Skeletal dysplasia

Gene: NPR3

Green List (high evidence)

Additional cases reported in:

PMID: 35233476 - Lauffer et al 2022 - 2 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. The authors note that compared to other patients with NPR-C (encoded by NPR3) loss-of-function, the phenotype appears to be milder.

PMID: 40171685 - Moffat et al 2025 - 3 siblings with a novel homozygous missense variant in NPR3 that in vitro data shows causes loss-of-function. All had tall stature but in addition 1 sibling had severe scoliosis developed and mild scoliosis was observed in the two others. Scoliosis has not been previously reported in NPR3-related tall stature and therefore extends the phenotype.

Created: 7 Apr 2025, 8:23 p.m. | Last Modified: 7 Apr 2025, 8:23 p.m.

Panel Version: 7.36

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 6 Mar 2022, 5:41 p.m. | Last Modified: 6 Mar 2022, 5:41 p.m.

Panel Version: 2.176

Comment on list classification: Promoting this gene from grey to amber with a recommendation for green rating following GMS review. 3 unrelated cases with a similar phenotype and supporting functional data and mouse model.

Created: 21 Jan 2021, 4:43 p.m. | Last Modified: 21 Jan 2021, 4:43 p.m.

Panel Version: 2.75

PMID: 30032985 Boudin et al 2018 - report 4 individuals from 3 unrelated families (1 Dutch, 1 Pakistani, 1 unknown ancestry) presenting with tall stature, long digits, and extra epiphyses in the hands and feet. WES was used in 2 families and targeted NPR3 screening in the third. Biallelic variants were found in NPR3 in all affected individuals. In one family 2 affected individuals were compound heterozygous for a missense and nonsense variant. The other two individuals were homozygous for missense and frameshift variants. The variants segregated with the phenotype in all 3 families. All variants were either not reported or appear at low frequency in dbSNP, ExAC and gnomAD databases and never in the homozyous state. Functional studies show that 3 of the variants either result in NMD or absent localization at the plasma membrane.

PMID: 10468599 Jaubert 1999 - analysis of mouse strains that have elongated bodies show that in each have mutations in the Npr3 gene.

Created: 21 Jan 2021, 4:41 p.m. | Last Modified: 21 Jan 2021, 4:41 p.m.

Panel Version: 2.73

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Boudin-Mortier syndrome, OMIM:619543

Publications

• 30032985
• 10468599
• 35233476
• 40171685

Green List (high evidence)

4 individuals in 3 families reported with striking phenotypic similarity.
Functional evidence compelling.
Mouse model recapitulates phenotype (including skeletal features).
Sources: Literature

Created: 19 Feb 2020, 6:54 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Tall stature; arachnodactyly; extra epiphyses; aortic dilatation

Publications

• PMID: 30032985
• 10468599

Variants in this GENE are reported as part of current diagnostic practice