Table 2.

Summary of Molecular Genetic Testing Used in Familial Hyperinsulinism

Gene 1Proportion of FHI Attributed to Mutations in This Gene 2Test MethodMutations Detected 3
ABCC845% 4Targeted mutation analysisp.Phe1387del, c.3989-9G>A 5
p.Val187Asp, p.Glu1506Lys 6
Deletion/duplication analysis 7Exonic and multiexonic deletions 8
Sequence analysis 9Sequence variants
KCNJ115% 10Sequence analysis 9Sequence variants
Deletion/duplication analysis 7Unknown, none reported 11
GLUD15% 12Sequence analysis 9Sequence variants
Sequence analysis of select exonsExons 6,7,10,11,12 13
HNF4A5% 14Sequence analysis 9Sequence variants
Deletion/duplication analysis 7Unknown, none reported 11
GCK<1% 15Sequence analysis 9Sequence variants
Deletion/duplication analysis 7None reported 16
HADH<1% 17Sequence analysis 9Sequence variants
Deletion/duplication analysis 7Exonic and multiexonic deletions 18
UCP2<<1% 19Sequence analysis 9Sequence variants

Percentages are different in populations with known founder mutations, such as the Ashkenazi Jewish and Finnish populations.


See Molecular Genetics for information on allelic variants.


Approximately 40%-45% of affected individuals have mutations in ABCC8 (previously known as SUR1) [Nestorowicz et al 1998, Aguilar-Bryan & Bryan 1999, Meissner et al 1999, Fournet & Junien 2003, Tornovsky et al 2004].


In the Ashkenazi Jewish population, two ABCC8 founder mutations are responsible for approximately 97% of FHI [Glaser et al 2011].


Two founder mutations have been identified in Finnish population [Otonkoski et al 1999, Huopio et al 2000].


Testing that identifies exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


A few exonic or multiexonic deletions have been reported in ABCC8 (see Table A).


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


Approximately 5% of individuals have mutations in KCNJ11 (The proteins encoded by ABCC8 and KCNJ11 make up the beta cell KATP channel, which regulates insulin secretion.) [Thomas et al 1996, Nestorowicz et al 1997, Tornovsky et al 2004].


No deletions or duplications involving KCNJ11 or HNF4A have been reported to cause hyperinsulinism.


Approximately 5% of individuals have activating mutations in GLUD1, the gene encoding the enzyme glutamine dehydrogenase (GDH) [Stanley et al 2000, Bahi-Buisson et al 2008].


Exons sequenced may vary by laboratory.


Approximately 5% of patients with diazoxide-responsive FHI have HNF4A mutations [Flanagan et al 2010].


Rarely, individuals have activating mutations in GCK, the gene encoding the enzyme glucokinase [Glaser et al 1998, Christesen et al 2002, Cuesta-Muñoz et al 2004, Sayed et al 2009].


No deletions or duplications involving GCK have been reported to cause hyperinsulinism.


Rarely, individuals have recessive, inactivating mutations in HADH, the gene encoding the enzyme L-3-hydroxyacyl-coenzyme A dehydrogenase, short chain [Clayton et al 2001, Molven et al 2004, Di Candia et al 2009].


Rare large deletions including exon 1 have been reported [Flanagan et al 2011].


Two families with dominant mutations in UCP2, the gene encoding mitochondrial uncoupling protein 2, have been reported [González-Barroso et al 2008].

From: Familial Hyperinsulinism

Cover of GeneReviews®
GeneReviews® [Internet].
Pagon RA, Adam MP, Ardinger HH, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-2015.
Copyright © 1993-2015, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.