Late preterm birth, post-term birth, and abnormal fetal growth as risk factors for severe mental disorders from early to late adulthood.

BACKGROUND: Late preterm births constitute the majority of preterm births. However, most evidence suggesting that preterm birth predicts the risk of mental disorders comes from studies on earlier preterm births. We examined if late preterm birth predicts the risks of severe mental disorders from early to late adulthood. We also studied whether adulthood mental disorders are associated with post-term birth or with being born small (SGA) or large (LGA) for gestational age, which have been previously associated with psychopathology risk in younger ages. METHOD: Of 12 597 Helsinki Birth Cohort Study participants, born 1934-1944, 664 were born late preterm, 1221 post-term, 287 SGA, and 301 LGA. The diagnoses of mental disorders were identified from national hospital discharge and cause of death registers from 1969 to 2010. In total, 1660 (13.2%) participants had severe mental disorders. RESULTS: Individuals born late preterm did not differ from term-born individuals in their risk of any severe mental disorder. However, men born late preterm had a significantly increased risk of suicide. Post-term birth predicted significantly increased risks of any mental disorder in general and particularly of substance use and anxiety disorders. Individuals born SGA had significantly increased risks of any mental and substance use disorders. Women born LGA had an increased risk of psychotic disorders. CONCLUSIONS: Although men born late preterm had an increased suicide risk, late preterm birth did not exert widespread effects on adult psychopathology. In contrast, the risks of severe mental disorders across adulthood were increased among individuals born SGA and individuals born post-term.

Maternal hypertensive disorders during pregnancy: adaptive functioning and psychiatric and psychological problems of the older offspring.

OBJECTIVE: To study whether pre-eclampsia and hypertension without proteinuria during pregnancy are associated with adaptive functioning, and psychiatric and psychological problems, of older offspring. DESIGN: Retrospective longitudinal cohort study. SETTING: Participants in the Helsinki Birth Cohort 1934-44 Study. POPULATION: A cohort of 778 participants born after normotensive, pre-eclamptic, or hypertensive pregnancies, defined based on the mother's blood pressure and urinary protein measurements at maternity clinics and birth hospitals. METHODS: Pearson's chi-squared tests and multivariable logistic regression. MAIN OUTCOME MEASURES: Achenbach System of Empirically Based Assessment Older Adult Self-Report scores, completed at age 69.3 years (SD 3.1 years). RESULTS: Compared with offspring born after normotensive pregnancies, offspring born after pre-eclamptic pregnancies had increased odds of reporting total problems (aOR 4.00, 95%CI 1.64-9.77) and problems of particular concern to clinicians (critical items; aOR 5.28, 95%CI 1.87-14.96), as well as: anxious/depressed, functional impairment, memory, thought, and irritable/disinhibited problems on syndrome scales; depressive, somatic, and psychotic problems on Diagnostic and Statistical Manual of Mental Disorders scales; and adjustment problems in relationship satisfaction with spouse/partner. Maternal hypertension without proteinuria was not consistently associated with adjustment and problems (total problems, aOR 1.08, 95%CI 0.75-1.57; critical items, aOR 1.58, 95%CI 0.91-2.72). CONCLUSIONS: Maternal hypertensive disorders in pregnancy, during a period of expectant treatment, carry an increased risk of problems in adaptive functioning and mental wellbeing in the offspring seven decades later. Being the longest follow-up on transgenerational consequences of maternal hypertensive disorders reported thus far, our study points to the life-time increased risk of an adverse intrauterine environment.

Intergenerational effects of in utero exposure to Ramadan in Tunisia.

UNLABELLED: We have reported that changes in the lifestyle of pregnant women during Ramadan affect more than one generation. In a series of newborn babies in Saudi Arabia, those whose mothers had been in utero during Ramadan differed from those whose mothers had not been in utero during Ramadan. These were unexpected findings and require replication. METHODS: We examined body size at birth in 1,321 babies (682 boys and 639 girls) born in Gafsa, a small city in Tunisia. RESULTS: Babies whose mothers had been in utero during Ramadan were smaller and thinner, and had smaller placentas, than those whose mothers had not been in utero during Ramadan. After adjustment for sex, the babies were 93 g lighter (95% confidence interval, 32-153, P=0.003) than those whose mother had not been in utero during Ramadan, their mean ponderal index was 0.52 kg/m(3) lower (0.24-0.79, P<0.001) and their placental weight was 21 g lower (5-37, P=0.01). The findings did not differ by trimester of maternal exposure to Ramadan. They were similar in boys and girls and in primiparous and multiparous mothers CONCLUSION: This study provides further evidence that changes in lifestyle during Ramadan have intergenerational effects.

