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

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.

Keywords: LZTR1; Noonan syndrome; RAS-MAPK signalling; developmental disorder; exome.

Figure 1

Clinical images showing Noonan‐like features in patients where consent was obtained. A, Patient 303983 aged 7.5 and 14 years showing hypertelorism and low‐set posteriorly rotated ears. B, Patient 287232 aged 5 years showing low‐set ears, pointed chin and pectus excavatum. C, Patient 278971 shown at 11 months and 3.7 years showing epicanthic folds and depressed nasal bridge and D, Patient 272332 aged 8.6 years and 10.2 years with interrupted eyebrow, long palpebral fissures, low‐set posteriorly rotated ears, thin top lip and narrow chin. E, Patient 279914 aged 6.8 years showing a convergent squint, ptosis, low‐set posteriorly rotated ears and wide neck. F, Patient 284672 aged 8 years showing long face, hypertelorism, proptosis, downslanting palpebral fissures, retrognathia, macrodontia and a high, narrow palate. G, Patient 284673 (284672's elder sister) aged 11 years—while both siblings had biallelic NEB variants, the elder sister did not have both LZTR1 variants and so is shown for comparison. Although both sisters have myopathy and bilateral ptosis, the younger sibling has a stronger NS gestalt. H, Patient O1409410 aged 12 years showing down‐slanting palpebral fissures, palpebral ptosis, low‐set posteriorly rotated ears and fetal finger‐tip pads. I, Patient O1409412 aged 28 years showing a narrow nasal root and broad nasal tip

Figure 2

Sanger validation of de novo mutations and distribution of autosomal dominant and recessive variants across LZTR1. A, Validation data for the c.290G>T; p.R97L variant. B, Validation data for two de novo variants that disrupt Tyr136. C, Validation data for de novo variants disrupting Ser244/Gly248 alongside other variants reported to be associated with Noonan syndrome (NS). D, Distribution of variants identified in this study along the LZTR1 protein. Figure adapted from protein summary view at DECIPHER (https://decipher.sanger.ac.uk/gene/LZTR1#overview/protein‐info). Likely loss of function variants shown in red, missense and 5’‐UTR variants shown in green