Table 2.

Molecular Genetic Testing Used in 6q24-Related Transient Neonatal Diabetes Mellitus (TNDM)

MethodPathogenic Variants/Alterations DetectedProportion of 6q24-TNDM Alterations Detected
Methylation analysis 1Hypomethylation within the 6q24 DMR region including imprinting center defects100% 2
Microarray (SNP based)Duplication of 6q24, UPD6 3~70%
UPD studies 4UPD6~41%
Targeted duplication analysis 5Duplication of 6q24~29% 6
Single-gene testingSequence analysis 7ZFP57 pathogenic variants 89% 9
Gene-targeted deletion/duplication analysis 5ZFP57 intragenic deletion or duplicationNone reported

DMR = differentially methylated region; UPD = uniparental disomy

1.

Can establish diagnosis, but will not distinguish genetic mechanism; can be done by Southern blot, methylation-specific multiple ligation-mediated PCR analysis (MS-MLPA), or methylation-specific PCR.

2.

Note: Only methylation analysis will detect an imprinting center defect, which is causative in ~30% of individuals.

3.

Paternal disomy occurs by postzygotic somatic recombination resulting in isodisomy and can therefore be identified by proband-only SNP array analysis.

4.

Use of genetic markers (usually short tandem repeats) to determine parental identity (maternal or paternal) of a chromosome or chromosomal segment in a proband. Note: This testing requires a DNA sample from the proband, mother, and father.

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, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Reported duplications range in size from 200 kb to several megabases [Docherty et al 2010]. A small minority of individuals have a cytogenetically visible duplication of 6q24 [Temple et al 1996, Arthur et al 1997]. If conventional karyotype analysis identifies a visible chromosome translocation or duplication of 6q24, parental studies are required to determine if the abnormality is paternal in origin.

7.

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

8.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

9.

From: Diabetes Mellitus, 6q24-Related Transient Neonatal

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