Andrew T. Hattersley

Wolcott-Rallison Syndrome Is the Most Common Genetic Cause of Permanent Neonatal Diabetes in Consanguineous Families

CONTEXT AND OBJECTIVE Mutations in EIF2AK3 cause Wolcott-Rallison syndrome (WRS), a rare recessive disorder characterized by early-onset diabetes, skeletal abnormalities, and liver dysfunction. Although early diagnosis is important for clinical management, genetic testing is generally performed after the full clinical picture develops. We aimed to identify patients with WRS before any other abnormalities apart from diabetes are present and study the overall frequency of WRS among patients with permanent neonatal diabetes. RESEARCH DESIGN AND METHODS The coding regions of EIF2AK3 were sequenced in 34 probands with infancy-onset diabetes with a clinical phenotype suggestive of WRS (n = 28) or homozygosity at the WRS locus (n = 6). RESULTS Twenty-five probands (73.5%) were homozygous or compound heterozygous for mutations in EIF2AK3. Twenty of the 26 mutations identified were novel. Whereas a diagnosis of WRS was suspected before genetic testing in 22 probands, three patients with apparently isolated diabetes were diagnosed after identifying a large homozygous region encompassing EIF2AK3. In contrast to nonconsanguineous pedigrees, mutations in EIF2AK3 are the most common known genetic cause of diabetes among patients born to consanguineous parents (24 vs. < 2%). Age at diabetes onset and birth weight might be used to prioritize genetic testing in the latter group. CONCLUSIONS WRS is the most common cause of permanent neonatal diabetes mellitus in consanguineous pedigrees. In addition to testing patients with a definite clinical diagnosis, EIF2AK3 should be tested in patients with isolated neonatal diabetes diagnosed after 3 wk of age from known consanguineous families, isolated populations, or countries in which inbreeding is frequent.

Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight

IMPORTANCE Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. OBJECTIVE To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. DESIGN, SETTING, AND PARTICIPANTS Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. EXPOSURES Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. MAIN OUTCOME AND MEASURE Offspring birth weight from 18 studies. RESULTS Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. CONCLUSIONS AND RELEVANCE In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

Cigarette Smoking during Pregnancy Is Associated with Alterations in Maternal and Fetal Thyroid Function

CONTEXT Studies in the general population have shown lower serum TSH levels in smokers as compared with nonsmokers. AIM Our aim was to examine whether smoking is associated with changes in thyroid function of pregnant women and their fetus. SUBJECTS AND METHODS We examined the relationship between smoking and thyroid function (serum TSH, free T4, and free T3) in two independent cohorts of pregnant women without a history of thyroid disorder or an overt biochemical thyroid dysfunction: 1) first-trimester cohort (median gestation 9 wk) (n = 1428) and 2) third-trimester cohort (gestation 28 wk) (n = 927). We also analyzed the relationship between maternal smoking and thyroid hormone levels in cord serum of 618 full-term babies born to the women in the third-trimester cohort. RESULTS In smokers compared with nonsmokers, median serum TSH was lower (first-trimester cohort: 1.02 vs. 1.17 mIU/liter, P = 0.001; third-trimester cohort: 1.72 vs. 1.90 mIU/liter, P = 0.037), and median serum FT3 was higher (first-trimester cohort: 5.1 vs. 4.9 pmol/liter, P < 0.0001; third-trimester cohort: 4.4 vs. 4.1 pmol/liter, P < 0.0001). In both cohorts, serum FT4 in smokers and nonsmokers were similar. The prevalence of anti-thyroperoxidase antibodies was also similar in smokers and nonsmokers in both cohorts. Cord serum TSH of babies born to smokers was lower than of those born to nonsmokers (6.7 vs. 8.1 mIU/liter, P = 0.009). CONCLUSIONS Cigarette smoking is associated with changes in maternal thyroid function throughout the pregnancy and in fetal thyroid function as measured in cord blood samples.

Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type 1.

MEN1 is an autosomal dominant disorder characterized by parathyroid, pituitary, and pancreatic tumors. The MEN1 gene is located on chromosome 11q13 and encodes a 610-amino acid protein. MEN1 mutations are of diverse types and are scattered throughout the coding region, such that almost every MEN1 family will have its individual mutation. To further characterize such mutations we ascertained 34 unrelated MEN1 probands and undertook DNA sequence analysis. This identified 17 different mutations in 24 probands (2 nonsense, 2 missense, 2 in-frame deletions, 5 frameshift deletions, 1 frameshift deletional-insertion, 3 frameshift insertions, 1 donor splice site mutation, and a g-->a transition that resulted in a novel acceptor splice site in intron 4). The intron 4 mutation was found in 7 unrelated families, and the tumors in these families varied considerably, indicating a lack of genotype-phenotype correlation. However, this intron 4 mutation is the most frequently occurring germline MEN1 mutation ( approximately 10% of all mutations), and together with 5 others at codons 83-84, 118-119, 209-211, 418, and 516, accounts for 36.6% of all mutations, a finding that indicates an approach for identifying the widely diverse MEN1 mutations.

