Table 1.

Molecular Genetic Testing Used in Permanent Neonatal Diabetes Mellitus

Gene 1Proportion of Permanent Neonatal Diabetes Mellitus Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 2 Detectable by Method
Sequence
analysis 3		Gene-targeted deletion/duplication analysis 4
ABCC8 19% 5100%None reported 7
GCK 4% 8100%None reported 7
INS 20% 9>99%1 family 10
KCNJ11 30% 11100%None reported 7
PDX1 <1% 12100%None reported 7
Unknown 13NA
1.

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

2.

See Molecular Genetics for information on allelic 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 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.

4.

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.

5.

Attributed to activating pathogenic variants of ABCC8 [Babenko et al 2006]

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

7.

No deletions or duplications involving ABCC8, GCK, KCNJ11, or PDX1 have been reported to cause permanent neonatal diabetes mellitus. Note that the KCNJ11 and ABCC8 defects are activating pathogenic variants and therefore must be missense. Duplication/deletion analysis would not identify ABCC8 and KCNJ11 defects.

8.

Njølstad et al [2001], Njølstad et al [2003]. Note: Carrier parents have mild diabetes mellitus or glucose intolerance (GCK-familial monogenic diabetes, previously known as MODY2).

9.
10.

A 646-bp deletion in INS was reported in individuals with neonatal diabetes [Raile et al 2011, Garin et al 2010, Støy et al 2010]; see Table 5.

11.

Attributed to activating pathogenic variants in KCNJ11 [Ellard et al 2007]

12.

Attributed to inactivating pathogenic variants [Stoffers et al 1997a]. Note: Carrier parents have mild, adult-onset diabetes mellitus (PDX1-familial monogenic diabetes, previously known as MODY4).

13.

The genetic causes of approximately 30% of PNDM remain unknown [Rubio-Cabezas et al 2014].

From: Permanent Neonatal Diabetes Mellitus

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