Next Generation Mendelian Genetics: Congenital Hyperinsulinism

The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Congenital Hyperinsulinism (CHI) is the most common cause of hypoglycemia in the newborn and it is due to mutations in 8 different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and UCP2). It is a heterogeneous disease with variable onset (birth to adulthood) and a persistent, intermittent, or transient course with possible later conversion to non-autoimmune diabetes. Although mutations in the two subunits of the KATP channel (ABCC8 and KCNJ11) account for 50% of the cases, the other half is still genetically unexplained. CHI can be inherited in a dominant or recessive and can also present as a 'de novo' mutation. We became part of this study when we submitted 8 DNA samples for exome sequencing, from patients with CHI of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations in new genes or genetic variants.]]>
Eight patients with Congenital Hyperinsulinism were chosen and none of the 1st degree relatives were included. The patients were chosen from a multiethnic/racial group in accordance to the control sample available, which was Caucasian.]]>
We started collecting DNA samples from patients with Congenital Hyperinsulinism and their families, after our laboratory (Aguilar-Bryan and Bryan) cloned and reconstituted KATP channel activity. This important channel links cell metabolism with electrical activity. This subset of patients had an IRB approved consent form and are Caucasians from North America, chosen from a total population of ~135 cases, which included patients of Caucasian, Latino and a few of Asian and African American origin. We sequenced DNA from patients with several insulin secretory abnormalities, including Congenital Hyperinsulinism and Neonatal Diabetes. Several of the patients have been treated with oral medication that inhibits insulin release (Diazoxide and somatostatin), the rest has been treated surgically, because of a lack of response to clinical treatment.]]>