| NDM - Sanger (ABCC8, KCNJ11 & INS) (International cohorts) |
4 |
26-1020 |
49% (580/1183) |
A |
ABCC8 and KCNJ11 are common causes of NDM and inform transfer from insulin to sulphonylurea. Rapid diagnosis by initial Sanger is recommended, although tNGS that includes these genes as a first line test is suitable if result within 1-2 weeks. INS may be included in first line Sanger testing given the small size of this gene.
|
| NDM - Methylation status at 6q24 locus (International cohorts) |
4 |
18-1020 |
11% (125/1137) |
A |
Abnormal methylation at the 6q24 locus causes transient NDM but detection requires a specific assay (MS-MLPA) that requires additional resources. Testing may be offered to all newly diagnosed NDM patients after negative Sanger and/or NGS testing. Alternatively testing may be offered only to patients with TNDM or where DM later remits to reduce cost, but this may delay time to diagnosis.
|
| NDM - NGS (all known NDM genes) (International cohorts) |
8 |
7-1020 |
70% (837/1196) |
A |
ABCC8 and KCNJ11 are the common NDM subtypes but an additional 19 different genetic subtypes were diagnosed using NGS. NGS testing increased diagnostic yield by 30% Rare recessive NDM syndromes were more common than ABCC8 & KCNJ11 in consanguineous populations, and NGS testing is essential; the distal enhancer of PTF1A is mutated in 3% of cases and must be specifically targeted by NGS. NGS may detect variants missed by Sanger sequencing due to sequence variation in primer binding sites.
|
| MODY - Sanger (France, USA, Greece) |
3 |
84-140 |
13% (24/181) |
A |
Sanger sequencing of the most common cause MODY genes is a viable option where NGS is not available but has lower sensitivity and will miss cases. Testing of HNF1A, HNF4A, GCK and m.3243A>G will diagnose around 75% of genetically confirmed MODY referred to a diagnostic testing laboratory. Laboratories issuing a no diagnosis Sanger report must inform the clinician that a diagnosis of other MD subtypes has not been excluded and advise on further testing.
|
| MODY - CNV detection (International cohorts) |
11 |
31-1564 |
1% (63/5051) |
A |
CNVs are a rare cause of MODY. Most common CNV is the deletion of HNF1B associated with diabetes and structural renal disease. Use of MLPA in Sanger or tNGS negative cases gives a small increase in diagnostic yield (~1%) but may not justify the increased cost and resources. Read depth from NGS testing can be used simply and freely to detect CNVs and is recommended.
|
| MODY - NGS (International cohorts) |
16 |
9-4016 |
30% (1700/5790) |
A |
Recommended option for first line testing, especially in populations with higher levels of consanguinity. NGS increases diagnostic yield through testing of many more genes related less common MODY subtypes and syndromic forms of MD. Diagnoses MD in 20-30% of cases with a clinical suspicion. Yield further increased when detection for CNVs and the m.3243A>G mutation is included in the NGS assay. Targeted custom gene panels, exome or whole genome sequencing can be undertaken, although exome and genome options are costly and better suited to novel gene discovery on a research basis. It is possible for a patient to be diagnosed with more than one monogenic diabetes subtype.
|
| m.3243A>G Genotyping (UK, China) |
2 |
57-230 |
83% (47/57) |
B |
The m.3243A>G is the 4th most common genetic diagnosis in patients referred for MODY testing. It must be tested in all patients with suspected MODY, even if there is no hearing loss in the family, due to variable penetrance. It can be detected by NGS but requires specific targeting. Alternatively, a rapid quantitative genotyping assay such as pyrosequencing can be used. Sanger sequencing is possible but requires a minimum heteroplasmy detection level of ~5%.
|
| GCK - Sanger & MLPA (Czech Republic) |
1 |
140 |
74% (103/140) |
A |
The clinical phenotype is easily recognised in children and in pregnancy. This enables specific and rapid sequencing of GCK with a high diagnostic yield (>70%). A rapid diagnosis in pregnancy enables non-invasive prenatal testing to aid clinical management by using a digital PCR technique that is 100% accurate.
|
| GCK – non-invasive prenatal testing by ddPCR (UK) |
1 |
33 |
100% concordance with cord blood result. |
C |
