Monogenic short stature

Gene: PAPPA2

The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before changing the rating and mode of inheritance of this gene.

Created: 11 Dec 2025, 1:25 p.m. | Last Modified: 11 Dec 2025, 1:25 p.m.

Panel Version: 1.27

The following is the review left by Melissa Connolly (WMRGL GLH) for this gene in R147 Growth failure in early childhood panel (https://panelapp.genomicsengland.co.uk/panels/473/gene/PAPPA2/)

The addition of this gene to the panel would be useful from a GLH perspective for interpretation purposes. ACGS guidelines state that when trying to incorporate phenotypic data into classification of variants that all other known causes of the phenotype should be excluded. In practice we often receive biochemical data for patients who have abnormal endocrine results in the GH-IGF axis and using this information for assessment of variants becomes easier if all the genes known to cause defects in the GH-IGF1 axis have been included in the analysis.

Rating: Green List (high evidence)
Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Phenotypes: Short stature; dysmorphism; mild microcephaly
Publications: 31555216; Durkie et al, 2024 https://www.acgs.uk.com/media/12533/uk-practice-guidelines-for-variant-classification-v12-2024.pdf

Created: 28 May 2024, 1:47 p.m. | Last Modified: 28 May 2024, 1:48 p.m.

Panel Version: 0.175

The OMIM entry for this gene is OMIM:619485, which has been cross-checked with Ensembl, HGNC and G2P. Hence, gene-checked tag has been added.

Created: 17 Oct 2023, 11:32 a.m. | Last Modified: 17 Oct 2023, 11:32 a.m.

Panel Version: 3.3

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains RED. The additional comments from GLH's is "No model to prove genotype to phenotype association. Individuals in Dauber et al 2016 (PMID:26902202) would not meet eligibility criteria for R147 (height). Siblings in Babiker et al 2021 (PMID: 34272725) meet height criteria but both have moderate microcephaly. Remain as amber until further information is available to support inclusion in this panel."

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

Panel Version: 2.33

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains RED

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

Panel Version: 2.33

Inclusion of the PAPPA2 gene on this panel was previously reviewed and disagreed by the GMS expert group. However, this should now be re-evaluated in light of the new review Melissa Connolly (WMRGL GLH) stating that inclusion would benefit GLH interpretation.

Created: 3 Jun 2024, 2:04 p.m. | Last Modified: 3 Jun 2024, 2:04 p.m.

Panel Version: 0.175

This gene was recently reviewed by the Endocrine Specialist Group (Sept 2022) and it was decided that there is not enough evidence to support this gene-disease association and therefore should remain Red.

Created: 6 Jan 2023, 11:51 a.m. | Last Modified: 6 Jan 2023, 11:51 a.m.

Panel Version: 2.31

At least 9 individuals from 5 unrelated families reported in literature with biallelic variants in this gene (PMID: 26902202; 33875846; 34272725). Birth lengths and weights were in the normal range for all individuals except possibly in one case displaying IUGR (but childhood medical history not provided). Clinical presentation is most notable for short stature and dysmorphic features but growth restriction appears to become apparent with age which is outside the scope of this panel (with exception of F2 on PMID: 26902202). Furthermore, microcephaly is a reported feature which is an exclusion criterion for this clinical indication.

Overall the phenotype is not appropriate for this panel and therefore maintaining the Red gene rating. It is probably more fitting for the R27 Paediatric disorders panel and so I will add to this panel to ensure cases can be picked up.

Created: 5 Jan 2023, 3:30 p.m. | Last Modified: 5 Jan 2023, 3:30 p.m.

Panel Version: 2.12

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Short stature, Dauber-Argente type, OMIM:619489

Publications

• 26902202
• 33875846
• 34272725

Review submitted on behalf of Helen Storr. Mode of inheritance: AR. Phenotypes: PAPPA2 is a metalloproteinase member of the pappalysin family, which specifically cleaves IGFBP-5 and IGFBP-3. It plays a key role in freeing IGF-1 from the ternary complex and thereby regulating the bioavailability of free IGF-1. PAPPA2 deficiency causes growth hormone insenstivity - severe short stature, free (biologically active) IGF-1 deficiency, elevated total circulating IGF-1. It is associated with dysmorphic feature - slim face, micrognathia, moderate microcephaly, long thin bones, low bone mineral density. Publications: Well established - described in 2016 and since then more than 10 cases / mutations identified but not routinely screened for so cases may be more. Mechansim: Reduction in IGF-1 bioavailability. 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
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

"Dauber et al. reported the finding of two homozygous variants (missense and frameshift) in two unrelated families, with several children having significant postnatal growth retardation, long thin bones, long fingers and toes, mild microcephaly, abnormal dentine and teeth enamel, and mild dysmorphisms." with functional evidence in PMID: 26902202. Now also "two patients with short stature and dysmorphic features with no evident NDD" reported in PMID: 33875846

Created: 30 Oct 2021, 11:42 a.m. | Last Modified: 30 Oct 2021, 11:42 a.m.

Panel Version: 1.90

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Short stature; dysmorphism; mild microcephaly

Publications

• PMID: 33875846
• 26902202

I don't know

Following discussion with members of the Endocrine Specialist Group at the Webex call on 23.05.19, it was agreed that this gene was outside the scope of this clinical indication. Therefore demoted gene from Green to Red.

Created: 30 May 2019, 9:49 a.m.