Clinical and molecular genetic characteristics of MODY cases with digenic and oligogenic inheritance as defined by targeted next-generation sequencing

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Abstract


The diagnosis of MODY should be verified by molecular genetic analysis. Recently the introduction of next-generation sequencing, allowing simultaneous analysis of several candidate genes, greatly facilitates the diagnosis of monogenic diseases including MODY. In addition, the simultaneous analysis of several candidate genes allows to identify cases with digenic and oligogenic inheritance. In this work we present the first description of MODY cases with digenic and oligogenic inheritance in our country.

Aim — to characterize MODY cases with digenic and oligogenic inheritance as defined by targeted next-generation sequencing.

Material and methods. 256 subjects (age range, 0.3—25 yrs; males, n=149, females, n=107) were included in the study. The patients fulfilled the following MODY criteria: diabetes or intermediate hyperglycemia, absence of β-cell autoimmunity (ICA, GAD, IA2, IAA antibodies), preserved C-peptide secretion. Molecular genetic analysis was performed by next-generation sequencing using custom Ion Ampliseq gene panel and PGM semiconductor sequencer (Ion Torrent). All mutations were confirmed by Sanger sequencing.

Results. 10 patients (8 probands, 1 sibling and 1 parent) showed digenic inheritance of MODY: 3 patients with combination of mutations in 2 candidate genes of MODY, 7 — in a candidate genes of MODY and another gene, associated with diabetes mellitus. In 1 case (sibling) showed oligogenic inheritance (mutations in GCK, HNF4A and INSR genes). Seven of the identified mutations were not previously described.

Conclusion. Next-generation sequencing is useful in identifying of MODY cases with digenic and oligogenic inheritance, which is extremely important with potentially modifying effect on the phenotype.


Olesya A. Gioeva

Author for correspondence.
olesyasogma@mail.ru
Endocrinology Research Centre, Moscow
Russian Federation, 11 Dm.Ulyanova street, 117036 Moscow

MD

Natalya A. Zubkova

zunata2006@yandex.ru
Endocrinology Research Centre, Moscow
Russian Federation, 11 Dm.Ulyanova street, 117036 Moscow

MD, PhD

Yulia V. Tikhonovich

sunflower25@mail.ru
Endocrinology Research Centre, Moscow
Russian Federation, 11 Dm.Ulyanova street, 117036 Moscow

MD, PhD

Vasiliy M. Petrov

petrov.vasiliy@gmail.com
Endocrinology Research Centre, Moscow
Russian Federation, 11 Dm.Ulyanova street, 117036 Moscow

PhD

Evgeniy V. Vasilyev

vas-evg@yandex.ru
Endocrinology Research Centre, Moscow
Russian Federation, 11 Dm.Ulyanova street, 117036 Moscow

PhD

Alexey V. Kiyaev

thyroend@mail.ru
Ural State Medical University, Ekaterinburg
Russian Federation, 3, Repina street, Ekaterinburg, 620028

MD, PhD, Professor

Lyudmila G. Chernich

lgchern@mail.ru
Regional Children Hospital №1, Ekaterinburg
Russian Federation, ул. Серафимы Дерябиной, 32, Екатеринбург, 620149

заведующая эндокринологическим отделением 

Olga Y. Pollyak

opollyak@mail.ru
Regional Children Hospital №1, Ekaterinburg
Russian Federation, ул. Серафимы Дерябиной, 32, Екатеринбург, 620149

сотрудник эндокринологического отделения

Albina R. Yusupova

albi79@mail.ru
Regional Children Hospital №1, Ekaterinburg
Russian Federation, ул. Серафимы Дерябиной, 32, Екатеринбург, 620149

сотрудник эндокринологического отделения

Anatoly N. Tiulpakov

anatolytiulpakov@gmail.com
Endocrinology Research Centre, Moscow
Russian Federation, 11 Dm.Ulyanova street, 117036 Moscow

MD, PhD

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Copyright (c) 2017 Gioeva O.A., Zubkova N.A., Tikhonovich Y.V., Petrov V.M., Vasilyev E.V., Kiyaev A.V., Chernich L.G., Pollyak O.Y., Yusupova A.R., Tiulpakov A.N.

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