Evidence map›Paper›PMID 29469822›Full record

ArticleGenetics in medicine : official journal of the American College of Medical Genetics2018

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

Jennifer J Johnston, Jasper J van der Smagt, Jill A Rosenfeld, Alistair T Pagnamenta, Abdulrahman Alswaid, Eva H Baker, Edward Blair, Guntram Borck, Julia Brinkmann, William Craigen and 28 more

Registry-linked trialAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 121 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
121citing papers in PubMed, 1 pooled it
8.0field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT02450851 recruitingnot on this map

Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network

TypeobservationalSponsorNational Human Genome Research Institute (NHGRI)Ran2015 to 2028Enrolled20,000ConditionsGenetic Disease
3 · Its place in the literature

Who cites it

121 citing papers in PubMed, 1 synthesis or guideline pooled it, 214 citations in OpenAlex.

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  9. The value of repeating genetic analysis over time illustrated by familial childhood onset HCM caused by a homozygous LZTR1 variant.Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation · 2026
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61 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

38 authors at 17 institutions in 7 countries.

Jennifer J Johnston *Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Jasper J van der Smagt *Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Jill A Rosenfeld *Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA, Texas.
Alistair T Pagnamenta *National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Abdulrahman AlswaidKing Abdulaziz Medical City, Riyadh, Saudi Arabia.
Eva H BakerDepartment of Radiology and Imaging Services; Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
Edward BlairOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Guntram BorckInstitute of Human Genetics, University of Ulm, Ulm, Germany.
Julia BrinkmannInstitute of Human Genetics, University Hospital, Magdeburg, Germany.
William CraigenDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA, Texas.
Vu Chi DungRare Disease and Newborn Screening Service, Department of Medical Genetics and Metabolism, The National Children's Hospital, Hanoi, Vietnam.
Lisa EmrickDivision of Neurology and Developmental Neuroscience and Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
David B EvermanGreenwood Genetic Center, Greenwood, South Carolina, USA.
Koen L van GassenDepartment of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Suleyman GulsunerDivision of Medical Genetics, University of Washington, Seattle, Washington, USA.
Margaret H HarrCenter for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Mahim JainDepartment of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Alma KuechlerInstitut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
Kathleen A LeppigGenetic Services, Kaiser Permanente of Washington, Seattle, Washington, USA.
Donna M McDonald-McGinnDivision of Human Genetics and Department of Pediatrics, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Ngoc Thi Bich CanRare Disease and Newborn Screening Service, Department of Medical Genetics and Metabolism, The National Children's Hospital, Hanoi, Vietnam.
Amir PelegInstitute of Human Genetics, Carmel Medical Center, Haifa, Israel.
Elizabeth R RoederDepartment of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, San Antonio, Texas, USA.
R Curtis RogersGreenwood Genetic Center, Greenwood, South Carolina, USA.
Lena Sagi-DainInstitute of Human Genetics, Carmel Medical Center, Haifa, Israel.
Julie C SappMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Alejandro A SchäfferComputational Biology Branch, National Center for Biotechnology Information, NIH, Bethesda, Maryland, USA.
Denny SchanzeInstitute of Human Genetics, University Hospital, Magdeburg, Germany.
Helen StewartOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Jenny C TaylorNational Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Nienke E VerbeekDepartment of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Magdalena A WalkiewiczDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA, Texas.
Elaine H ZackaiDivision of Human Genetics and Department of Pediatrics, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Christiane ZweierInstitute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Members of the Undiagnosed Diseases Network
Martin ZenkerInstitute of Human Genetics, University Hospital, Magdeburg, Germany.
Brendan LeeDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA, Texas.
Leslie G BieseckerMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. lesb@mail.nih.gov.
Baylor College of Medicine · USNational Institutes of Health · USChildren's Hospital of Philadelphia · USUniversity Hospital Magdeburg · DEUniversity Medical Center Utrecht · NLCarmel Medical Center · ILCentre for Human Genetics · GBGreenwood Genetic Center · USOxford University Hospitals NHS Trust · GBVietnam National Children's Hospital · VNEssen University Hospital · DEFriedrich-Alexander-Universität Erlangen-Nürnberg · DEKaiser Permanente · USKing Abdulaziz Medical City · SANational Center for Biotechnology Information · USUniversität Ulm · DEUniversity of Washington Medical Center · US

Funding

Rare & Mosaic Disorders Molecular ResearchZIAHG200328 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI BIESECKER, LESLIE · 2009 to 2025
$26.8M
Rare & Mosaic Disorders - Clinical ResearchZIAHG200388 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI BIESECKER, LESLIE · 2013 to 2025
$17.3M
Pilot of New Technologies to Increase the Genomic Diagnosis of Undiagnosed Disease Network (UDN) PatientsU01HG007709 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI BACINO, CARLOS A., LEE, BRENDAN · 2014 to 2022
$14.3M
Project 2: Genetic Mechanisms of Non-syndromic Congenital Cardiac DefectsP01HD070454 · NICHD · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI GOLDMUNTZ, ELIZABETH · 2011 to 2020
$14.0M
Clinical and Molecular Studies of MalformationsZ01HG200328 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI BIESECKER, LESLIE G · 2005 to 2008
$5.5M
Department of HealthIntramural NIH HHS Z01 HG200328Intramural NIH HHS ZIA HG200328Intramural NIH HHS ZIA HG200388NHGRI NIH HHS U01 HG007709NHGRI NIH HHS ZIA HG200328-11NHGRI NIH HHS ZIA HG200328-12NHGRI NIH HHS ZIA HG200388-03NHGRI NIH HHS ZIA HG200388-04NICHD NIH HHS P01 HD070454Wellcome TrustWellcome Trust 090532/Z/09/Z
6 · The paper itself

Abstract

purposeTo characterize the molecular genetics of autosomal recessive Noonan syndrome.

methodsFamilies underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.

resultsTwelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.

conclusionThese clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.

Indexed as

Genetic Predisposition to DiseaseAdolescentChildChild, PreschoolExomeFemaleGenetic LinkageGenotypeHeterozygoteHumansInfantMaleMutationNoonan SyndromePedigreeProtein IsoformsLZTR1 protein, humanProtein IsoformsTranscription Factorsautosomal recessive inheritancecardiomyopathyleukemiamultiple congenital anomaliesNoonan syndrome

Identifiers

PMID29469822
PMCPMC6105555
OpenAlexW2791145262

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.