Phenotypic and Genetic Heterogeneity in a Thai Glucokinase MODY Family Reveals the Complexity of Young-Onset Diabetes

Glucokinase-Maturity-Onset Diabetes of the Young (GCK-MODY) is characterized by asymptomatic, non-progressive and fasting hyperglycemia, albeit not without phenotypic variability. We used next generation sequencing (NGS) to screen for 34 MODY genes in a non-obese person with familial young-onset diabetes followed by screening in 24 family members within three generations with varying presentations of young-onset diabetes and sensorineural hearing loss. The index patient was found to carry a paternally-inherited heterozygous missense variant (c.716 A>G) of GCK in exon 7 with amino acid change (Q239R). This variant was associated with phenotypic heterogeneity ranging from normal glucose tolerance to diabetes with complications amongst the siblings which might be modified by obesity and chronic hepatitis B infection. Two paternally-inherited variants of SLC29A3 encoding a nucleoside transporter protein and Apo-A1 genes also co-segregated with glucose and lipid traits. Co-occurrence of diabetes and deafness in maternal aunts led to discovery of WFS1 (Wolfram syndrome type 1) as a cause of non-syndromic deafness in multiple members of the maternal pedigree. Our findings highlight the complex causes of familial young-onset diabetes and the need of a multidisciplinary approach to interpret the clinical relevance of discoveries made by NGS in this era of genomic medicine.

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Familial Young-Onset Diabetes, Pre-Diabetes and Cardiovascular Disease Are Associated with Genetic Variants of DACH1 in Chinese

PLoS ONE ◽

10.1371/journal.pone.0084770 ◽

2014 ◽

Vol 9 (1) ◽

pp. e84770 ◽

Cited By ~ 10

Author(s):

Ronald Ching Wan Ma ◽

Heung Man Lee ◽

Vincent Kwok Lim Lam ◽

Claudia Ha Ting Tam ◽

Janice Siu Ka Ho ◽

...

Keyword(s):

Cardiovascular Disease ◽

Genetic Variants ◽

Young Onset ◽

Onset Diabetes

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Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility

Cell Discovery ◽

10.1038/s41421-020-00231-4 ◽

2020 ◽

Vol 6 (1) ◽

Cited By ~ 2

Author(s):

Fang Wang ◽

Shujia Huang ◽

Rongsui Gao ◽

Yuwen Zhou ◽

Changxiang Lai ◽

...

Keyword(s):

Genome Wide Association Study ◽

Phenotypic Variability ◽

Missense Variant ◽

Pedigree Analysis ◽

Chinese Patients ◽

Genetic Contribution ◽

Loss Of Function ◽

Genomic Study ◽

Significant Gene ◽

Host Genetic

Abstract The COVID-19 pandemic has accounted for millions of infections and hundreds of thousand deaths worldwide in a short-time period. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed interindividual phenotypic variability. Here, we report the first host genetic study in the Chinese population by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People’s Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe, and critical ill patients after the correction of potential confounding factors. Pedigree analysis suggested a potential monogenic effect of loss of function variants in GOLGA3 and DPP7 for critically ill and asymptomatic disease demonstration. Genome-wide association study suggests the most significant gene locus associated with severity were located in TMEM189–UBE2V1 that involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We identified that the HLA-A*11:01, B*51:01, and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial genomic study of Chinese patients provides genetic insights into the phenotypic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host–pathogen interaction for COVID-19 and other infectious and complex diseases.

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Differential Effects of HNF-1α Mutations Associated with Familial Young-Onset Diabetes on Target Gene Regulation

Molecular Medicine ◽

10.2119/molmed.2010.00097 ◽

2010 ◽

Vol 17 (3-4) ◽

pp. 256-265 ◽

Cited By ~ 16

Author(s):

Maria Galán ◽

Carmen-Maria García-Herrero ◽

Sharona Azriel ◽

Manuel Gargallo ◽

Maria Durán ◽

...

