FGLDS1) is an autosomal dominant malformation syndrome, characterized by skeletal anomalies, microcephaly, facial dysmorphism, gastrointestinal atresias and learning disabilities. Mutations in the MYCN gene are known to be the cause of this syndrome. Congenital absence of the flexor pollicis longus (CAFPL) tendon is a rare hand anomaly. Most cases are sporadic and no genetic variants have been described associated with this abnormality. We describe here a pedigree combining familial CAFPL tendon as a feature of FGLDS1. Molecular analyses of whole exome sequence data in five affected family members spanning three generations of this family revealed a novel mutation in the MYCN gene (c.1171C>T; p.Arg391Cys). Variants in MYCN have not been published in association with isolated or syndromic CAFPL tendon, nor has this been described as a skeletal feature of Feingold syndrome. This report expands on the clinical and molecular spectrum of MYCN-related disorders and highlights the importance of MYCN protein in normal human thumb and foramen development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCD.0000000000000342DOI Listing
April 2021

A novel heterozygous loss-of-function DCC Netrin 1 receptor variant in prenatal agenesis of corpus callosum and review of the literature.

Am J Med Genet A 2020 01 7;182(1):205-212. Epub 2019 Nov 7.

The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.

Agenesis of the corpus callosum (ACC) is a common prenatally-detected brain anomaly. Recently, an association between mutations in the DCC Netrin 1 receptor (DCC) gene and ACC, with or without mirror movements, has been demonstrated. In this manuscript, we present a family with a novel heterozygous frameshift mutation in DCC, review the available literature, and discuss the challenges involved in the genetic counseling for recently discovered disorders with paucity of medical information. We performed whole exome sequencing in a healthy nonconsanguineous couple that underwent two pregnancy terminations due to prenatal diagnosis of ACC. A heterozygous variant c.2774dupA (p.Asn925Lysfs*17) in the DCC gene was demonstrated in fetal and paternal DNA samples, as well as in a healthy 4-year-old offspring. When directly questioned, both father and child reported having mirror movements not affecting quality of life. Segregation analysis demonstrated the variant in three paternal siblings, two of them having mirror movements. Brain imaging revealed normal corpus callosum. Summary of literature data describing heterozygous loss-of-function variants in DCC (n = 61) revealed 63.9% penetrance for mirror movements, 9.8% for ACC, and 5% for both. No significant neurodevelopmental abnormalities were reported among the seven published patients with DCC loss-of-function variants and ACC. Prenatal diagnosis of ACC should prompt a specific anamnesis regarding any neurological disorder, as well as intentional physical examination of both parents aimed to detect mirror movements. In suspicious cases, detection of DCC pathogenic variants might markedly improve the predicted prognosis, alleviate the parental anxiety, and possibly prevent pregnancy termination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61404DOI Listing
January 2020

The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis.

Genet Med 2020 02 7;22(2):389-397. Epub 2019 Aug 7.

Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Purpose: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function.

Methods: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains.

Results: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains.

Conclusion: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0612-0DOI Listing
February 2020

Gaucher disease type 3c: New patients with unique presentations and review of the literature.

Mol Genet Metab 2019 06 21;127(2):138-146. Epub 2019 May 21.

The Genetics Institute, Rambam Health Care Campus, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. Electronic address:

Gaucher disease (GD) is the most prevalent lysosomal disorder caused by GBA mutations and abnormal glucocerebrosidase function, leading to glucocerebrosideaccumulation mainly in the liver, spleen, bone marrow, lungs, and occasionally in the central nervous system. Gaucher disease type 3c (GD3c) is a rare subtype of the subacute/chronic neuronopathic GD3, caused by homozygosity for the GBA p.Asp448His (D409H) mutation. GD3c is characterized mainly by cardiovascular and neuro-ophthalmological findings. In this paper, we describe four new GD3c patients exhibiting rare cardiovascular, pulmonary and psychiatric findings, as well as atypical disease courses. Review of the GD3c-related literature revealed clinical descriptions of 36 patients, presenting predominantly with cardiovascular calcifications; 15%, including Patient 1b in this study, had non-calcified lesions - fibrosis and atherosclerosis. Only 7.5% of patients have been described without heart disease, including Patient 3; however, Patient 2 had a fulminant coronary disease. Neurological findings in GD3c consist mainly of oculomotor apraxia (80%), which is absent in Patient 3, while other neurological findings are common (65%) but diverse. Patient 1b developed a psychiatric behavioral disorder, which has not been previously described in GD3c. Patient 1b also had interstitial lung disease, which was only described in one GD3c patient as pulmonary fibrosis. In view of these unique features, we recommend a revised surveillance protocol; however, further studies are required to establish the management of these patients and the role of GBA in the described pathologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2019.05.011DOI Listing
June 2019

