Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations
Abstract
:1. Introduction
2. Experimental Section
2.1. Subjects
2.2. Genetic Studies
2.3. Statistical Analysis
3. Results
4. Discussion
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Gene (a) | Nucleotide Change | Amino Acid Change | Mutation Type | Population Allele Frequency (gnomAD/Portuguese Controls) | Computational Programs That Support a Pathogenic Effect (b) | Classification (ACMG Criteria) (c) | Previously Reported (Reference) |
---|---|---|---|---|---|---|---|
GCK | c.130G>A | p.Gly44Ser | missense | 0 | SIFT, PPh-2, MT | L. Pathogenic (PM1, PM2, PM5, PP2, PP3) | Yes [15] |
c.386G>A | p.Cys129Tyr | missense | 0 | SIFT, PPh-2, MT | L. Pathogenic (PM1, PM2, PP2, PP3) | Yes [16] | |
c.494T>C | p.Leu165Pro | missense | 0/0 (d) | SIFT, PPh-2, MT | L. Pathogenic (PM1, PM2, PP2, PP3, PP5) | No | |
c.544G>A | p.Val182Met | missense | 0 | SIFT, PPh-2, MT | L. Pathogenic (PM1, PM2, PP2, PP3, PP5) | Yes [17] | |
c.556C>T | p.Arg186* | nonsense | 0 | MT | Pathogenic (PVS1, PM1, PM2, PP3, PP5) | Yes [18] | |
c.563C>G | p.Ala188Gly | missense | 0/0 (h) | SIFT, PPh-2, MT | L. Pathogenic (PM1, PM2, PM5, PP2, PP3) | No | |
c.698G>A | p.Cys233Tyr | missense | 0 | SIFT, PPh-2, MT | L. Pathogenic (PM1, PM2, PP2, PP3) | Yes [19] | |
c.757G>C | p.Val253Leu | missense | 0 | SIFT, PPh-2, MT | L. Pathogenic (PM1, PM2, PM5, PM6, PP2, PP3) | Yes [20] | |
c.1099G>A | p.Val367Met | missense | 0 | SIFT, PPh-2, MT | L. Pathogenic (PM1, PM2, PP2, PP3, PP5) | Yes [21] | |
c.1268T>A | p.Phe423Tyr | missense | 0 | SIFT, PPh-2, MT | L. Pathogenic (PM1, PM2, PP2, PP3, PP5) | Yes [22] | |
HNF1A | c.425C>T | p.Ser142Phe | missense | 0 | SIFT, PPh-2, MT | L. Pathogenic (PM2, PP1, PP2, PP3, PP5) | Yes [23] |
c.475C>T | p.Arg159Trp | missense | 0.0000039 | SIFT, PPh-2, MT | L. Pathogenic (PM1, PM2, PM5, PP2, PP3, PP5) | Yes [24] | |
c.511C>T | p.Arg171* | nonsense | 0 | MT | Pathogenic (PVS1, PM2, PP3, PP5) | Yes [23] | |
c.521C>T | p.Ala174Val | missense | 0.0001951 | MT | VUS (PP2, PP3, BS2) | Yes [25] | |
c.607C>A | p.Arg203Ser | missense | 0 | SIFT, PPh-2, MT | L. Pathogenic (PM1, PM2, PM5, PP2, PP3) | Yes [26] | |
c.1623G>A | p.Gln541Gln | synonymous | 0/0 (e) | MT, HSF | VUS (PM2, PP1, PP3) | No | |
c.1729C>G | p.His577Asp | missense | 0.0001429/0.001 (i) | SIFT, MT | VUS (PP1, PP2, PP3, BS2) | No | |
HNF4A | c.68delG | p.Gly23Alafs*81 | frameshift | 0 | MT | Pathogenic (PVS1, PM2, PP3) | No |
c.422G>C | p.Arg141Pro | missense | 0/0 (f) | SIFT, MT | L. Pathogenic (PM1, PM2, PP1, PP2, PP3) | No | |
c.602A>C | p.His201Pro | missense | 0/0 (g) | SIFT, PPh-2, MT | L. Pathogenic (PM1, PM2, PP2, PP3) | No |
Patient ID | Sex/Age (yrs) | Age at Diagnosis (yrs) | Family History (a) | Presenting Signs and Symptoms | BMI (kg/m2) | A1c (%) | C-Peptide (ng/mL) (b) | Abs | Treatment | Complications | Last A1c (%) | Mutation |
---|---|---|---|---|---|---|---|---|---|---|---|---|
2476 | M/28 | 9 | Yes | Asymptomatic | 21.8 (*) | 7.2 | 0.10 | Yes | Insulin | Retinopathy, neuropathy, nephropathy (kidney transplant) | 5.2 | HNF1A c.1729C>G (p.His577Asp) |
5035 | F/48 | 15 | No | Asymptomatic | 19.4 (*) | n/a | n/a | n/a | No | No | 6.5 | GCK c.563C>G (p.Ala188Gly) |
5227 | M/9 | 8 | No | Asymptomatic | 17.5 | 6.4 | 0.84 | No | No | No | 6.7 | GCK c.130G>A (p.Gly44Ser) |
6243 | F/22 | 10 | Yes | Asymptomatic | 22.3 (*) | n/a | 7.20 | No | OHA | No | 6.6 | GCK c.544G>A (p.Val182Met) |
6291 | F/12 | 11 | No | Weight loss | 17.9 | 6.0 | 4.80 | No | No | No | 6.0 | GCK c.757G>C (p.Val253Leu) |
