ESPE Abstracts

Background: A few patients with NS have been reported to harbour pathogenic mutations in LZTR1 gene. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease. Mutations in this gene could hence lead to NS phenotype. Three patients with mutations in this gene and compatible NS phenotype are herein described.

Case 1: A 5 year-old boy with bilateral cryptorchidism, supravalvular pulmonary stenosis, low set and posteriorly rotated ears, curly hair, low posterior hairline, hypertelorism and pectus excavatum. No mutations were identified in genes PTPN11 and SOS1 through direct sequencing. Whole exome sequencing (WES) identified a heterozygous missense mutation in gene LZTR1: NM_006767:c.742T>C (p.Gly248Arg), (exon 8; Kelch 4 functional domain). A deleterious effect of this mutation has been predicted by bioinformatic algorithms and has been previously described to cause NS.

Case 2: A 4 year-old boy with short stature (-3.2 SD), pulmonary valve stenosis, right cryptorchidism, Von Willebrand disease, down slanted palpebral fissures, low set ears and posterior hairline and hypertelorism. Sanger sequencing of 8 genes associated to NS identified no mutations; however, WES localized a homozygous missense mutation in the gene LZTR1: NM_006767:c.2074T>C (p.Phe692Leu), (exon 18). This mutation has not been previously described and is predicted to have a deleterious effect on the protein.

Case 3: An 8 year-old boy with almond shaped eyes, cupped shaped and low set ears, low posterior hairline, pterigium colli, wide thorax, speech delay and a mother with typical NS facial features and a stature of -1.9 SD. A multigene panel for rasopathies found no mutations, but a subsequent WES, showed a heterozygous missense variant in LZTR1: NM_c.730T>C(p.Ser244Pro), (exon 8; Kelch 4 functional domain) that is maternally inherited. This variant has not been previously described. Nevertheless, multiple in silico predictors classify this variant as deleterious. Familial segregation suggests the pathogenicity of this variant.

Conclusions: Whole exome sequencing rather than direct sequencing of individual genes should be the approach for syndromic phenotypes associated to various genes. Albeit functional studies are still required to confirm causality of each mutation in LZTR1 leading to NS, this gene ought to be incorporated into RASopathy genetic panels. Patients with pathogenic mutations in LZTR1 seem to exhibit characteristic NS facial features but variable expression in heart, stature and neurodevelopment, where dominant inheritance may associate a milder phenotype.