Annals of Case Reports

Introduction

Monogenic Diabetes (MD) accounts for about 1-5% of all diabetes cases with different subtypes such as neonatal diabetes (NDM), maturity onset diabetes of young (MODY) and syndromic forms such as Wolfram syndrome and Wolcott-Rallison syndrome [1]. Mendelian diseases, though individually rare, collectively represent a significant portion of the global population, affecting more than 5%. It encompasses more than 6000 rare phenotypes including MD. The phenomenon unique to Mendelian diseases is incomplete penetrance with variable expressivity [1]).

Penetrance refers to the proportion of individuals who carry a specific genotype and exhibit the expected clinical phenotype associated with that genotype. In other words, it is the likelihood or probability that a person with a particular genetic variant will express the associated trait or disease. If everyone with  a particular genotype presents with clinical symptoms by a particular age, then it is said to be fully penetrant, whereas if it falls below this, it is said to be reduced or incomplete penetrance. The severity of the phenotype caused by a particular genotype can vary among affected individuals (wide variation in terms of severity and age of onset).

This phenomenon is defined as variable expressivity displayed by that particular genotype. A said genotype can vary both in the severity of presentation and in level of penetrance across the population. This variable expressivity and penetrance are different from pleiotropy. Pleiotropy implies that different variants of a particular gene cause multiple phenotypes [2].

Case presentation

3-month-old female infant, second child of non-consanguineous parentage, full term birth by normal vaginal delivery (birth weight 3kg) presented in severe diabetic ketoacidosis (DKA). She presented to the emergency room with a Glasgow coma scale of 3, blood glucose was 31mmol/L, beta hydroxy butyrate 5.2mmol/L, venous pH 6.9, bicarbonate 4.2mmol/L and glycated hemoglobin (HbA1c)12.5%. She was critically ill and required intubation and mechanical ventilation. The working diagnosis was neonatal diabetes considering the age of onset, presenting in severe DKA. The DKA was managed as per the ISPAD (International Society for pediatric and Adolescent Diabetes) protocol. DKA resolved within 8 hours and she was extubated in around 24 hours. The child was initially initiated on insulin Detemir 1 unit once a day and bolus insulin Lispro 0.5 units pre feeds if blood glucose was >14mmol/L. She was discharged on detemir 2units twice a day and bolus insulin pre feeds as correction bolus with target blood sugar 14mmol/L.

Diagnostic Assessment

Table 1: Variant identified by WGS with clinical relevance to the patient phenotype.

Using whole genome sequencing (WGS) the patient and the mother (aged 28years) were found to carry a heterozygous variant in ABCC8 gene (variant c.4136G>T, Arg1379Leu) on exon 11. In silico analysis based on PolyPhen-2, CADD, GERP and pLI, predicted that this mutation was likely to be pathogenic (Table 1 summarises the variant details detected by WGS). The father and healthy sibling were negative for this finding. Meng Li et al demonstrated the same variant in a proband after the proband was diagnosed early onset type 2 diabetes mellitus (T2DM) at the age of 16 years. Functional studies revealed that the variant was located on the nucleotide binding domain 2 of the ABCC8 gene. The hyperglycaemia was the possible result of the variant impacting the ATPase activity [3]).The variant Arg1379Leu has been reported before with the phenotype of transient neonatal diabetes in an infant who was 42 days of age at the time of presentation with DKA . The mother was negative for the variant and the father was unavailable for testing [4].