Invaluable Role of Consanguinity in Providing Insight into Paediatric Endocrine Conditions: Lessons Learnt from Congenital Hyperinsulinism, Monogenic Diabetes, and Short Stature

Abstract

Consanguineous families have often played a role in the discovery of novel genes, especially in paediatric endocrinology. At this time, it has been estimated that over 8.5% of all children worldwide have consanguineous parents. Consanguinity is linked to demographic, cultural and religious practises and is more common in some areas around the world than others. In children with endocrine conditions from consanguineous families, there is a greater probability that a single gene condition with autosomal recessive inheritance is causative. From 1966 and the first description of Laron syndrome, through the discovery of the first KATP channel genes ABCC8 and KCNJ11 causing congenital hyperinsulinism in the 1990s, to recent discoveries of mutations in YIPF5 as the first cause of monogenic diabetes due to the disruption of the endoplasmic reticulum (ER)-to-Golgi trafficking in the β-cell and increased ER stress; positive genetic findings in children from consanguinity have been important in elucidating novel genes and mechanisms of disease, thereby expanding knowledge into disease pathophysiology. The aim of this narrative review is to shed light on the lessons learned from consanguineous pedigrees with the help of three fundamental endocrine conditions that represent an evolving spectrum of pathophysiological complexity – from congenital hyperinsulinism, a typically single cell condition, to monogenic diabetes which presents with uniform biochemical parameters (hyperglycaemia and glycosuria), despite varying aetiologies, up to the genetic regulation of human growth – the most complex developmental phenomenon.

Paediatric diabetes subtypes in a consanguineous population: a single-centre cohort study from Kurdistan, Iraq

“…In comparison, the study from Turkey had a predominance of recessive variants in the WFS1 and SLC19A3 genes [ 20 ]. Therefore, it can be concluded that each consanguineous population is unique, which can allow specific insights into the genetics of conditions such as monogenic diabetes [ 26 ].…”

“…Enabling genetic testing of people with diabetes in consanguineous populations is important in improving diagnostic criteria for monogenic diabetes [ 20 ]. In addition, studies in consanguineous populations have led to the ongoing discovery of novel genes and pathophysiological pathways [ 26 ]. One pathogenic variant among our cohort was in the ZNF808 gene (Table 1 ), which was identified very recently as causing neonatal diabetes in consanguineous families [ 27 ].…”

KATP channel mutations in congenital hyperinsulinism: Progress and challenges towards mechanism-based therapies

“…The estimated incidence of CHI is 1:28,000–1:50,000 in Western populations but as high as 1:2,500 in populations with higher rates of consanguinity ( 3 , 13 , 14 ). Variants in at least ten genes have now been linked to congenital hyperinsulinism, including genes that encode the K ATP channel subunits ( ABCC8 and KCNJ11 ), glucokinase ( GCK ), glutamate dehydrogenase ( GLUD1 ), the mitochondrial enzyme 3-hydroxyacyl-CoA dehydrogenase ( HADH ), proton-linked monocarboxylate transporter ( SLC16A1 ), mitochondrial uncoupling protein 2 ( UCP2 ), hepatocyte nuclear factor 1 alpha ( HNF1A ) and 4 alpha ( HNF4A ), and hexokinase 1 ( HK-1 ) ( 15 ).…”