A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant.

J Clin Immunol 2019 05 11;39(4):430-439. Epub 2019 May 11.

The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.

Purpose: This study aimed to characterize the clinical phenotype, genetic basis, and consequent immunological phenotype of a boy with severe infantile-onset colitis and eosinophilic gastrointestinal disease, and no evidence of recurrent or severe infections.

Methods: Trio whole-exome sequencing (WES) was utilized for pathogenic variant discovery. Western blot (WB) and immunohistochemical (IHC) staining were used for protein expression analyses. Immunological workup included in vitro T cell studies, flow cytometry, and CyTOF analysis.

Results: WES revealed a homozygous variant in the capping protein regulator and myosin 1 linker 2 (CARMIL2) gene: c.1590C>A; p.Asn530Lys which co-segregated with the disease in the nuclear family. WB and IHC analyses demonstrated reduced protein levels in patient's cells compared with controls. Moreover, comprehensive immunological workup revealed severely diminished blood-borne regulatory T cell (T) frequency and impaired in vitro CD4 T cell proliferation and T generation. CyTOF analysis showed significant shifts in the patient's innate and adaptive immune cells compared with healthy controls and ulcerative colitis patients.

Conclusions: Pathogenic variants in CARMIL2 have been implicated in an immunodeficiency syndrome characterized by recurrent infections, occasionally with concurrent chronic diarrhea. We show that CARMIL2-immunodeficiency is associated with significant alterations in the landscape of immune populations in a patient with prominent gastrointestinal disease. This case provides evidence that CARMIL2 should be a candidate gene when diagnosing children with very early onset inflammatory and eosinophilic gastrointestinal disorders, even when signs of immunodeficiency are not observed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-019-00631-6DOI Listing
May 2019

Identification of a novel PCNT founder pathogenic variant in the Israeli Druze population.

Eur J Med Genet 2020 Feb 25;63(2):103643. Epub 2019 Mar 25.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Majewski Osteodysplastic Primordial Dwarfism type II (MOPDII) is a form of dwarfism associated with severe microcephaly, characteristic skeletal findings, distinct dysmorphic features and increased risk for cerebral infarctions. The condition is caused by bi-allelic loss-of-function variants in the gene PCNT. Here we describe the identification of a novel founder pathogenic variant c.3465-1G > A observed in carriers from multiple Druze villages in Northern Israel. RNA studies show that the variant results in activation of a cryptic splice site causing a coding frameshift. The study was triggered by the diagnosis of a single child with MOPDII and emphasizes the advantages of applying next generation sequencing technologies in community genetics and the importance of establishing population-specific sequencing databases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2019.03.007DOI Listing
February 2020

A novel TUFM homozygous variant in a child with mitochondrial cardiomyopathy expands the phenotype of combined oxidative phosphorylation deficiency 4.

J Hum Genet 2019 Jun 22;64(6):589-595. Epub 2019 Mar 22.

The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.

