Mutations in glucokinase and other genes detected in neonatal and type 1B diabetes patient using whole exome sequencing may lead to disease-causing changes in protein activity

Lin, Dao Chen; Huang, Chi‐Yu; Ting, Wei-Hsin; Lo, Fu‐Sung; Lin, Chiung‐Ling; Yang, Horng‐Woei; Chang, Tzu-Yang; Lin, Chao‐Hsu; Tzeng, Yao-Wei; Yang, Wan-Syuan; Juang, Yue‐Li; Lee, Yann-Jinn

doi:10.1016/j.bbadis.2018.11.013

Cited by 7 publications

(5 citation statements)

References 30 publications

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“…Neonates present with severe IUGR, are usually diagnosed with diabetes during the first few days of life, and require exogenous insulin therapy. Apart from diabetes, they do not show any relevant extrapancreatic features 106–113 …”

Section: Specific Subtypes Of Monogenic Diabetes and Their Managementmentioning

confidence: 99%

“…Apart from diabetes, they do not show any relevant extrapancreatic features. [106][107][108][109][110][111][112][113] GCK is responsible for not more than 2%-3% of cases of PNDM overall, 47 but has an increased prevalence in regions with a high degree of consanguinity. 114 This type of PNDM is inherited in a recessive manner so the recurrence risk for future siblings is 25%.…”

Section: Neonatal Diabetes Due To Gck Mutationsmentioning

confidence: 99%

“…Apart from diabetes, they do not show any relevant extrapancreatic features. 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 …”

Section: Specific Subtypes Of Monogenic Diabetes and Their Managementmentioning

confidence: 99%

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ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents

et al. 2022

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Section: Specific Subtypes Of Monogenic Diabetes and Their Managementmentioning

confidence: 99%

Section: Neonatal Diabetes Due To Gck Mutationsmentioning

confidence: 99%

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ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents

et al. 2022

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“…Consequently, both H50D and R191Q were given PM5 instead of PS3, nevertheless, either variant ensured adequate points to be classified as pathogenic. Other variants with a functional study were Arg36Trp (Osbak et al, 2009), Gly44Ser (Wang et al, 2019), Gly72Arg (Raimondo et al, 2014), Gly223Ser (Valentinova et al, 2012), Glu265Lys (Osbak et al, 2009), Met393Thr (Raimondo et al, 2014), Thr431Lys (Lin et al, 2019), and Gly448Ser (Li et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Expanding the mutational spectrum ofGCKin Turkish pediatric population

Topcu,

Buyukyilmaz,

Adiguzel

et al. 2024

Preprint

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Glucokinase (GCK) is a central enzyme that keeps integrity of glucose metabolism. Heterozygous loss-of-function variants in GCK cause persistent, mildly elevated plasma glucose beginning at birth. Recently, clinical phenotype created by deleterious variants in GCK is called GCK-MODY, although currently registered as MODY, type 2 (maturity-onset diabetes of the young type 2, MODY2, MIM # 125851) in OMIM. Severity of clinical phenotype is consistent among patients due to the compensation from the unaffected allele. The hyperglycemia of GCK-MODY is a benign and non-progressive condition, usually suspected upon detection of hyperglycemia in adulthood. Medication is not essential, nevertheless, pregnant females may require special attention. Here, we report recurrent and novel GCK variants detected in 43 pediatric patients who were investigated for hyperglycemia by the referring pediatric endocrinologist. Electronic medical records (EMR) of the patients were collected and reviewed retrospectively. All patients applied to Ankara City Hospital between April 2019 and June 2022. GCK variants were screened on NovaSeq 6000 next-generation sequencing platform (Illumina). Variants detected in GCK were checked with recent literature for a proper pathogenicity classification. In 43 patients, 28 distinct GCK variants were identified. Of these variants, 25 were classified as likely pathogenic/pathogenic variants (c.1342G>A, c.112C>T, c.1178T>C, c.130G>A, c.565A>G, c.208+3A>T, c.349G>C, c.863+5G>A, c.214G>A, c.1292C>A, c.830_831delTG, c.106C>T, c.572G>A, c.107G>C, c.454T>C, c.793G>A, c.645C>A, c.377T>A, c.667G>A, c.46-1G>A, c.149A>C, c.1079C>G, c.401T>C, c.758T>G, c.467_483+6del; NM_000162.5), while remaining 3 variants (c.950A>C, c.186G>T, c.188G>A; NM_000162.5) were classified as variant of uncertain significance. According to the variant effect, missense variants accounted for the majority (71%; 20/28), followed by splice junction (14%; 4/28), premature termination (7%; 2/28), frameshift (4%; 1/28), and synonymous (4%; 1/28) alterations. There were 3 novel variants: c.830_831del, c.377T>A, c.467_483+6del.

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“…They are usually detected later in childhood or during young adult life. However, several homozygous inactivating mutations are described in PNDM [86,87]. Recessive mutations, when in homozygous or compound homozygous states, cause complete lack of insulin secretion and PNDM, especially in consanguineous families.…”

Section: Introductionmentioning

confidence: 99%

Genetic spectrum of neonatal diabetes

Kočova

2020

Balkan Journal of Medical Genetics

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Neonatal diabetes (ND) appears during the first months of life and is caused by a single gene mutation. It is heterogenous and very different compared to other forms of multi-factorial or polygenic diabetes. Clinically, this form is extremely severe, however, early genetic diagnosis is pivotal for successful therapy. A large palette of genes is demonstrated to be a cause of ND, however, the mechanisms of permanent hyperglycemia are different. This review will give an overview of more frequent genetic mutations causing ND, including the function of the mutated genes and the specific therapy for certain sub-forms.

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Mutations in glucokinase and other genes detected in neonatal and type 1B diabetes patient using whole exome sequencing may lead to disease-causing changes in protein activity

Cited by 7 publications

References 30 publications

ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents

ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents

Expanding the mutational spectrum ofGCKin Turkish pediatric population

Genetic spectrum of neonatal diabetes

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