Monogenic short stature

Gene: BTK

Red List (low evidence)

Comment on list classification: The association between BTK and 'isolated growth hormone deficiency type III' has been classified as Disputed by ClinGen: 'No experimental evidence supporting a relationship with the isolated growth hormone deficiency has been reported and no convincing genetic evidence has emerged relating BTK to the isolated growth hormone deficiency since it was last reported in 1994. The evidence supporting the originally asserted relationship between BTK and x-linked isolated growth hormone deficiency type III has been disputed and no valid evidence remains to support the claim.' - Antibody Deficiencies GCEP, Nov 2020. More information can be found here: https://search.clinicalgenome.org/CCID:004296.
The gene was linked to Bruton-type agammaglobulinemia with a Definitive classification in a separate curation (https://search.clinicalgenome.org/CCID:004297)
BTK is linked to Isolated growth hormone deficiency, type III, with agammaglobulinemia, 307200 and Agammaglobulinemia, X-linked 1, 300755 in OMIM (accessed 29th Oct 2025).

Created: 29 Oct 2025, 4:33 p.m. | Last Modified: 29 Oct 2025, 4:33 p.m.

Panel Version: 1.23

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Isolated growth hormone deficiency, type III, with agammaglobulinemia, OMIM:307200

Publications

• 7849697
• 8013627
• 1880652

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

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: Promoted from Red to Amber. BTK is confirmed to be associated with isolated growth hormone deficiency in OMIM but not in Gene2Phenotype. There are >3 unrelated cases of patients diagnosed with growth hormone deficiency who have variants in BTK.

There is enough evidence to support a gene-disease association. This gene is also Green on the Pituitary hormone deficiency (ID: 483, version 2.7). This gene has been tagged for review by the GMS specialist group to determine whether this gene is appropriate for this panel.

Created: 1 Nov 2021, 8:31 a.m. | Last Modified: 1 Nov 2021, 8:31 a.m.

Panel Version: 1.92

Green List (high evidence)

At least 4 families reported with GH deficiency plus agammaglobulinaemia.

Created: 14 Aug 2021, 5:20 a.m. | Last Modified: 14 Aug 2021, 5:20 a.m.

Panel Version: 1.71

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Isolated growth hormone deficiency, type III, with agammaglobulinaemia, MIM# 307200

Publications

• 8013627
• 7849697
• 9554752