
Maturity-onset diabetes of the young (MODY) is a rare disease that accounts for only 1% to 6% of all pediatric diabetes cases; however, it is one of the most common forms of monogenic hereditary diabetes mellitus caused by autosomal dominant pathogenic variants [1-5]. Accurate and timely diagnoses can be difficult as MODY may be misdiagnosed due to overlap of its clinical manifestations with type 2 and type 1 diabetes mellitus [6]. To date, 14 candidate genes have been identified to be associated with MODY:
To determine which gene is involved in any particular case of MODY, molecular genetic testing is needed. Direct Sanger sequencing has been traditionally used for molecular genetic testing. However, this technique is labor-intensive and only a few genes can be tested at a time. Therefore, it is limited in its application for genetically heterogeneous diseases, including MODY. As gene-panel testing using next-generation sequencing (NGS) allows for the simultaneous analysis of several candidate genes, it is currently the preferred approach for the diagnosis of MODY in which several subtypes are known. According to the literature, the molecular diagnosis rate of monogenic diabetes through a gene-panel test is approximately 20% in clinically suspected patients [7,8].
Here, we report a patient with MODY type 2 associated with a rare “likely pathogenic” glucokinase (GCK) variant (NM_000162.5:c.1289T>C) that was identified by gene-panel testing using targeted NGS. This study includes our experience regarding the challenge of the missense variant interpretation process according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) 2015 guidelines [9]. To our knowledge, only two cases with this variant have been reported.
An eight-year-old Korean female was transferred to our hospital from a local clinic with a complaint of fasting hyperglycemia lasting three months. She had no symptoms of diabetes. The patient was born small for her gestational age of 38 weeks, weighing 2.38 kg. When transferred to our hospital, her height was 131.6 cm (75th-90th percentile), weight was 31.1 kg (75th-90th percentile), and body mass index was 17.9 kg/m2 (75th-85th percentile).
Laboratory test results were as follows: fasting blood glucose, 134 mg/dL; 2-hour postprandial glucose, 179 mg/dL; glycated hemoglobin (HbA1c), 7.0%; insulin, 4.8 μIU/mL (normal range: 2.5-25.0 μIU/mL), C-peptide 1.17 ng/mL (normal range: 1.1-4.4 ng/mL); and negative for insulin, glutamic acid decarboxylase, and islet cell antibodies. She was initially diagnosed with type 2 diabetes and treated with glimepiride. Meanwhile, family history revealed the father was diagnosed with diabetes in his 40s. The mother of the patient was healthy. Diabetes had also been diagnosed in her father’s twin brother at a health checkup when he was in his 40s and in the patient’s paternal grandmother.
The possibility of monogenic diabetes was explored based on the evidence of the patient being diagnosed with diabetes under 25 years of age, autosomal dominant inheritance over three generations, fasting insulin levels within the normal range (insulin ≥2.0 μIU/mL or plasma C-peptide ≥0.6 ng/mL), and not being associated with obesity [8]. Accordingly, the patient underwent gene-panel testing for suspected MODY. The gene-panel testing used NGS (Illumina, San Diego, CA, USA) and included 38 genes associated with different MODY subtypes or syndrome with diabetes phenotype:
The gene-panel analysis revealed the heterozygous missense variant NM_000162.5(
The patient was ultimately diagnosed with MODY type 2 based on the gene-panel testing and stopped taking oral medication. Her diabetes was controlled with exercise and diet, and her HbA1c level was maintained at 6.7% to 7.0%.