Keyword(s):

Gene Regulation ◽

Target Gene ◽

Young Onset ◽

Differential Effects ◽

Onset Diabetes

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Homozygous Hypomorphic HNF1A Alleles Are a Novel Cause of Young-Onset Diabetes and Result in Sulfonylurea-Sensitive Diabetes

Diabetes Care ◽

10.2337/dc19-1843 ◽

2020 ◽

Vol 43 (4) ◽

pp. 909-912 ◽

Cited By ~ 4

Author(s):

Shivani Misra ◽

Neelam Hassanali ◽

Amanda J. Bennett ◽

Agata Juszczak ◽

Richard Caswell ◽

...

Keyword(s):

Young Onset ◽

Onset Diabetes

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Premature Mortality and Comorbidities in Young-onset Diabetes: A 7-Year Prospective Analysis

The American Journal of Medicine ◽

10.1016/j.amjmed.2014.03.018 ◽

2014 ◽

Vol 127 (7) ◽

pp. 616-624 ◽

Cited By ~ 57

Author(s):

Juliana C.N. Chan ◽

Eric S.H. Lau ◽

Andrea O.Y. Luk ◽

Kitty K.T. Cheung ◽

Alice P.S. Kong ◽

...

Keyword(s):

Premature Mortality ◽

Prospective Analysis ◽

Young Onset ◽

Onset Diabetes

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The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes

Diabetologia ◽

10.1007/s00125-011-2418-8 ◽

2012 ◽

Vol 55 (5) ◽

pp. 1265-1272 ◽

Cited By ~ 115

Author(s):

B. M. Shields ◽

T. J. McDonald ◽

S. Ellard ◽

M. J. Campbell ◽

C. Hyde ◽

...

Keyword(s):

Prediction Model ◽

Clinical Prediction ◽

Clinical Prediction Model ◽

Young Onset ◽

Onset Diabetes ◽

Development And Validation

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High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations

Thorax ◽

10.1136/thoraxjnl-2017-209999 ◽

2017 ◽

Vol 73 (2) ◽

pp. 157-166 ◽

Cited By ~ 34

Author(s):

Amelia Shoemark ◽

Eduardo Moya ◽

Robert A Hirst ◽

Mitali P Patel ◽

Evelyn A Robson ◽

...

Keyword(s):

South Asian ◽

Situs Inversus ◽

Diagnostic Tests ◽

Primary Ciliary Dyskinesia ◽

Clinical Phenotype ◽

Phenotypic Variability ◽

Asian Population ◽

Missense Variant ◽

South Asian Population ◽

Ciliary Dyskinesia

RationalePrimary ciliary dyskinesia is a genetically heterogeneous inherited condition characterised by progressive lung disease arising from abnormal cilia function. Approximately half of patients have situs inversus. The estimated prevalence of primary ciliary dyskinesia in the UK South Asian population is 1:2265. Early, accurate diagnosis is key to implementing appropriate management but clinical diagnostic tests can be equivocal.ObjectivesTo determine the importance of genetic screening for primary ciliary dyskinesia in a UK South Asian population with a typical clinical phenotype, where standard testing is inconclusive.MethodsNext-generation sequencing was used to screen 86 South Asian patients who had a clinical history consistent with primary ciliary dyskinesia. The effect of a CCDC103 p.His154Pro missense variant compared with other dynein arm-associated gene mutations on diagnostic/phenotypic variability was tested. CCDC103 p.His154Pro variant pathogenicity was assessed by oligomerisation assay.ResultsSixteen of 86 (19%) patients carried a homozygous CCDC103 p.His154Pro mutation which was found to disrupt protein oligomerisation. Variable diagnostic test results were obtained including normal nasal nitric oxide levels, normal ciliary beat pattern and frequency and a spectrum of partial and normal dynein arm retention. Fifteen (94%) patients or their sibling(s) had situs inversus suggesting CCDC103 p.His154Pro patients without situs inversus are missed.ConclusionsThe CCDC103 p.His154Pro mutation is more prevalent than previously thought in the South Asian community and causes primary ciliary dyskinesia that can be difficult to diagnose using pathology-based clinical tests. Genetic testing is critical when there is a strong clinical phenotype with inconclusive standard diagnostic tests.

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