Translation of mitochondrial-specific DNA is required for proper mitochondrial function and energy production. For this purpose, an elaborate network of dedicated molecular machinery including initiation, elongation and termination factors exists. We describe a patient with an unusual phenotype and a novel homozygous missense variant in TUFM (c.344A>C; p.His115Pro), encoding mtDNA translation elongating factor Tu (EFTu). To date, only four patients have been reported with bi-allelic mutations in TUFM, leading to combined oxidative phosphorylation deficiency 4 (COXPD4) characterized by severe early-onset lactic acidosis and progressive fatal infantile encephalopathy. The patient presented here expands the phenotypic features of TUFM-related disease, exhibiting lactic acidosis and dilated cardiomyopathy without progressive encephalopathy. This warrants the inclusion of TUFM in differential diagnosis of metabolic cardiomyopathy. Cases that further refine genotype-phenotype associations and characterize the molecular basis of mitochondrial disorders allow clinicians to predict disease prognosis, greatly impacting patient care, as well as provide families with reproductive planning options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-019-0592-6DOI Listing
June 2019

Homozygosity for CHEK2 p.Gly167Arg leads to a unique cancer syndrome with multiple complex chromosomal translocations in peripheral blood karyotype.

J Med Genet 2020 07 11;57(7):500-504. Epub 2019 Mar 11.

The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.

Background: Chromosomal instability, as reflected by structural or copy-number changes, is a known cancer characteristic but are rarely observed in healthy tissue. Mutations in DNA repair genes disrupt the maintenance of DNA integrity and predispose to hereditary cancer syndromes.

Objective: To clinically characterise and genetically diagnose two reportedly unrelated patients with unique cancer syndromes, including multiorgan tumourogenesis (patient 1) and early-onset acute myeloid leukaemia (patient 2), both displaying unique peripheral blood karyotypes.

Methods: Genetic analysis in patient 1 included TruSight One panel and whole-exome sequencing, while patient 2 was diagnosed by FoundationOne Heme genomic analysis; Sanger sequencing was used for mutation confirmation in both patients. Karyotype analysis was performed on peripheral blood, bone marrow and other available tissues.

Results: Both patients were found homozygous for c.499G>A; p.Gly167Arg and exhibited multiple different chromosomal translocations in 30%-60% peripheral blood lymphocytes. This karyotype phenotype was not observed in other tested tissues or in an ovarian cancer patient with a different homozygous missense mutation in (c.1283C>T; p.Ser428Phe).

Conclusions: The multiple chromosomal translocations in patient lymphocytes highlight the role of CHK2 in DNA repair. We suggest that homozygosity for p.Gly167Arg increases patients' susceptibility to non-accurate correction of DNA breaks and possibly explains their increased susceptibility to either multiple primary tumours during their lifetime or early-onset tumourigenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2018-105824DOI Listing
July 2020

Clinical diversity of MYH7-related cardiomyopathies: Insights into genotype-phenotype correlations.

Am J Med Genet A 2019 03 27;179(3):365-372. Epub 2018 Dec 27.

The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.

MYH7-related disease (MRD) is the most common hereditary primary cardiomyopathy (CM), with pathogenic MYH7 variants accounting for approximately 40% of familial hypertrophic CMs. MRDs may also present as skeletal myopathies, with or without CM. Since pathogenic MYH7 variants result in highly variable clinical phenotypes, from mild to fatal forms of cardiac and skeletal myopathies, genotype-phenotype correlations are not always apparent, and translation of the genetic findings to clinical practice can be complicated. Data on genotype-phenotype correlations can help facilitate more specific and personalized decisions on treatment strategies, surveillance, and genetic counseling. We present a series of six MRD pedigrees with rare genotypes, encompassing various clinical presentations and inheritance patterns. This study provides new insights into the spectrum of MRD that is directly translatable to clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61017DOI Listing
March 2019

Eculizumab Is Safe and Effective as a Long-term Treatment for Protein-losing Enteropathy Due to CD55 Deficiency.

J Pediatr Gastroenterol Nutr 2019 03;68(3):325-333

The Genetics Institute, Rambam Health Care Campus.

Objectives: Loss of the complement inhibitor CD55 leads to a syndrome of early-onset protein-losing enteropathy (PLE), associated with intestinal lymphangiectasia and susceptibility to large-vein thrombosis. The in vitro and short-term treatment benefits of eculizumab (C5-inhibitor) therapy for CD55-deficiency have been previously demonstrated. Here we present the 18-months treatment outcomes for 3 CD55-deficiency patients with sustained therapeutic response.

