Variable presentations of GCK gene mutation in a family

Abstract

We describe siblings born from non-consanguineous parents, with older sibling having asymptomatic hyperglycaemia while younger sibling presented with low birth weight and persistent hyperglycaemia from first month of life. Our case, the older sibling was heterozygous for paternally inherited GCK pathogenic variant resulting in diabetes of maturity-onset in the young (MODY) manifested as mild fasting hyperglycaemia. GCK gene sequencing revealed that the younger sibling was compound heterozygous for missense mutations (two) combined in a novel GCK-permanent neonatal diabetes mellitus (PNDM) genotype. Thus, heterozygous inactivating GCK mutations are likely to lead to maturity-onset diabetes of the young type 2 (MODY 2) and the homozygous inactivating or compound heterozygous GCK mutations are a cause of PNDM.

Background

Around 1%–5% of all diabetes occurs due to abnormalities at a single gene or locus. These entities as a group are referred as monogenic diabetes.¹ More than 30 genes are identified as causing monogenic diabetes, where they are classified in three overlapping phenotypic categories: maturity-onset diabetes of the young (MODY), neonatal diabetes and syndromic diabetes.² GCK and PDX1 are the two genes that cause MODY when a heterozygous mutation (MODY2 and MODY4, respectively) is present and permanent neonatal diabetes mellitus (PNDM) in compound heterozygous or homozygous form. Inactivating heterozygous mutation of GCK causes mild diabetes because the 30% glucose phosphorylating capacity needed for the glucose stimulated insulin release occurs when glucose concentrations are higher. A peak of just 50%–60% of phosphorylating capacity is attained which is sufficient to clear all glucose after a meal, but with periods of hyperglycaemia before this.³

GCK inactivating heterozygous mutation present asymptomatically as an incidental finding.⁴ GCK-MODY is commonly presented in pregnancy since that may be the first time a woman’s blood glucose level is assessed. Meanwhile, presence of homozygous inactivating mutation or a compound heterozygous mutation can lead to permanent neonatal diabetes from the first day of life. Overall, these mutations are rare in neonatal diabetes mellitus as shown in a study comparing the aetiologies of PNDM in Arab versus European populations.⁵

Case presentation

We present the case of an 11-year-old girl who was referred to us for incidental hyperglycaemia on two occasions 1 year apart. All her blood reports including thyroid function test were normal. She had fasting hyperglycaemia with 2-hour postprandial hyperglycaemia (blood glucose: 7.8–11.1 mmol/L, noted from her medical records). Her HbA1c was 6.8% (normal: 4%–5.6%). On anthropometric examination, her height was 136.5 cm (Z-score: −0.95), weight was 30 kg (Z-score: −0.77), body mass index of 16.1 kg/m² (Z-score: −0.43).³ She was non-obese and had no clinical signs of insulin resistance like acanthosis nigricans. Her mother (first pregnancy) was diagnosed to have gestational diabetes mellitus (GDM) at the time of pregnancy with this child and required insulin. Postdelivery she was well controlled on oral antihyperglycemic agents (OHA), metformin 500 mg two times a day, sitagliptin 100 mg once daily and glimepiride 2 mg once daily (other details of gestational weight gain and anthropometry at birth are not available). Family history revealed that the father was diagnosed with type-2 diabetes mellitus on a routine health check (high fasting glucose and HbA1c) at 33 years of age and was being treated with OHA Metformin 500 mg two times a day along with glimepiride 2 mg once daily. Her younger sibling who was born full term, small for gestational age (SGA) with birth weight of 2.2 kg, length of 44 cm and head circumference of 30 cm was diagnosed to have neonatal diabetes on the 15th day of life; she had severe hyperglycaemia requiring neonatal intensive care admission for 15 days. She was admitted again at 6 months of age when she presented in diabetic ketoacidosis. Her HbA1c at that time was 11.9% with a low c-peptide (0.2 ng/dL) and the diagnosis of NDM was confirmed. She is being treated with multidose insulin injection therapy by basal-bolus regimen at dose of 1.3 U/kg/day. Maternal grandfather and paternal grandfather of the patient are also being treated with OHA’s for diabetes (details not known). Family tree of the affected child is illustrated in figure 1.

Figure 1.

Family tree of affcted child.

The genetic work up of the entire family was performed. Targeted next-generation sequencing of the case revealed a genetic diagnosis of MODY, subtype glucokinase by detection of pathogenic GCK mutation of NM_000162.5: c.764C>A, p. (Thr255Asn) on Chr7: g.44187348T of paternal inheritance. The younger sibling had a compound heterozygous biallelic autosomal recessive pathogenic GCK missense variant causing neonatal diabetes. She inherited pathogenic heterozygous GCK mutation NM_000162.5:c.572G>A, p.(Arg191Gln) on Chr7:g.44189575 from her mother and NM_000162.5:c.764C>A, p.(Thr255Asn) on Chr7:g.44187348T from her father. Sanger sequencing of GCK exons 5 and 7 and the flanking intronic regions to test for the familial variant (NM_000162.5) detected corresponding mutations in parents. In summary, the clinical and laboratory details of the family are shown in table 1.

