Skeletal dysplasia

Gene: GNPNAT1

Green List (high evidence)

Comment on list classification: There are now 4 unrelated individuals reported with biallelic GNPNAT1 missense variants and skeletal dysplasia. Hence, this gene should be promoted to Green at the next update.

Created: 11 May 2026, 4:27 p.m. | Last Modified: 11 May 2026, 4:28 p.m.

Panel Version: 9.4

PMID: 35427807 Sabbagh et al., 2022
Report of an 8yo girl with Spondyloepimetaphyseal dysplasia and a homozygous GNPNAT1 variant c.226G > A p.(Glu76Lys) - method: Trio WGS. Moroccan consanguineous parents. Language and motor development was normal. She had severe short stature due to rhizomelic shortening of the limbs.

PMID: 36097642 Elhossini et al., 2022
Report of an Egyptian patient (consanguineous parents), who presented with severe Spondylo-epi-metaphyseal dysplasia. WES identified a homozygous c.77T>G, (p.Phe26Cys) variant in GNPNAT1. His main symptoms were severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings.
In the same family, a fetus was aborted at 4 months of pregnancy due to detected skeletal deformities diagnosed intrauterine - genotype not confirmed.

PMID: 39945447 Pan et al., 2025
No. 2 WES case. Ultrasound findings revealed TE, nuchal fold (NF) thickening, short limbs, and a narrow thorax, indicative of skeletal dysplasia. WES identified compound heterozygous mutations in the GNPNAT1 gene: c.305C>T/p.Thr102Ile & c.506G>T/p.Gly169Val- both rare / absent from gnomAD v4, classified as VUS according to ACMG but reported to the family due to consistent phenotype.

Created: 11 May 2026, 4:18 p.m. | Last Modified: 11 May 2026, 4:27 p.m.

Panel Version: 9.4

Comment on phenotypes: OMIM phenotype updated 11th May 2026.

Created: 11 May 2026, 3:59 p.m. | Last Modified: 11 May 2026, 3:59 p.m.

Panel Version: 9.2

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Rhizomelic dysplasia, Ain-Naz type, OMIM:619598; rhizomelic dysplasia, Ain-Naz type, MONDO:0859203

Publications

• 35427807
• 36097642
• 39945447

Green List (high evidence)

Autosomal recessive. All variants described so far are missense

Created: 7 May 2026, 4:07 a.m. | Last Modified: 7 May 2026, 4:07 a.m.

Panel Version: 9.1

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Skeletal dysplasia; Rhizomelic dysplasia, Ain-Naz type

Publications

• 32591345
• 35427807
• 36097642

Mode of pathogenicity
Other

I don't know

one consanguineous family described, 4 affected individuals, all homozygous for p.Glu76Lys. not seen in population dbs.
not a partiuclarly highly conserved residue, prediction software conflicting results. linkage supports. keep as amber.

Created: 30 Jan 2021, 12:30 p.m. | Last Modified: 30 Jan 2021, 12:30 p.m.

Panel Version: 2.80

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
rhizomelic short stature

Publications

• 32591345

I don't know

Comment on list classification: Amber rating as only one family, but some supporting functional data. Additional cases required to validate pathogenicity of GNPNAT1.

Created: 30 Jul 2020, 12:30 p.m. | Last Modified: 30 Jul 2020, 12:30 p.m.

Panel Version: 2.11

PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation.
Sources: Literature

Created: 30 Jul 2020, 11:24 a.m. | Last Modified: 30 Jul 2020, 12:29 p.m.

Panel Version: 2.10

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Rhizomelic skeletal dysplasia

Publications

• 32591345