Monogenic short stature

Gene: NPR2

Green List (high evidence)

Comment on mode of inheritance: There are more than 3 unrelated individuals reported in literature with heterozygous NPR2 variants and idiopathic short stature, more severe than -3SD at age >2yrs. Biallelic variants are known to cause severe dwarfism, with stature well below -3SD. Hence, the MOI should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 5 Jun 2026, 2:12 p.m. | Last Modified: 5 Jun 2026, 2:12 p.m.

Panel Version: 2.1

PMID: 40424589 Renes et al., 2025
Report of 18 different NPR2 variants in 27 Dutch children with short stature (all heterozygous). Truncating variants (5/18) had a more severe effect than non-truncating variants (-3.3 vs -2.5 SDS respectively). Also, variants in the kinase homology domain (6/18 variants) were more severe than variants in other domains (-3.2 SDS vs -2.5 SDS). Majority of patients had mild features suggestive of skeletal dysplasia. 21/27 individuals had dysmorphic features of the hands, 13/27 with brachydactyly, clinodactyly and syndactyly also reported. All the children were 4-18 years old at the start of GH treatment (and height measurement) so the TD criteria are fulfilled for at least 5 individuals (> 2 years old and height <-3SD).

Created: 5 Jun 2026, 12:40 p.m. | Last Modified: 5 Jun 2026, 2:08 p.m.

Panel Version: 2.1

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Short stature with nonspecific skeletal abnormalities, OMIM:616255

Publications

• 40424589

The rating of this gene has been updated to GREEN and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 31 Jan 2023, 5:28 p.m. | Last Modified: 31 Jan 2023, 5:28 p.m.

Panel Version: 2.33

Comment on list classification: There is sufficient evidence to rate this gene as Green under a biallelic MOI - causes severe dwarfism that is usually diagnosed at birth and becomes more obvious in the first 2 years of life (MIM# 602875). Monoallelic variants can cause idiopathic short stature (MIM# 616255) however the associated height and age at which short stature becomes apparent does not meet the criteria of the panel (height ≤−3 SDS at the age of at least 2 years).

Created: 5 Jan 2023, 5:14 p.m. | Last Modified: 5 Jan 2023, 5:14 p.m.

Panel Version: 2.13

Review submitted on behalf of Helen Storr. Mode of inheritance: AR and AD. Phenotypes: Alteration of the NPR2 signaling cascade leads to growth disorders; downregulation leads to short stature, and upregulation leads to excessive growth. Biallelic defects lead to severe skeletal dysplasia (acromesomelic dysplasia, Maroteaux type) and heterozygous NPR2 variants cause short stature with possible presence of different signs of bone dysplasia. Publications: Well established. Severe Maroteaux type skeletal dysplasia described in 2003. Heterozgous defects assocuated with short stature from 2013 onwards. . Mechansim: The C-type natriuretic peptide receptor encoded by the NPR2 gene is a paracrine regulator of the growth plate. Penetrance: Full penetrance.

Created: 22 Dec 2022, 11:07 a.m. | Last Modified: 22 Dec 2022, 11:07 a.m.

Panel Version: 2.5

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal