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Clin Genet. 2019 Jun;95(6):693-703. doi: 10.1111/cge.13533. Epub 2019 Apr 3.

Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.

Author information

NIHR Oxford BRC, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
Oxford NHS Regional Molecular Genetics Laboratory, Oxford University Hospitals NHS Trust, Oxford, UK.
South West Thames Regional Genetics Service, St. George's University Hospitals NHS Foundation Trust, London, UK.
Department of Clinical Genetics, University Hospitals Bristol NHS Trust, Bristol, UK.
Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
West of Scotland Regional Genetics Service, Laboratory Medicine Building, Queen Elizabeth University Hospital, Glasgow, UK.
Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
Oxford Regional Clinical Genetics Service, Northampton General Hospital, Northampton, UK.
Clinical Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
Northern Ireland Regional Genetics Service, Belfast HSC Trust, Belfast City Hospital, Belfast, UK.
Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London, UK.
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.


Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly-acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound-heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss-of-function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS-like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.-38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1-4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.


LZTR1; Noonan syndrome; RAS-MAPK signalling; developmental disorder; exome

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