Table 1.

Molecular Genetic Testing Used in KMT2E-Related Neurodevelopmental Disorder

Gene 1MethodProportion of Pathogenic Variants 2, 3 Identified by Method
KMT2E Sequence analysis 4~95% 5
Gene-targeted deletion/duplication analysis 6Unknown; at least 2% 7
CMA 8~2% 5
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.

Six individuals with contiguous gene deletions have been reported and are also included in this calculation (see Genetically Related Disorders) [O'Donnell-Luria et al 2019, Kosma et al 2021, Velmans et al 2022].

4.

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.

5.
6.

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. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by O'Donnell-Luria et al [2019] and Kosma et al [2021]) may not be detected by these methods.

7.

No data on detection rate of gene-targeted deletion/duplication analysis are available, but this methodology should detect at least all of those deletions/duplications involving KMT2E detected through chromosomal microarray (CMA) analysis.

8.

CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including KMT2E) 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 7q22.3 region. CMA designs in current clinical use target the 7q22.3 region.

From: KMT2E-Related Neurodevelopmental Disorder

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