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Case Reports
. 2024 Dec 23;3(1):luae230.
doi: 10.1210/jcemcr/luae230. eCollection 2025 Jan.

A Unique Phenotype of Maturity-Onset Diabetes of the Young With a Novel Disease-Causing Insulin Gene Variant

Cherie Chua  1 , Clara Si Hua Tan  2 , Su Chi Lim  3   4 , Rashida Farhad Vasanwala  1
Affiliations
Case Reports

A Unique Phenotype of Maturity-Onset Diabetes of the Young With a Novel Disease-Causing Insulin Gene Variant

Cherie Chua et al. JCEM Case Rep. .

Abstract

Maturity-onset diabetes of the young (MODY) represents 1% to 5% of patients with diabetes mellitus (DM), and numerous genes associated with MODY have been identified. While mutations of the insulin gene (INS) are known to cause permanent neonatal DM, rare disease-causing variants have also been found in MODY. These patients demonstrate variable clinical phenotypes-from milder forms requiring lifestyle or oral agent interventions to severe forms requiring lifelong insulin. We present a case of MODY arising from a novel disease-causing INS variant, in an adolescent with atypical features. He was obese with clinical evidence of insulin resistance, diagnosed with DM through opportunistic oral glucose tolerance testing. He developed symptomatic hyperglycemia with worsening glycemic trend, requiring treatment with high-dose insulin and metformin. After 2.5 years, his glycemic profile normalized following weight loss, and pharmacotherapy was discontinued. Targeted gene testing revealed a de novo novel missense variant in exon 2 of the INS gene (p.His29Tyr), confirmed using bidirectional Sanger sequencing. Insulin resistance in patients with MODY can worsen their clinical course and increase risks of long-term complications. Management of these patients should be individualized. This case highlights the utility of genetic testing in diagnosing uncommon and variable forms of MODY, particularly those with atypical features.

Keywords: insulin gene; insulin resistance; maturity-onset diabetes of the young; pediatric diabetes mellitus.

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Figures

Figure 1.
Figure 1.
Family pedigree showing history of type 2 diabetes mellitus (T2DM) in affected family members of proband, III.3 (denoted by arrow). Neither of the parents (II.1 or II.2) has a history of DM. The proband's siblings were also unaffected.
Figure 2.
Figure 2.
Timeline of patient's clinical course.
Figure 3.
Figure 3.
Bidirectional Sanger sequencing chromatogram of a missense variant (p.His29Tyr) in exon 2 of the INS gene identified in the proband.
See this image and copyright information in PMC

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