Methods: Three CD55-deficiency patients received off-label eculizumab treatment. Clinical and laboratory treatment outcomes included frequency and consistency of bowl movements, weight, patient/parent reports of overall well-being, and serum albumin and total protein levels. Membrane attack complex deposition on leukocytes was tested by flow cytometry, before and during eculizumab treatment.

Results: Marked clinical improvement was noted in all 3 patients with resolution of PLE manifestations, that is, diarrhea, edema, malabsorption, overall well-being, growth, and quality of life. In correlation with the clinical observations, we observed progress in all laboratory outcome parameters, including increase in albumin and total protein levels, and up to 80% reduction in membrane attack complex deposition on leukocytes (P < 0.001). The progress persisted over 18 months of treatment without any severe adverse events.

Conclusions: CD55-deficiency patients present with early-onset diarrhea, edema, severe hypoalbuminemia, abdominal pain, and malnutrition. Targeted therapy with the terminal complement inhibitor eculizumab has positive clinical and laboratory outcomes in PLE related to CD55 loss-of-function mutations, previously a life-threatening condition. Our results demonstrate the potential of genetic diagnosis to guide tailored treatment, and underscore the significant role of the complement system in the intestine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0000000000002198DOI Listing
March 2019

Pathogenic variants in glutamyl-tRNA amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder.

Nat Commun 2018 10 3;9(1):4065. Epub 2018 Oct 3.

The Genetics Institute, Rambam Health Care Campus, Haifa, 3109601, Israel.

Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNA). mt-tRNA is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNA and mitochondrial protein translation are deficient in patients' fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-06250-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170436PMC
October 2018

Rare Disease Diagnostics: A Single-center Experience and Lessons Learnt.

Rambam Maimonides Med J 2018 Jul 30;9(3). Epub 2018 Jul 30.

The Genetics Institute, Rambam Health Care Center, Haifa, Israel.

Objective: The growing availability of next-generation sequencing technologies has revolutionized medical genetics, facilitating discovery of causative genes in numerous Mendelian disorders. Nevertheless, there are still many undiagnosed cases. We report the experience of the Genetics Institute at Rambam Health Care Campus in rare disease diagnostics using whole-exome sequencing (WES).

Methods: Phenotypic characterization of patients was done in close collaboration with referring physicians. We utilized WES analysis for diagnosing families suspected for rare genetic disorders. Bioinformatic analysis was performed in-house using the Genoox analysis platform.

Results: Between the years 2014 and 2017, we studied 34 families. Neurological manifestations were the most common reason for referral (38%), and 55% of families were consanguineous. A definite diagnosis was reached in 21 cases (62%). Four cases (19%) were diagnosed with variants in novel genes. In addition, six families (18%) had strong candidate novel gene discoveries still under investigation. Therefore, the true diagnosis rate is probably even higher. Some of the diagnoses had a significant impact such as alerting the patient management and providing a tailored treatment.

Conclusions: An accurate molecular diagnosis can set the stage for improved patient care and provides an opportunity to study disease mechanisms, which may lead to development of tailored treatments. Data from our genetic research program demonstrate high diagnostic and novel disease-associated or causative gene discovery rates. This is likely related to the unique genetic architecture of the population in Northern Israel as well as to our strategy for case selection and the close collaboration between analysts, geneticists, and clinicians, all working in the same hospital.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5041/RMMJ.10341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115477PMC
July 2018

Establishing the role of in protein-losing enteropathy: a homozygous missense variant leads to an attenuated phenotype.

J Med Genet 2018 11 6;55(11):779-784. Epub 2018 Jun 6.

The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.

Background: Intestinal integrity is essential for proper nutrient absorption and tissue homeostasis, with damage leading to enteric protein loss, that is, protein-losing enteropathy (PLE). Recently, homozygous nonsense variants in the plasmalemma vesicle-associated protein gene () were reported in two patients with severe congenital PLE. PLVAP is the building block of endothelial cell (EC) fenestral diaphragms; its importance in barrier function is supported by mouse models of Plvap deficiency.

Objective: To genetically diagnose two first-degree cousins once removed, who presented with PLE at ages 22 and 2.5 years.

