SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

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

Pagnamenta, AT; Kaisaki, PJ; Bennett, F; Burkitt-Wright, E; Martin, HC; Ferla, MP; Taylor, JM; Gompertz, L; Lahiri, N; Tatton-Brown, K; et al. Pagnamenta, AT; Kaisaki, PJ; Bennett, F; Burkitt-Wright, E; Martin, HC; Ferla, MP; Taylor, JM; Gompertz, L; Lahiri, N; Tatton-Brown, K; Newbury-Ecob, R; Henderson, A; Joss, S; Weber, A; Carmichael, J; Turnpenny, PD; McKee, S; Forzano, F; Ashraf, T; Bradbury, K; Shears, D; Kini, U; de Burca, A; DDD Study; Blair, E; Taylor, JC; Stewart, H (2019) Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome. Clin Genet, 95 (6). pp. 693-703. ISSN 1399-0004 https://doi.org/10.1111/cge.13533
SGUL Authors: Tatton-Brown, Katrina Louise

[img]
Preview
PDF Published Version
Available under License Creative Commons Attribution.

Download (11MB) | Preview

Abstract

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.

Item Type: Article
Additional Information: © 2019 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: LZTR1, Noonan syndrome, RAS-MAPK signalling, developmental disorder, exome, DDD Study, developmental disorder, exome, LZTR1, Noonan syndrome, RAS-MAPK signalling, 0604 Genetics, 1103 Clinical Sciences, Genetics & Heredity
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Journal or Publication Title: Clin Genet
ISSN: 1399-0004
Language: eng
Dates:
DateEvent
20 May 2019Published
3 April 2019Published Online
6 March 2019Accepted
Projects:
Project IDFunderFunder ID
HICF-1009-003Health Innovation Challenge FundUNSPECIFIED
090532/Z/09/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
UNSPECIFIEDNational Institute for Health Researchhttp://dx.doi.org/10.13039/501100000272
WT098051Wellcome Trusthttp://dx.doi.org/10.13039/100004440
PubMed ID: 30859559
Web of Science ID: WOS:000468472900005
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/111376
Publisher's version: https://doi.org/10.1111/cge.13533

Actions (login required)

Edit Item Edit Item