The use of precision diagnostics for monogenic diabetes: a systematic review and expert opinion
Authors: Murphy Rinki , Colclough Kevin , Pollin Toni I. , Ikle Jennifer M. , Svalastoga Pernille , Maloney Kristin A. , Saint-Martin Cécile , Molnes Janne ,   ADA/EASD PMDI, Tobias Deirdre K. , Merino Jordi , Ahmad Abrar , Aiken Catherine , Benham Jamie L. , Bodhini Dhanasekaran , Clark Amy L. , Colclough Kevin , Corcoy Rosa , Cromer Sara J. , Duan Daisy , Felton Jamie L. , Francis Ellen C. , Gillard Pieter , Gingras Véronique , Gaillard Romy , Haider Eram , Hughes Alice , Ikle Jennifer M. , Jacobsen Laura M. , Kahkoska Anna R. , Kettunen Jarno L. T. , Kreienkamp Raymond J. , Lim Lee-Ling , Männistö Jonna M. E. , Massey Robert , Mclennan Niamh-Maire , Miller Rachel G. , Morieri Mario Luca , Most Jasper , Naylor Rochelle N. , Ozkan Bige , Patel Kashyap Amratlal , Pilla Scott J. , Prystupa Katsiaryna , Raghaven Sridaran , Rooney Mary R. , Schön Martin , Semnani-Azad Zhila , Sevilla-Gonzalez Magdalena , Takele Wubet Worku , Tam Claudia Ha-ting , Thuesen Anne Cathrine B. , Tosur Mustafa , Wallace Amelia S. , Wang Caroline C. , Wong Jessie J. , Yamamoto Jennifer M. , Young Katherine , Amouyal Chloé , Andersen Mette K. , Bonham Maxine P. , Chen Mingling , Cheng Feifei , Chikowore Tinashe , Chivers Sian C. , Clemmensen Christoffer , Dabelea Dana , Dawed Adem Y. , Deutsch Aaron J. , Dickens Laura T. , DiMeglio Linda A. , Dudenhöffer-Pfeifer Monika , Evans-Molina Carmella , Fernández-Balsells María Mercè , Fitipaldi Hugo , Fitzpatrick Stephanie L. , Gitelman Stephen E. , Goodarzi Mark O. , Grieger Jessica A. , Guasch-Ferré Marta , Habibi Nahal , Hansen Torben , Huang Chuiguo , Harris-Kawano Arianna , Ismail Heba M. , Hoag Benjamin , Johnson Randi K. , Jones Angus G. , Koivula Robert W. , Leong Aaron , Leung Gloria K. W. , Libman Ingrid M. , Liu Kai , Long S. Alice , Lowe William L. , Morton Robert W. , Motala Ayesha A. , Onengut-Gumuscu Suna , Pankow James S. , Pathirana Maleesa , Pazmino Sofia , Perez Dianna , Petrie John R. , Powe Camille E. , Quinteros Alejandra , Jain Rashmi , Ray Debashree , Ried-Larsen Mathias , Saeed Zeb , Santhakumar Vanessa , Kanbour Sarah , Sarkar Sudipa , Monaco Gabriela S. F. , Scholtens Denise M. , Selvin Elizabeth , Sheu Wayne Huey-Herng , Speake Cate , Stanislawski Maggie A. , Steenackers Nele , Steck Andrea K. , Stefan Norbert , Støy Julie , Taylor Rachael , Tye Sok Cin , Ukke Gebresilasea Gendisha , Urazbayeva Marzhan , Van der Schueren Bart , Vatier Camille , Wentworth John M. , Hannah Wesley , White Sara L. , Yu Gechang , Zhang Yingchai , Zhou Shao J. , Beltrand Jacques , Polak Michel , de Franco Elisa , Flanagan Sarah E. , Maloney Kristin A. , McGovern Andrew , Nakabuye Mariam , Njølstad Pål Rasmus , Pomares-Millan Hugo , Provenzano Michele , Zhang Cuilin , Zhu Yeyi , Auh Sungyoung , de Souza Russell , Fawcett Andrea J. , Gruber Chandra , Mekonnen Eskedar Getie , Mixter Emily , Sherifali Diana , Eckel Robert H. , Nolan John J. , Philipson Louis H. , Brown Rebecca J. , Billings Liana K. , Boyle Kristen , Costacou Tina , Dennis John M. , Florez Jose C. , Gloyn Anna L. , Gomez Maria F. , Gottlieb Peter A. , Greeley Siri Atma W. , Griffin Kurt , Hattersley Andrew T. , Hirsch Irl B. , Hivert Marie-France , Hood Korey K. , Josefson Jami L. , Kwak Soo Heon , Laffel Lori M. , Lim Siew S. , Loos Ruth J. F. , Ma Ronald C. W. , Mathieu Chantal , Mathioudakis Nestoras , Meigs James B. , Misra Shivani , Mohan Viswanathan , Murphy Rinki , Oram Richard , Owen Katharine R. , Ozanne Susan E. , Pearson Ewan R. , Perng Wei , Pollin Toni I. , Pop-Busui Rodica , Pratley Richard E. , Redman Leanne M. , Redondo Maria J. , Reynolds Rebecca M. , Semple Robert K. , Sherr Jennifer L. , Sims Emily K. , Sweeting Arianne , Tuomi Tiinamaija , Udler Miriam S. , Vesco Kimberly K. , Vilsbøll Tina , Wagner Robert , Rich Stephen S. , Franks Paul W. , Misra Shivani , Aukrust Ingvild , de Franco Elisa , Flanagan Sarah E. , Njølstad Pål R. , Billings Liana K. , Owen Katharine R. , Gloyn Anna L. 
Published: October 2023

Background

Monogenic diabetes presents opportunities for precision medicine but is underdiagnosed. This review systematically assessed the evidence for (1) clinical criteria and (2) methods for genetic testing for monogenic diabetes, summarized resources for (3) considering a gene or (4) variant as causal for monogenic diabetes, provided expert recommendations for (5) reporting of results; and reviewed (6) next steps after monogenic diabetes diagnosis and (7) challenges in precision medicine field.

Methods

Pubmed and Embase databases were searched (1990-2022) using inclusion/exclusion criteria for studies that sequenced one or more monogenic diabetes genes in at least 100 probands (Question 1), evaluated a non-obsolete genetic testing method to diagnose monogenic diabetes (Question 2). The risk of bias was assessed using the revised QUADAS-2 tool. Existing guidelines were summarized for questions 3-5, and review of studies for questions 6-7, supplemented by expert recommendations. Results were summarized in tables and informed recommendations for clinical practice.

Results

There are 100, 32, 36, and 14 studies included for questions 1, 2, 6, and 7 respectively. On this basis, four recommendations for who to test and five on how to test for monogenic diabetes are provided. Existing guidelines for variant curation and gene-disease validity curation are summarized. Reporting by gene names is recommended as an alternative to the term MODY. Key steps after making a genetic diagnosis and major gaps in our current knowledge are highlighted.

Conclusions

We provide a synthesis of current evidence and expert opinion on how to use precision diagnostics to identify individuals with monogenic diabetes.