Antenatal Diagnosis of Fetal Genotype Determines if Maternal Hyperglycemia Due to a Glucokinase Mutation Requires Treatment

OBJECTIVE In women with hyperglycemia due to heterozygous glucokinase (GCK) mutations, the fetal genotype determines its growth. If the fetus inherits the mutation, birth weight is normal when maternal hyperglycemia is not treated, whereas intensive treatment may adversely reduce fetal growth. However, fetal genotype is not usually known antenatally, making treatment decisions difficult. HISTORY AND EXAMINATION We report two women with gestational diabetes mellitus resulting from GCK mutations with hyperglycemia sufficient to merit treatment. INVESTIGATION In both women, DNA from chorionic villus sampling, performed after high-risk aneuploidy screening, showed the fetus had inherited the GCK mutation. Therefore, maternal hyperglycemia was not treated. Both offspring had a normal birth weight and no peripartum complications. CONCLUSIONS In pregnancies where the mother has hyperglycemia due to a GCK mutation, knowing the fetal GCK genotype guides the management of maternal hyperglycemia. Fetal genotyping should be performed when fetal DNA is available from invasive prenatal diagnostic testing.

Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene

Heterozygous activating mutations of KCNJ11 (Kir6.2) are the most common cause of permanent neonatal diabetes mellitus (PNDM) and several cases have been successfully treated with oral sulfonylureas. We report on the attempted transfer of insulin therapy to glibenclamide in a 4-year old child with PNDM and DEND syndrome, bearing a C166Y mutation in KCNJ11. An inpatient transition from subcutaneous NPH insulin (0.2 units/kg/d) to oral glibenclamide (1 mg/kg/d and 1.5 mg/kg/d) was performed. Glucose and C-peptide responses stimulated by oral glucose tolerance test (OGTT), hemoglobin A1c levels, the 8-point self-measured blood glucose (SMBG) profile and the frequency of hypoglycemia episodes were analyzed, before and during treatment with glibenclamide. Neither diabetes control nor neurological improvements were observed. We concluded that C166Y mutation was associated with a form of PNDM insensitive to glibenclamide.

Neonatal hyperinsulinaemic hypoglycaemia and monogenic diabetes due to a heterozygous mutation of the HNF4A gene

Recent research has demonstrated that mutations of the hepatocyte nuclear factor 4‐alpha (HNF4A) gene are associated with neonatal hyperinsulinaemic hypoglycaemia. Mutations of this gene also cause one of the subtypes of monogenic diabetes, a form of diabetes formerly known as maturity‐onset diabetes of the young. This article describes a family discovered to have a novel frame‐shift mutation of the HNF4A gene in the setting of early‐onset maternal diabetes and severe neonatal hyperinsulinaemic hypoglycaemia. The implications of a diagnosis of HNF4A gene mutation for obstetric and paediatric practice are discussed.

Genetic Disorders of the Pancreatic Beta Cell and Diabetes (Permanent Neonatal Diabetes and Maturity-Onset Diabetes of the Young)

Mutations in critical beta-cell genes can result in monogenic diabetes. This clinically heterogeneous group of disorders usually presents soon after birth as neonatal diabetes, or during childhood or early adulthood as maturity-onset diabetes of the young (MODY). Most defects arise in genes involved in pancreatic beta-cell development or the maintenance of beta-cell function. Studying the phenotype of patients with mutations and the mechanisms by which these mutations result in diabetes gives new insights into normal and pathological functioning of the beta cell. The most common genetic etiology in patients with MODY are mutations in the genes that encode the transcription factors hepatocyte nuclear factor (HNF)-1 alpha (TCF1), HNF-4 alpha (HNF4A) and HNF-1 beta (TCF2), and the glycolytic enzyme glycokinase (GCK). Mutations in each of these genes result in different clinical phenotypes and cause beta-cell dysfunction through different mechanisms. The commonest causes of neonatal diabetes are defects in betacell function, arising from mutations in genes encoding the subunits which form the KATP channel, Kir6.2 (KCNJ11) and SUR1 (ABCC8).

Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Abstract Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother–child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10−8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

Maternal and fetal genetic contribution to gestational weight gain

Background:Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.Participants and methods:A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight).Results:Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10−8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG.Conclusions:We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.