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Delineation of dominant and recessive forms of LZTR1 ‐associated Noonan syndrome
Author(s) -
Pagnamenta Alistair T.,
Kaisaki Pamela J.,
Bennett Fenella,
BurkittWright Emma,
Martin Hilary C.,
Ferla Matteo P.,
Taylor John M.,
Gompertz Lianne,
Lahiri Nayana,
TattonBrown Katrina,
NewburyEcob Ruth,
Henderson Alex,
Joss Shelagh,
Weber Astrid,
Carmichael Jenny,
Turnpenny Peter D.,
McKee Shane,
Forzano Francesca,
Ashraf Tazeen,
Bradbury Kimberley,
Shears Deborah,
Kini Usha,
de Burca Anna,
Blair Edward,
Taylor Jenny C.,
Stewart Helen
Publication year - 2019
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13533
Subject(s) - exome sequencing , genetics , exome , phenotype , noonan syndrome , biology , compound heterozygosity , genetic heterogeneity , gene , medicine
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.