Information regarding the GCK missense variant NM_ 000162.5(
According to ACMG/AMP 2015 guidelines [9], the following evidence codes could be applied to the variant identified in the current case study: PM2 (absent from control population databases), PP3 (a deleterious effect proven by multiple lines of computational evidence), and PS4_supporting (increased odds ratios with case control study data, downgraded as supporting level of evidence if previously identified in one unrelated affected individual) (Table 1). Another possible evidence code that could be applied to the variant was PP2, which is used for missense variants in genes with a low rate of benign variation. According to the 2020 Association for Clinical Genetics Science (ACGS) practice guidelines [10], PP2 evidence can be considered significant when the missense Z-score of a gene according to gnomAD constraint scores is more than 3.09. The Z-score from gnomAD for the
The evidence code PP1 (proven co-segregation, four or more segregations in an autosomal dominant gene) could be applied based on the familial genetic test results; however, the evidence code was not applied to the current variant due to the lack of four or more segregations. Had co-segregation been confirmed through the genetic testing of the other affected family members (uncle and grandmother), supporting evidence could have been added. However, this additional evidence could not be gathered as the extended family members refused testing.
An additional consideration was the evidence code PP4. This code is the evidence criterion applied when a “patient’s phenotype or family history is highly specific for a disease with a single genetic etiology”. In our case, the patient’s phenotype was young-onset diabetes with mild elevation of fasting blood glucose levels and no positive beta-cell autoantibodies. Additionally, we calculated the chance of testing positive using MODY Probability Calculator (https://www.diabetesgenes.org/exeter-diabetes-app/ModyCalculator) resulting in 75.5%. Accordingly, we applied the PP4 code. Finally, the variant identified in our case was classified as “likely pathogenic” according to the 2015 ACMG [9] and ACGS best practice guidelines [10].
Gene-panel testing data are routinely generated in clinical practice and various rare variants have been identified using gene-panel testing [11,12]. In the past, clinical laboratories had interpreted the variants using their own criteria. Their interpretation was often subjective and therefore resulted in inconsistent classifications among different clinical laboratories [13]. Since the 2015 ACMG guidelines were published, most clinical laboratories have interpreted the germline variants according to the guidelines. The guidelines introduced a scoring system to classify a variant into five tiers using specific rules and evidence, and help to interpret variants in a consistent manner among clinical laboratories. Since the guidelines, several recommendations have been published to specifically apply each piece of evidence, which can reduce the rate of inconsistent classification [10,14-16]. Despite the systemic interpretation approach, determining the pathogenicity of rare variants remains challenging, especially for rare missense variant types. Evidence of variant pathogenicity strength depends on the type of the variant and effects of its genetic mechanism. For the interpretation of novel or rare missense variants, the strength of available evidence is usually weaker than that of evidence applied to insertion-deletion (INDEL)-type variants [10,14]. Therefore, assessing the pathogenicity of novel missense variants compared to INDEL variants is a challenge and many missense variants remain classified as a “variant of uncertain significance.
The
We report here a LPV
In our current case, the patient exhibited mild fasting hyperglycemia (134 mg/dL), relatively steady 2-hour glucose levels (179 mg/dL), and 7% HbA1c, which was consistent with the clinical features of
In conclusion, we have reported a patient with MODY type 2 having a rare and likely pathogenic
The authors declare that they do not have any conflicts of interest.
Conception and design: JH and HSK. Acquisition of data: MKS. Analysis and interpretation of data: MKS. Drafting the article: MKS. Critical revision of the article: HSK and JH. Final approval of the version to be published: all authors.
The causative variant characteristics of
Information | Variant | |
---|---|---|
Chromosome | 7 | |
Position | 44184844 | |
Reference | A | |
Alteration | G | |
Gene | GCK | |
Reference sequence | NM_000162.5 | |
Nucleotide change | c.1289T>C | |
Protein change | p.Leu430Pro | |
Variant type | Missense variant | |
Zygosity | Heterozygous | |
GnomAD/KRGDB | Not found | |
In silico database | PROVEAN | –6.21 (deleterious) |
PolyPhen-2 HVAR | 0.999 (probably damaging) | |
SIFT | 0 (damaging) | |
REVEL score | 0.986 (pathogenic) | |
Final classification | Likely pathogenic variant (evidence: PM2, PP3, PS4_supporting [ref 1], PP2, PP4) |
KRGDB, Korean Reference Genome Database.
aSee the context of the variant interpretation part.
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