Table 1.

Clinical and laboratory details of the family

	Patient age	Age at diagnosis	Presenting feature	Current treatment	Genetic diagnosis
Proband	11	11 years	Incidental	None	GCK mutation NM_000162.5: c.764C>A, p.(Thr255Asn)
Sibling	4.5	15 days	Neonatal diabetes	Insulin basal bolus regimen	GCK mutation NM_000162.5:c.572G>A, p.(Arg191Gln) and NM_000162.5:c.764C>A, p.(Thr255Asn)
Mother	34	23 years	Gestational diabetes	Metformin, sitagliptin, glimepiride	GCK mutation NM_000162.5:c.572G>A, p.(Arg191Gln)
Father	38	33 years	Routine health check-up	Metformin, glimepiride	GCK mutation of NM_000162.5: c.764C>A, p.(Thr255Asn)

Outcome and follow-up

As the rise in glucose that occurs with alterations in the GCK gene is mild, there are usually no symptoms and complications of diabetes are very rare, therefore usually no treatment is needed. Thus, the subject is currently only being monitored for HbA1c periodically. The mother of the subject is currently being treated with glimepiride, metformin and sitagliptin while father is being treated with glimepiride and metformin. The younger sibling is on insulin therapy at dose of 1.3 U/kg with last HbA1c of 9.3%.

Discussion

GCK gene, located in the 7p15.3-p15.1 region consists of 12 exons and 11 introns that span _~45 168 bp. The protein that is encoded has 465 amino acids and a molecular weight of 52 191 Da and is expressed chiefly in the pancreas, the liver and brain.⁶ Cases of GCK-PNDM are extremely rare in children of non-consanguineous parents and only a total of nine mutations have been described so far, that too in consanguineous Arabian and European GCK-MODY families.^{7 8} Both the parents suffer from different monoallelic pathogenic loss-of-function variants in GCK causing MODY subtype glucokinase. The risk that their off-spring could be compound heterozygous for the GCK variants and affected by neonatal diabetes is one in our (25%). There is also a one in two risk for each offspring being heterozygous for the GCK variant and being affected with fasting hyperglycaemia (5.5–8 mmol/L) from birth (GCK MODY). Both the scenarios are found in this case with the subject being affected by MODY-2 and younger sister of subject affected by PNDM.

Compound heterozygous or homozygous mutations of the GCK gene (OMIM*138079) are a very rare cause of PNDM, further, inactivating heterozygous mutations in GCK gene cause autosomal dominant subtype GCK-MODY (previously termed as MODY-2).⁹ A case similar to the one we report was described from Brazil where p.Asn254His and p.Arg447Gly missense pathological variants led to GCK-PNDM in one of the offspring and GCK-MODY in the other.¹⁰ Over 600 GCK mutations have so far been described in families with MODY, PNDM or hyperinsulinaemic hypoglycaemia. These mutations have been distributed throughout the GCK gene, with no mutation ‘hot spots’.¹¹ Patients with GCK-PNDM require insulin therapy and the addition of glibenclamide may be beneficial. Patients with GCK-MODY, however, do not require any treatment except in pregnancy when there is evidence that the baby is growing more quickly than usual on antenatal ultrasound scans. These mothers (with GCK-MODY) may be treated with insulin to control blood glucose and hence optimise the baby’s growth. Non-invasive prenatal testing in pregnant women with monogenic diabetes is recommended to decide on the management of the pregnancy according to fetal genotype. However, as fetal genotype is rarely known, assessment of fetal growth on second trimester ultrasound may be useful to interpret if the fetus is carrying mutation. If the fetal growth is accelerated with abdominal circumference >75%, it is suggestive that the fetus does not carry GCK mutation. If the fetus has GCK mutation, it will have a higher glucose set point and will sense maternal hyperglycaemia as normal, leading to normal growth.¹² If the mother is subjected to glucose-lowering therapy in this scenario, the risk for SGA is increased as noted in our case.

To conclude, our case suggests that a high index of suspicion is required for diagnosis of GCK-MODY in patients with asymptomatic hyperglycaemia, atypical presentations of type-2 DM or GDM and the diagnosis needs to be confirmed by genetic analysis. Separate heterozygous pathogenic variants in parents may cause severe autosomal recessive compound heterozygous PNDM in their off-spring. Thus, in families where various types of diabetes cluster at a younger age, genetic analysis proves to be beneficial in managing diabetes.

Learning points.

• GCK-maturity-onset diabetes of the young has asymptomatic hyperglycaemia and may be diagnosed as an incidental finding in patient with family history of diabetes or for the first time in pregnancy as gestational diabetes mellitus during initial screening.

• Different missense heterozygous pathogenic variants in parents can lead to severe GCK-permanent neonatal diabetes mellitus in offspring with probability of 25%.

• Around 50% of off-springs born to a parent with a pathogenic variation in GCK gene are likely to inherit the same variation leading to a mildly raised blood glucose concentration throughout life. This is due to 50% chance of affected gene being inherited from a parent at the time of conception.

• In families where unusual forms of diabetes present at a younger age, genetic testing proves to be essential for management of these children.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s)