Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants

Journal article

Publication Details

Author(s): Johnston JJ, Van Der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W, Vu Chi Dung , Emrick L, Everman DB, Van Gassen KL, Gulsuner S, Harr MH, Jain M, Kuechler A, Leppig KA, Mcdonald-Mcginn DM, Ngoc Thi Bich Can , Peleg A, Roeder ER, Rogers RC, Sagi-Dain L, Sapp JC, Schaffer AA, Schanze D, Stewart H, Taylor JC, Verbeek NE, Walkiewicz MA, Zackai EH, Zweier C, Zenker M, Lee B, Biesecker LG
Journal: Genetics in Medicine
Publication year: 2018
ISSN: 1098-3600


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.Genet Med advance online publication, 22 February 2018; doi:10.1038/gim.2017.249.

External institutions with authors

Carmel Medical Center
Children's Hospital of Philadelphia
Greenwood Genetic Center
Houston Texas Medical Center
Kaiser Permanente
​King Abdulaziz Medical City
National Human Genome Research Institute (NHGRI)
Oxford University Hospitals NHS Foundation Trust
Universität Duisburg-Essen (UDE)
Universitätsklinikum Magdeburg A.ö.R.
Universität Ulm
University Medical Centre Utrecht (UMC Utrecht)
University of Oxford
University of Pennsylvania
University of Washington
US National Institutes of Health (NIH)
Vietnam National Hospital of Pediatrics

How to cite

Johnston, J.J., Van Der Smagt, J.J., Rosenfeld, J.A., Pagnamenta, A.T., Alswaid, A., Baker, E.H.,... Biesecker, L.G. (2018). Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genetics in Medicine.

Johnston, Jennifer J., et al. "Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants." Genetics in Medicine (2018).


Last updated on 2018-23-11 at 10:53