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Genet Med. 2018 Oct;20(10):1175-1185. doi: 10.1038/gim.2017.249. Epub 2018 Feb 22.

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

Author information

1
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
2
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA, Texas.
4
National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
5
King Abdulaziz Medical City, Riyadh, Saudi Arabia.
6
Department of Radiology and Imaging Services; Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
7
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
8
Institute of Human Genetics, University of Ulm, Ulm, Germany.
9
Institute of Human Genetics, University Hospital, Magdeburg, Germany.
10
Rare Disease and Newborn Screening Service, Department of Medical Genetics and Metabolism, The National Children's Hospital, Hanoi, Vietnam.
11
Division of Neurology and Developmental Neuroscience and Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
12
Greenwood Genetic Center, Greenwood, South Carolina, USA.
13
Division of Medical Genetics, University of Washington, Seattle, Washington, USA.
14
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
15
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
16
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
17
Genetic Services, Kaiser Permanente of Washington, Seattle, Washington, USA.
18
Division 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.
19
Institute of Human Genetics, Carmel Medical Center, Haifa, Israel.
20
Department of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, San Antonio, Texas, USA.
21
Computational Biology Branch, National Center for Biotechnology Information, NIH, Bethesda, Maryland, USA.
22
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
23
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. lesb@mail.nih.gov.

Abstract

PURPOSE:

To characterize the molecular genetics of autosomal recessive Noonan syndrome.

METHODS:

Families 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.

RESULTS:

Twelve 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.

CONCLUSION:

These 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.

KEYWORDS:

Noonan syndrome; autosomal recessive inheritance; cardiomyopathy; leukemia; multiple congenital anomalies

PMID:
29469822
PMCID:
PMC6105555
DOI:
10.1038/gim.2017.249
[Indexed for MEDLINE]
Free PMC Article

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