Next Generation Sequencing Analysis of MODY-X Patients: A Case Report Series
2. Subjects and Methods
- Patients from 0 to 18 years with confirmed persistent hyperglycemia (two or more occasions) and/or diabetes onset in the period from January 2000 to December 2016, recruited at the Pediatric Diabetic Clinic, S. Orsola Malpighi, Bologna and S. Chiara Hospital in Trento;
- Absence of an autoimmune marker: glutamic acid decarboxylase antibodies (GAD), insulin antibodies (IAA), autoantibody to protein tyrosine phosphatase (IA-2), autoantibody to the cation efflux transporter zinc transporter (ZnT8);
- One first-degree relative diagnosed with hyperglycemia or diabetes before age 25 years (non-binding criterion for inclusion in the study);
- Diabetes treatment with diet and/or oral agents and/or reduced insulin need after at least 1 year from diabetes onset;
- Negative results of genetic analysis of the most prevalent types of MODY in Italy (GCK-, HNF1A-, and HNF4A-MODY).
Case 1: An 18-year-old boy was referred to our center for mild to moderate hyperglycemia (110–170 mg/dL) since adolescence, with HbA1c levels between 6 and 6.5% (42–47 mmol/mol). Autoantibodies for type 1 diabetes (T1D) were negative. Due to the family history of diabetes (mother and grandmother on treatment with oral hypoglycemic drugs), genetic tests for the most common forms of MODY were performed (GCK-, HNF1A-, and HNF4A- MODY) and found negative. He then underwent an NGS panel test, and a WFS1 (wolframin) stop codon variant p.Arg42* (c.124C > T), classified as pathogenic, was found. The same mutation was identified in his mother. As his metabolic control was acceptable (HbA1c constantly <7%, 53 mmol/mol), no treatment was started.
Case 2: A 10-year-old boy was admitted for sustained hyperglycemia (blood glucose > 300 mg/dL, HbA1c > 9%, 75 mmol/mol) without DKA. Given the age and the consistent insulin requirement (0.8 IU/kg/day), he was initially diagnosed as T1D. All autoantibodies for beta cells were negative. Remarkably, he was under treatment in another center for congenital cataract as his mother had gradually developed mild to moderate hyperglycaemia.
Case 3: A 12-year-old girl was referred for diabetes with mild DKA and negative T1D specific antibodies. Her HbA1C at diagnosis was 16.8% and insulin treatment (0.5 IU/kg/day) was started. Basal C-peptide was 1.3 ng/mL and 3.8 ng/mL after glucagon stimulation, consistent with a good residual β-cell function. A predisposing HLA to T1D (DR3 and DR4) was found. After 2 years, rapid insulin was discontinued and therapy with basal insulin (0.3–0.4 U/kg/d) and metformin was started due to the low daily insulin requirement and recurrent hypoglycaemia. Her HbA1C ranged between 6.5% and 7.2% (48–55 mmol/mol). Her father, affected by diabetes, was treated with basal insulin and metformin.
Case 4: An adolescent presented with very high blood glucose (>400 mg/dL) and HbA1c 8.9% (74 mmol/mol) at diagnosis with negative T1D specific antibodies. At the age of 16 years old, his father was diagnosed with DM, generically labelled as insulin-dependent, even if initially treated with oral hypoglycaemic agents and then shifted to insulin treatment. After an initial period on insulin treatment, for the rapid decreasing insulin requirement, the subject was put on sulfonylurea treatment (glimepiride) with a good metabolic response and HbA1C ranging from 6.5 to 7.5% (48–58 mmol/mol). Thus, the Sanger genetic test for the principal forms of MODY was performed, but no mutations were found.
Case 5: A 15-year-old boy came to our attention for suspected T1D. His blood glucose was 436 mg/dL, and his HbA1c was 9.1%, 76 mmol/mol. He presented polyuria and polydipsia as well as weight loss.
Case 6: A 13-year-old boy presented with a blood glucose of 491 mg/dL, HbA1c 8.6%, and negative T1D-specific antibodies. He needed only basal insulin of 0.66 IU/kg/day. The father of the proband was diagnosed with T2DM when he was 25 years old, and his paternal grandmother was also affected by T2DM. The Sanger genetic test for the principal forms of MODY found no mutations. By NGS, the patient was identified with a change in the HNF1B (hepatocyte nuclear factor-1B) gene (c.704G > A, p.Arg235Gln). This variant has previously been reported as pathogenic in the literature . An abdominal ultrasound did not identify renal cysts, and an abdominal MRI did not reveal pancreatic body or tail agenesis; he had normal kidney and liver function. Therefore, he did not show typical features of MODY-5.
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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|Patient||Gender||Age at the Hyperglycemia||BG (mg/dL) HbA1c at First Observation||Phenotype||Therapy||Family History||Gene||Nucleotide Change||Amino Acid||Segregation||Allele Frequency (gnomAD)||PolyPhen-2 SIFT||ClinVar Classification||Literature Reports|
|-||None||Mother and grandmother on OHA||WFS1||c.124C > T||p.Arg42Ter||Mother||0.00009||Pathogenic||Pathogenic/Likely pathogenic|||
|Congenital cataract||Insulin 0.8 IU/kg/day||Mother with mild/moderate hyperglycemia||WFS1||c.1153G > A||p.Glu385Lys||Mother||0.00057||VUS||VUS/Likely benign|||
|-||Metformin||Father with DM on insulin and metformin; sister on insulin||WFS1|
|c.1249T > G|
c.211G > A
|0.01485||VUS benign||VUS Benign/Likely benign|||
|-||Sulfonylurea||Father with DM on insulin||KCNJ11||c.685G > A||p.Glu229Lys||Father||-||Likely pathogenic||Pathogenic/Likely risk allele|||
|-||Insulin||Brother and sister with diabetes; three sisters on OHA; mother with T2D||INS||c.187 + 2T > C||Intron variant||Mother, 2 brothers, and 4 sisters||-||Pathogenic||Pathogenic|||
|Normal abdomen US||Insulin 0.66 IU/kg/day||Father and grandmother with T2D||HNF1B||c.704G > A||p.Arg235Gln||Father and grandmother||-||Pathogenic||Likely pathogenic/VUS|||
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Maltoni, G.; Franceschi, R.; Di Natale, V.; Al-Qaisi, R.; Greco, V.; Bertorelli, R.; De Sanctis, V.; Quattrone, A.; Mantovani, V.; Cauvin, V.; et al. Next Generation Sequencing Analysis of MODY-X Patients: A Case Report Series. J. Pers. Med. 2022, 12, 1613. https://doi.org/10.3390/jpm12101613
Maltoni G, Franceschi R, Di Natale V, Al-Qaisi R, Greco V, Bertorelli R, De Sanctis V, Quattrone A, Mantovani V, Cauvin V, et al. Next Generation Sequencing Analysis of MODY-X Patients: A Case Report Series. Journal of Personalized Medicine. 2022; 12(10):1613. https://doi.org/10.3390/jpm12101613Chicago/Turabian Style
Maltoni, Giulio, Roberto Franceschi, Valeria Di Natale, Randa Al-Qaisi, Valentina Greco, Roberto Bertorelli, Veronica De Sanctis, Alessandro Quattrone, Vilma Mantovani, Vittoria Cauvin, and et al. 2022. "Next Generation Sequencing Analysis of MODY-X Patients: A Case Report Series" Journal of Personalized Medicine 12, no. 10: 1613. https://doi.org/10.3390/jpm12101613