ClinGen Dosage Sensitivity Curation Page

BTK

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

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.

Evidence for Triplosenstive Phenotype

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.