Methods: Family-based whole exome sequencing was performed based on an autosomal recessive inheritance model. analyses were used to predict variant impact on protein structure and function.

Results: We identified a rare homozygous variant (NM_031310.2:c.101T>C;p.Leu34Pro) in , which co-segregated with the disease. Leu34 is predicted to be located in a highly conserved, hydrophobic, α-helical region within the protein's transmembrane domain, suggesting Leu34Pro is likely to disrupt protein function and/or structure. Electron microscopy and PLVAP immunohistochemistry demonstrated apparently normal diaphragm morphology, predicted to be functionally affected.

Conclusions: Biallelic missense variants in can cause an attenuated form of the PLE and hypertriglyceridaemia syndrome. Our findings support the role of PLVAP in the pathophysiology of PLE, expand the phenotypic and mutation spectrums and underscore PLVAP's importance in EC barrier function in the gut.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2018-105299DOI Listing
November 2018

CD55 Deficiency and Protein-Losing Enteropathy.

N Engl J Med 2017 10;377(15):1500

Rambam Health Care Campus, Haifa, Israel

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMc1710011DOI Listing
October 2017

Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine.

Am J Hum Genet 2016 Nov 20;99(5):1172-1180. Epub 2016 Oct 20.

The Genetics Institute, Rambam Health Care Campus, Haifa 3109601, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525433, Israel. Electronic address:

Glycine is a major neurotransmitter that activates inhibitory glycine receptors and is a co-agonist for excitatory glutamatergic N-methyl-D-aspartate (NMDA) receptors. Two transporters, GLYT1 and GLYT2, regulate extracellular glycine concentrations within the CNS. Dysregulation of the extracellular glycine has been associated with hyperekplexia and nonketotic hyperglycinemia. Here, we report four individuals from two families who presented at birth with facial dysmorphism, encephalopathy, arthrogryposis, hypotonia progressing to hypertonicity with startle-like clonus, and respiratory failure. Only one individual survived the respiratory failure and was weaned off ventilation but has significant global developmental delay. Mildly elevated cerebrospinal fluid (CSF) glycine and normal serum glycine were observed in two individuals. In both families, we identified truncating mutations in SLC6A9, encoding GLYT1. We demonstrate that pharmacologic or genetic abolishment of GlyT1 activity in mice leads to mildly elevated glycine in the CSF but not in blood. Additionally, previously reported slc6a9-null mice and zebrafish mutants also display phenotypes consistent with the affected individuals we examined. Our data suggest that truncating SLC6A9 mutations lead to a distinct human neurological syndrome hallmarked by mildly elevated CSF glycine and normal serum glycine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2016.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097939PMC
November 2016

LRRK2, GBA and SMPD1 Founder Mutations and Parkinson's Disease in Ashkenazi Jews.

Dement Geriatr Cogn Disord 2016 23;42(1-2):1-6. Epub 2016 Jul 23.

Department of Nursing, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel.

Background/aim: Parkinson's disease (PD) is associated with mutations in LRRK2, GBA, and SMPD1 genes. We describe the clinical characteristics of PD patients related to their carrier status of the Ashkenazi founder mutations in the aforementioned genes.

Methods: Ashkenazi PD patients (n = 270) were recruited following informed consent, and tested for the founder Ashkenazi mutations in the above genes. Clinical characteristics were compared between carriers and noncarriers. Homozygotes for mutations in GBA or LRRK2, and those who carried mutations in two causative genes were excluded from the analysis.

Results: Five (1.85%), 54 (20%), and 22 (8.1%) PD patients carried mutations in SMPD1, GBA or LRRK2, respectively. By post hoc Bonferroni analysis, GBA carriers were singled at a significantly earlier age at diagnosis compared to noncarriers (58.06 ± 10.84 and 62.65 ± 10.86 years, respectively; p = 0.036), and due to bilateral manifestation at diagnosis compared to all other PD groups (n = 8, 15.7% compared to n = 2, 1.1%, respectively; p < 0.001). Other clinical manifestations were comparable between groups.

Conclusion: Although only GBA mutation carriers, compared to noncarriers, reached statistical significance regarding age at diagnosis, it appears that LRRK2 and SMPD1 mutation carriers may reach significance with larger group numbers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000447450DOI Listing
January 2018

Is one diagnosis the whole story? patients with double diagnoses.

