ClinGen Dosage Sensitivity Curation Page

BTK

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
16159644 Lopez-Granados, et al (2005) identified BTK variants in 52 Spanish patients with XLA from 40 unrelated families. Of these 52 patients, at least 29 patients harbored a truncating BTK variant (10 nonsense, 8 splicing, 8 frameshift, and 3 larger partial gene deletions/duplications) and the remaining patients harbored missense variants or in-frame indels. All patients with truncating variants showed minimal to no expression of the BTK protein, supporting haploinsufficiency as the mechanism of disease for XLA.
27512878 Chen, et al. (2016) performed sequence analysis of the BTK gene for 142 patients with a diagnosis of X-linked agammaglobulinemia (XLA) and found a BTK gene mutation in 127 patients from 124 unique families. Of 127 individuals with BTK variants, at least 64 patients harbored BTK variants expected to truncate the BTK protein (21 nonsense, 24 frameshift, 15 canonical splice site variants, 4 multi-exon deletions), while the remaining individuals harbor other types of BTK variants (i.e. missense, in-frame insertion/deletion, etc). Although pedigree analysis was not well documented in this publication, at least 6 patients with maternally inherited truncating variants appear to have a positive maternal family history of immunodeficiency (Table 1 and 2 patients 68, 80, 86, 93 and 97). Notably, this study identified a smaller proportion of XLA patients of Chinese ancestry harbor gross deletions of BTK in comparison to XLA patients of European ancestry.
32169379 Lougaris, et al (2020) provide a comprehensive long term follow-up of 168 male patients with XLA, 157 of which were evaluated for variants in the BTK gene. Many of the patients included in this study have been characterized in prior publications (see Table E3), however none of these overlap with the publications used in this curation. Of the 157 individuals with BTK variants, 104 distinct BTK variants were observed with nearly half assumed to result in premature protein truncation (18% indels, 17% nonsense, 12% splice sites, 4% large deletions). Of the 168 patients included in this study, almost 40% had a positive family history for XLA, however specific details for each family were not included.

Haploinsufficiency phenotype comments:

Loss of function variants in the BTK gene are associated with X-linked agammaglobulinemia (XLA), an immunodeficiency disorder resulting from extremely low numbers of B cells and low serum immunoglobulin levels (IgG, IgM, and IgA). Individuals with XLA typically present with recurrent severe infections (often bacterial in origin), such as respiratory tract infections, otitis media (ear infections) and recurrent diarrhea. The majority of affected individuals are male, given the X-linked inheritance pattern, and according to GeneReviews almost 90% of males with features consistent with XLA have detectable pathogenic variants in BTK. It is well established that the BTK protein is essential for B cell survival and the majority of patients with BTK-associated XLA have minimal or absent expression of the BTK protein (PMID: 9427714). The majority of causative BTK variants result in premature truncation of the protein and up to 8% of individuals have a large deletion, however missense variants that alter protein function can also cause disease. There are many more publications beyond the ones described here that support BTK loss of function mutations as causative for XLA. The BTK gene is also implicated in a contiguous deletion syndrome referred to as Mohr-Tranebjaerg syndrome with XLA (PMID: ?17851739, 11338284), which is characterized by deafness, dystonia, optic neuropathy and XLA. This deletion encompasses the TIMM8A (previously DDP) gene which is located adjacent to the 3' end of the BTK gene. Lastly, there have been some publications in the 1990's that suggested BTK variants are associated with x-linked isolated growth hormone deficiency type III, however the ClinGen Antibody Immunodeficiencies Expert Panel has curated this gene-disease associated and deemed it as being disputed in November 2020 (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6341781b-9ba9-41b1-889a-8d65a9b3ebb7-2020-11-17T170000.000Z).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.