Broadening the Spectrum of Loss-of-Function Variants in NPR-C-Related Extreme Tall Stature

Abstract

Context Natriuretic peptide receptor-C (NPR-C, encoded by NPR3) belongs to a family of cell membrane-integral proteins implicated in various physiological processes including longitudinal bone growth. NPR-C acts as a clearance receptor of natriuretic peptides, including C-type natriuretic peptide (CNP), which stimulate the cGMP-forming guanylyl cyclase-coupled receptors NPR-A and NPR-B. Pathogenic variants in CNP, NPR2 and NPR3 may cause a tall stature phenotype associated with macrodactyly of the halluces and epiphyseal dysplasia. Here we report on a boy with two novel biallelic inactivating variants of NPR3. Design History and clinical characteristics were collected. Biochemical indices of natriuretic peptide clearance and in vitro cellular localization of NPR-C were studied to investigate causality of the identified variants. Results We identified two novel compound heterozygous NPR3 variants c.943G>A p.(Ala315Thr) and c.1294A>T p.(Ile432Phe) in a boy with tall stature and macrodactyly of the halluces. In silico analysis indicated decreased stability of NPR-C, presumably resulting in increased degradation or trafficking defects. Compared to other patients with NPR-C loss-of-function, the phenotype seemed to be milder: pseudo-epiphyses in hands and feet were absent, biochemical features were less severe, and there was some co-localization of p.(Ile432Phe) NPR-C with the cell membrane, as opposed to complete cytoplasmic retention. Conclusion With this report on a boy with tall stature and macrodactyly of the halluces we further broaden the genotypic and phenotypic spectrum of NPR-C-related tall stature.

Comprehensive genetic testing approaches as the basis for personalized management of growth disturbances: current status and perspectives

“…3 In case of a positive result of a first line test, additional genetic tests might be required, to confirm the first result, to characterize it more precisely, or to determine its inheritance as the basis for an adequate genetic counselling. 4 Depending on the disorder, national regulations, and clinical consensus guidelines, positive reports may also include recommendations for further action such as clinical management and counseling. In general, laboratory reports have to follow international standards (i.e.…”

“…mutations in SHOX or ACAN (for reviews see 1 , 2 ). Tall stature can also be caused by single gene variants like in NPR2 or NPR3 ( 3 , 4 , 5 ). However, the transition between syndromic and non-syndromic growth disturbances is not clearly defined: even in families with the same genetic variant, the phenotype can vary considerably, as is, for example, shown for CDKN1C variants in families with Beckwith–Wiedemann syndrome (BWS) ( 6 ).…”