Am J Med Genet A 2016 09 8;170(9):2338-48. Epub 2016 Jun 8.

The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.

One of the goals of evaluating a patient in the genetics clinic is to find the diagnosis that would explain his or her clinical presentation. Sometimes the patient's diagnosis remains undefined or does not explain all of the clinical findings. As clinicians are often guided by a "single disorder" paradigm, diagnosing multiple genetic conditions in the same patient requires a heightened sense of awareness. Over the last few years, we evaluated several patients (n = 14) who were found to have more than one genetic diagnosis. In this paper, we will describe their natural history and diagnoses, and draw on the lessons learned from this phenomenon, which we expect to grow in this era of next-generation diagnostic technologies. To our knowledge, this is by far the largest series of patients with double diagnoses. Based on our findings, we strongly recommend that physicians question every diagnosis to determine whether it indeed explains all of the patients' symptoms, and consider whether they should continue the diagnostic evaluation to look for a more accurate and complete set of diagnoses. © 2016 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.37799DOI Listing
September 2016

A Novel Missense Mutation in FLT4 Causes Autosomal Recessive Hereditary Lymphedema.

Lymphat Res Biol 2015 Jun 2;13(2):107-11. Epub 2015 Jun 2.

1 Institute of Human Genetics , Rambam Health Care Campus, Haifa, Israel .

Background: Primary lymphedema covers around 10% of all lymphedema cases. Most cases segregate as an autosomal dominant trait and rarely manifest autosomal recessive inheritance. Our research aimed to map and ultimately to hunt the mutation that causes hereditary lymphedema in an extended consanguineous Muslim family consisting of several affected individuals.

Methods And Results: We attempted molecular diagnosis by applying homozygosity mapping and whole genome linkage analysis. A candidate locus of 2.3 Mb located on chromosome 5q35.3 was identified, yielding an overall LOD score of 3.18. This locus has been previously linked to congenital lymphedema, namely by the FLT4 gene. Mutations in FLT4 that were previously described in Muslim-Israeli families were discarded as culprit using sequence analysis. Sanger sequencing the gene revealed a novel missense variant in exon 28 (NM_182925.4: c.3704C>G; p.Ser1235Cys). This variant has perfect segregation within the extended family and was not previously reported in either common or pathogenic variants databases.

Conclusions: Our mutation is the first reported pathogenic variant located outside the tyrosine kinase domains of the VEGFR3 receptor, and the second to portray autosomal recessive inheritance. The homozygous substitution of serine by cysteine at position 1235 affects protein tyrosine kinase activity, possibly through a null effect mechanism rather than a negative dominant effect. Our variant is associated with a mild phenotype, possibly reflecting some residual receptor activity, most probably attributed to the variant's location beyond the TK domains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/lrb.2014.0044DOI Listing
June 2015

"I do not want my baby to suffer as I did"; prenatal and preimplantation genetic diagnosis for BRCA1/2 mutations: a case report and genetic counseling considerations.

Genet Test Mol Biomarkers 2014 Jul 10;18(7):461-6. Epub 2014 Jun 10.

1 Department of Nursing, University of Haifa , Haifa, Israel .

This article presents the complexity of prenatal genetic diagnosis and preimplantation genetic diagnosis for hereditary breast-ovarian cancer syndrome. These issues are discussed using a case report to highlight the genetic counseling process, together with decision-making considerations, in light of the clinical, psychological, and ethical perspectives, of both the mutation carriers and health professionals; and the health policy regarding these procedures in Israel compared to several European countries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/gtmb.2013.0513DOI Listing
July 2014

Kohlschutter-Tonz syndrome: clinical and genetic insights gained from 16 cases deriving from a close-knit village in Northern Israel.

Pediatr Neurol 2014 Apr 7;50(4):421-6. Epub 2014 Jan 7.

