Monogenic short statue: genes and variants

Genes linked to Monogenic short statue

• PTPN11: Tyrosine-protein phosphatase non-receptor type 11

  Its SHP2 phosphatase activity promotes RAS-MAPK signaling downstream of many receptor tyrosine kinases and cytokine receptors. Germline dysregulating variants cause Noonan-spectrum disorders, while somatic activating variants drive juvenile myelomonocytic leukemia and other cancers.

  6 disease-causing and 1 uncertain variants in PTPN11 are linked to Monogenic short statue.

• SOS1: Son of sevenless homolog 1

  It activates RAS by exchanging GDP for GTP downstream of receptor tyrosine kinases. Germline activating variants are a common cause of Noonan syndrome, while excessive SOS1-RAS signaling can contribute to cancer.

  1 disease-causing and 0 uncertain variants in SOS1 are linked to Monogenic short statue.

• GHR: Growth hormone receptor

  Its activation by growth hormone triggers JAK2-STAT signaling that promotes IGF-1 production, linear growth, and metabolic effects. Biallelic or dominant-negative loss-of-function variants can cause growth-hormone insensitivity, while activating alterations are rare.

  1 disease-causing and 1 uncertain variants in GHR are linked to Monogenic short statue.

• ACAN: Aggrecan core protein

  Its highly charged glycosaminoglycan-rich structure enables cartilage to retain water and resist compressive forces, making it essential for growth-plate and articular-cartilage mechanics. Pathogenic variants can cause short-stature and skeletal-dysplasia phenotypes, including spondyloepimetaphyseal dysplasia and familial osteochondritis dissecans.

  0 disease-causing and 7 uncertain variants in ACAN are linked to Monogenic short statue.

Weakly linked (only a few uncertain records): BLM, CBL, RECQL4, FANCA, FGFR3 and RIT1.

Where Monogenic short statue variants cluster

• PTPN11 Tyrosine-protein phosphatase (positions 247–517): 6 of 6 disease-causing changes, 2.2× more than its size predicts.

Known disease-causing variants in Monogenic short statue

Which prediction tools work for Monogenic short statue

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 83 out of 100

Same protein, different disease

• RASopathy is also caused by PTPN11 variants; they fall mostly in different places as the Monogenic short statue variants (51 disease-causing).
• Noonan syndrome is also caused by PTPN11 variants; they fall mostly in different places as the Monogenic short statue variants (44 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by PTPN11 variants; they fall mostly in different places as the Monogenic short statue variants (29 disease-causing).
• LEOPARD syndrome 1 is also caused by PTPN11 variants; they fall mostly in different places as the Monogenic short statue variants (16 disease-causing).
• Metachondromatosis is also caused by PTPN11 variants; they fall mostly in different places as the Monogenic short statue variants (11 disease-causing).
• Noonan syndrome is also caused by SOS1 variants; they fall mostly in different places as the Monogenic short statue variants (30 disease-causing).
• RASopathy is also caused by SOS1 variants; they fall mostly in different places as the Monogenic short statue variants (22 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by SOS1 variants; they fall mostly in different places as the Monogenic short statue variants (9 disease-causing).
• Fibromatosis, gingival, 1 is also caused by SOS1 variants; they fall mostly in different places as the Monogenic short statue variants (4 disease-causing).
• Laron-type isolated somatotropin defect is also caused by GHR variants; they fall partly in the same places as the Monogenic short statue variants (7 disease-causing).

Diseases related to Monogenic short statue

• RASopathy, also linked to PTPN11 and SOS1
• Noonan syndrome, also linked to PTPN11 and SOS1
• Noonan syndrome and Noonan-related syndrome, also linked to PTPN11 and SOS1
• Male infertility with azoospermia or oligozoospermia due to single gene mutation, also linked to PTPN11 and SOS1
• Hypercholesterolemia, familial, 1, also linked to GHR
• Acute myeloid leukemia, also linked to PTPN11
• LEOPARD syndrome 1, also linked to PTPN11
• Metachondromatosis, also linked to PTPN11
• Juvenile myelomonocytic leukemia, also linked to PTPN11
• Laron-type isolated somatotropin defect, also linked to GHR
• Microcephaly, also linked to PTPN11
• Noonan syndrome with multiple lentigines, also linked to PTPN11

Frequently asked questions

Which genes are linked to Monogenic short statue?

In CATVariant, Monogenic short statue is linked to 4 analyzed proteins: PTPN11 (Tyrosine-protein phosphatase non-receptor type 11), SOS1 (Son of sevenless homolog 1), GHR (Growth hormone receptor) and ACAN (Aggrecan core protein).

How many genetic variants are linked to Monogenic short statue?

26 variants: 8 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 18 are of uncertain significance or have conflicting reports.

Which uncertain variants in Monogenic short statue look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Monogenic short statue?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.83, based on 8 disease-causing and 307 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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