Table 1.

Molecular Genetic Testing Used in X-Linked Agammaglobulinemia

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
BTK Sequence analysis 3, 492%
Gene-targeted deletion/duplication analysis 58%
CMA 63%-5% 7
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

BTK deep intronic pathogenic variants have been identified; sequence analysis that detects these deep intronic variants should be considered [Kralovicova et al 2011, Mohiuddin et al 2013, Rattanachartnarong et al 2014]. Sequence analysis of peripheral blood cell mRNA may be helpful.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

6.

Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays to detect genome-wide large deletions/duplications (including BTK) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the Xq22.1 region. CMA designs in current clinical use target the Xq22.1 region.

7.

Approximately 3%-5% of individuals (a subset of the 8% detected by gene-targeted deletion/duplication analysis) with a BTK pathogenic variant have a large deletion that extends through the closely linked gene TIMM8A (also called DDP) and sometimes through TAF7L and DRP2 [Richter et al 2001, Sedivá et al 2007]. Individuals with these multigene deletions have XLA and deafness-dystonia-optic neuropathy syndrome (DDON; also called Mohr-Tranebjærg syndrome).

From: X-Linked Agammaglobulinemia

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