Institute of Human Genetics, Rambam Health Care Campus, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. Electronic address:

Background: Kohlschutter-Tonz syndrome (KTS; MIM 22675) is a rare autosomal recessive disorder characterized by intellectual impairment, spasticity, epilepsy, and amelogenesis imperfecta. We have recently identified the causative gene and mutation underlying KTS, namely, p.R157X, corresponding to ROGDI c.571C>T, which creates a premature stop codon in ROGDI homolog (Drosophila), a gene of unknown function, in KTS patients of Druze origin.

Patients: To better delineate the phenotype of KTS, 16 cases (eight female, eight male), from seven families (five kindreds) originating from a Druze village in Northern Israel, all homozygous for the same deleterious mutation, were investigated. Medical records were reviewed, and a detailed medical history was obtained by interview of parents.

Results: Age at onset between six and 12 months of age and the intensity of convulsions were variably manifested by affected sibs and mirror the progression of mental and motor deterioration. Amelogenesis imperfecta and deficient speech occur in all cases. By late adolescence and early twenties, individuals with KTS are bedridden, fed by a gastrostomy tube, spastic, and practically have no cognitive and language perception.

Conclusions: KTS, a genetic disease heralded by convulsions, "yellow teeth," and severe mental impairment, allows for a clinical variability as regarding age of onset and severity of seizures that per se predict the speed of mental deterioration. In all cases, however, the morbid course of the disease is ultimately equally devastating by the twenties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2014.01.006DOI Listing
April 2014

BRCA1/2 mutations and FMR1 alleles are randomly distributed: a case control study.

Eur J Hum Genet 2014 Feb 27;22(2):277-9. Epub 2013 Nov 27.

1] Institute of Human Genetics, Rambam Health Care Campus, Haifa, Israel [2] The Ruth and Bruce Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel.

BRCA mutation carriers were reported to display a skewed distribution of FMR1 genotypes, predominantly within the low normal range (CGG repeat number <26). This observation led to the interpretation that BRCA1/2 mutations are embryo-lethal, unless rescued by 'low FMR1 alleles'. We undertook to re-explore the distribution of FMR1 alleles subdivided into low, normal and high (<26, 26-34, and >34 CGG repeats, respectively) subgenotypes, on a cohort of 125 Ashkenazi women, carriers of a BRCA1/2 founder mutation. Ashkenazi healthy females (n=368), tested in the frame of the Israeli screening population program, served as controls. BRCA1/2 carriers and controls demonstrated a comparable and non-skewed FMR1 subgenotype distribution. Taken together, using a homogeneous ethnic group of Ashkenazi BRCA1/2 mutation carriers, we could not confirm the reported association between FMR1 low genotypes and BRCA1/2 mutations. The notion that BRCA1/2 mutations are embryo-lethal unless rescued by the low FMR1 subgenotypes is hereby refuted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2013.281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895656PMC
February 2014

A missense mutation in ALDH1A3 causes isolated microphthalmia/anophthalmia in nine individuals from an inbred Muslim kindred.

Eur J Hum Genet 2014 Mar 24;22(3):419-22. Epub 2013 Jul 24.

1] Institute of Human Genetics, Rambam Health Care Campus, Haifa, Israel [2] The Ruth and Bruce Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel.

Nine affected individuals with isolated anophthalmia/microphthalmia from a large Muslim-inbred kindred were investigated. Assuming autosomal-recessive mode of inheritance, whole-genome linkage analysis, on DNA samples from four affected individuals, was undertaken. Homozygosity mapping techniques were employed and a 1.5-Mbp region, homozygous in all affected individuals, was delineated. The region contained nine genes, one of which, aldehyde dehydrogenase 1 (ALDH1A3), was a clear candidate. This gene seems to encode a key enzyme in the formation of a retinoic-acid gradient along the dorsoventral axis during an early eye development and the development of the olfactory system. Sanger sequence analysis revealed a missense mutation, causing a substitution of valine (Val) to methionine (Met) at position 71. Analyzing the p.Val71Met missense mutation using standard open access software (MutationTaster online, PolyPhen, SIFT/PROVEAN) predicts this variant to be damaging. Enzymatic activity, studied in vitro, showed no changes between the mutated and the wild-type ALDH1A3 protein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2013.157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3925280PMC
March 2014