6518 | F/15 | 14 | Yes | Polyuria/polydipsia | 25.5 | 6.5 | 4.50 | No | OHA | No | 6.4 | GCK c.1099G>A (p.Val367Met) |
6856 | F/16 | 6 | No | Asymptomatic | 15.5 | 6.6 | 0.82 | No | OHA | No | 6.3 | GCK c.494T>C (p.Leu165Pro) |
6866 | M/33 | 3 | Yes | Asymptomatic | 25.2 (*) | 6.6 | 2.52 | n/a | No | No | 6.2 | GCK c.1268T>A (p.Phe423Tyr) |
6955 | F/34 | 34 | Yes | Asymptomatic | 26.2 | 6.4 | 3.40 | No | OHA | No | 5.9 | HNF1A c.521C>T (p.Ala174Val) |
7004 | F/32 | 31 | Yes | Gestational diabetes | 20.7 (*) | 6.1 | 0.80 | No | No | No | 6.1 | GCK c.1268T>A (p.Phe423Tyr) |
7018 | F/31 | 16 | Yes | Polyuria/polydipsia | 28.9 | 9.0 | 1.00 | No | Insulin | Retinopathy | 6.7 | HNF4A c.422G>C (p.Arg141Pro) |
7034 | M/20 | 14 | Yes | Asymptomatic | 23.4 (*) | 6.5 | 2.39 | n/a | No | No | 6.1 | GCK c.386G>A (p.Cys129Tyr) |
7071 | F/39 | 21 | Yes | Gestational diabetes | 19.1 (*) | n/a | 0.70 | No | No | No | 6.4 | HNF4A c.68delG (p.Gly23Alafs *81) |
7113 | M/7 | 4 | No | Asymptomatic | 17.4 (*) | 6.4 | 1.17 | No | No | No | 6.7 | GCK c.757G>C (p.Val253Leu) |
7396 | F/13 | 11 | Yes | Weight loss | 16.2 | 8.7 | 1.80 | No | Insulin | No | 5.9 | HNF1A c.425C>T (p.Ser142Phe) |
7422 | M/27 | 25 | No | Asymptomatic | 22.7 | n/a | 1.70 | No | OHA + Insulin | No | 5.1 | HNF1A c.607C>A (p.Arg203Ser) |
7451 | F/39 | 18 | Yes | Asymptomatic | 25.8 | 6.4 | 2.30 | No | OHA | No | 7.3 | GCK c.698G>A (p.Cys233Tyr) |
7467 | F/14 | 14 | No | Asymptomatic | 22.2 | 8.0 | 1.37 | No | OHA | No | 8.0 | HNF1A c.511C>T (p.Arg171 *) |
7613 | M/7 | 6 | No | Asymptomatic | 15.6 | 6.9 | 0.90 | No | No | No | 6.7 | GCK c.556C>T (p.Arg186 *) |
7629 | F/32 | 18 | Yes | Polyuria/polydipsia | 22.9 (*) | n/a | 1.50 | No | Insulin | No | 5.6 | HNF1A c.425C>T (p.Ser142Phe) |
7646 | M/35 | 17 | Yes | Polyuria/polydipsia | 19.3 (*) | n/a | 0.10 | No | Insulin | No | 5.5 | HNF1A c.475C>T (p.Arg159Trp) |
7690 | F/18 | 14 | No | Asymptomatic | 30.7 | 6.8 | 3.60 | No | OHA | No | 7.7 | HNF1A c.1623G>A (p.Gln541Gln) |
7797 | F/12 | 11 | Yes | Polyuria/polydipsia | 24.1 | 12.0 | 2.22 | No | OHA + Insulin | No | 8.1 | HNF4A c.602A>C (p.His201Pro) |
Mutation-Positive (n = 23) | Mutation-Negative (n = 23) | p-Value (c) | |
---|---|---|---|
Age at diagnosis (mean ± SD) (y) | 14.3 ± 7.7 | 23.0 ± 13.2 | 0.011* |
Family history (a) (n, %) | 14 (60.9) | 15 (65.2) | 1.000 |
Clinical presentation and course (b) (n, %) | 22 (95.7) | 22 (95.7) | 1.000 |
Presence of 2 inclusion criteria (n, %) | 12 (52.2) | 16 (69.6) | 0.365 |
Presence of 3 inclusion criteria (n, %) | 11 (47.8) | 7 (30.4) | 0.365 |
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Alvelos, M.I.; Gonçalves, C.I.; Coutinho, E.; Almeida, J.T.; Bastos, M.; Sampaio, M.L.; Melo, M.; Martins, S.; Dinis, I.; Mirante, A.; et al. Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations. J. Clin. Med. 2020, 9, 288. https://doi.org/10.3390/jcm9010288
Alvelos MI, Gonçalves CI, Coutinho E, Almeida JT, Bastos M, Sampaio ML, Melo M, Martins S, Dinis I, Mirante A, et al. Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations. Journal of Clinical Medicine. 2020; 9(1):288. https://doi.org/10.3390/jcm9010288
Chicago/Turabian StyleAlvelos, Maria I., Catarina I. Gonçalves, Eduarda Coutinho, Joana T. Almeida, Margarida Bastos, Maria L. Sampaio, Miguel Melo, Sofia Martins, Isabel Dinis, Alice Mirante, and et al. 2020. "Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations" Journal of Clinical Medicine 9, no. 1: 288. https://doi.org/10.3390/jcm9010288