Maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type
1 or type 2 diabetes. Correct diagnosis may result in a change in clinical
treatment and impacts prediction of complications and familial risk. In this
study, we aimed to assess the prevalence of MODY in multi-ethnic youth under
age 20 years with a clinical diagnosis of type 2 diabetes.
design and methods: We evaluated whole-exome sequence data of youth with a clinical diagnosis of type
2 diabetes. We considered participants
to have MODY if they carried a MODY gene variant classified as likely
pathogenic (LP) or pathogenic (P) according to current guidelines.
93 of 3,333 participants (2.8%) carried an LP/P variant in HNF4A (16 participants), GCK (23), HNF1A (44), PDX1 (5), INS (4), and CEL (1).
Compared with those with no LP/P variants, youth with MODY had a younger
age at diagnosis (12.9 ±
2.5 vs 13.6 ± 2.3 years, P=0.002) and lower fasting C-peptide
levels (3.0 ±
1.7 vs 4.7 ± 3.5 ng/mL, P<0.0001). Youth with MODY were less likely to have
hypertension (6.9% vs 19.5%, P=0.007) and had higher HDL cholesterol
(43.8 vs 39.7 mg/dL, P=0.006).
Conclusions: By comprehensively sequencing the
coding regions of all MODY genes, we identified MODY in 2.8% of youth with
clinically diagnosed type 2 diabetes; importantly, in 89% (n=83) the specific
diagnosis would have changed clinical management. No clinical criterion reliably separated the
two groups. New tools are needed to find
ideal criteria to select individuals for genetic testing.
Sequencing for T2D-GENES cohorts was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant U01DK085526: Multiethnic Study of Type Diabetes Genes and National Human Genome Research Institute (NHGRI) grant U54HG003067: Large Scale Sequencing and Analysis of Genomes. The TODAY study was completed with funding from NIDDK and the NIH Office of the Director (OD) through grants U01-DK61212, U01-DK61230, U01-DK61239, U01-DK61242, and U01-DK61254; from the National Center for Research Resources General Clinical Research Centers Program grant numbers M01-RR00036 (Washington University School of Medicine), M01-RR00043-45 (Children’s Hospital Los Angeles), M01-RR00069 (University of Colorado Denver), M01-RR00084 (Children’s Hospital of Pittsburgh), M01-RR01066 (Massachusetts General Hospital), M01-RR00125 (Yale University), and M01-RR14467 (University of Oklahoma Health Sciences Center); and from the NCRR Clinical and Translational Science Awards grant numbers UL1-RR024134 (Children’s Hospital of Philadelphia), UL1-RR024139 (Yale University), UL1-RR024153 (Children’s Hospital of Pittsburgh), UL1-RR024989 (Case Western Reserve University), UL1-RR024992 (Washington University in St Louis), UL1-RR025758 (Massachusetts General Hospital), and UL1-RR025780 (University of Colorado Denver). The SEARCH for Diabetes in Youth Cohort Study (SEARCH 4; 1UC4DK108173) is funded by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases and supported by the Centers for Disease Control and Prevention. The Population Based Registry of Diabetes in Youth Study (1U18DP006131, U18DP006133, U18DP006134, U18DP006136, U18DP006138, U18DP006139) is funded by the Centers for Disease Control and Prevention and supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Sites (SEARCH 1 through 4): Kaiser Permanente Southern California (U18DP006133, U48/CCU919219, U0