Enhanced beta cell proliferation in mice overexpressing a constitutively active form of Akt and one allele of p21Cip.

AIMS/HYPOTHESIS: The ability of pancreatic beta cells to proliferate is critical both for normal tissue maintenance and in conditions where there is an increased demand for insulin. Protein kinase B(Akt) plays a major role in promoting proliferation in many cell types, including the insulin-producing beta cells. We have previously reported that mice overexpressing a constitutively active form of Akt(caAkt (Tg)) show enhanced beta cell proliferation that is associated with increased protein levels of cyclin D1, cyclin D2 and cyclin-dependent kinase inhibitor 1A (p21(Cip)). In the present study, we sought to assess the mechanisms responsible for augmented p21(Cip) levels in caAkt(Tg) mice and test the role of p21(Cip) in the proliferative responses induced by activation of Akt signalling. METHODS: To gain a greater understanding of the relationship between Akt and p21(Cip), we evaluated the mechanisms involved in the modulation of p2(Cip) by Akt and the in vivo role of reduced p21(Cip) in proliferative responses induced by Akt. RESULTS: Our experiments showed that Akt signalling regulates p21(Cip) transcription and protein stability. caAkt(Tg) /p21(Cip+/-) mice exhibited fasting and fed hypoglycaemia as well as hyperinsulinaemia when compared with caAkt(Tg) mice. Glucose tolerance tests revealed improved glucose tolerance in caAkt(Tg)/p21(Cip+/-) mice compared with caAkt (Tg). These changes resulted from increased proliferation, survival and beta cell mass in caAkt(Tg)/p21(Cip+/-) compared with caAkt(Tg) mice. CONCLUSIONS/INTERPRETATION: Our data indicate that increased p21(Cip) levels in caAkt(Tg) mice act as a compensatory brake, protecting beta cells from unrestrained proliferation. These studies imply that p21(Cip) could play important roles in the adaptive responses of beta cells to proliferate in conditions such as in insulin resistance.

Growth from birth to adulthood and peak bone mass and density data from the New Delhi Birth Cohort.

UNLABELLED: Growth in early life may predict adult bone health. Our data showed that greater height and body mass index (BMI) gain in utero and infancy are associated with higher peak bone mass, and greater BMI gain in childhood/adolescence with higher peak bone density. These associations are mediated by attained adult height and BMI. INTRODUCTION: To study the relationship of height and BMI during childhood with adult bone mineral content (BMC), areal density (aBMD) and apparent density (BMAD, estimated volumetric density). METHODS: Participants comprised 565 men and women aged 33-39 years from the New Delhi Birth Cohort, India, whose weight and height were recorded at birth and annually during infancy (0-2 years), childhood (2-11 years) and adolescence (11 years-adult). Lumbar spine, femoral neck and forearm BMC and aBMD were measured using dual X-ray absorptiometry; lumbar spine and femoral neck BMAD were calculated. RESULTS: Birth length, and height and height gain during infancy, childhood and adolescence were positively correlated with adult BMC (p≤0.01 all sites except birth length with femoral neck). Correlations increased with height from birth to 6 years, then remained constant for later height measurements. There were no associations with BMAD. BMI at birth, and during childhood and adolescence was also positively correlated with BMC (p < 0.01 all sites). BMI at 11 years, and BMI gain in childhood and adolescence, were correlated with aBMD and BMAD (p < 0.001 for all); these correlations strengthened with increasing age of BMI measurement. The associations with height and BMI in early life became non-significant after adjustment for adult height and BMI. CONCLUSIONS: Greater skeletal growth and BMI gain in utero and during infancy are associated with higher peak BMC, and greater BMI gain in childhood and adolescence is associated with higher peak aBMD and BMAD. These associations are mediated by the attainment of adult height and BMI, respectively.

Inputs and losses by surface runoff and subsurface leaching for pastures managed by continuous or rotational stocking.

Pasture management practices can affect forage quality and production, animal health and production, and surface and groundwater quality. In a 5-yr study conducted at the North Appalachian Experimental Watershed near Coshocton, Ohio, we compared the effects of two contrasting grazing methods on surface and subsurface water quantity and quality. Four pastures, each including a small, instrumented watershed (0.51-1.09 ha) for surface runoff measurements and a developed spring for subsurface flow collection, received 112 kg N ha(-1) yr(-1) and were grazed at similar stocking rates (1.8-1.9 cows ha(-1)). Two pastures were continuously stocked; two were subdivided so that they were grazed with frequent rotational stocking (5-6 times weekly). In the preceding 5 yr, these pastures received 112 kg N ha(-1) yr(-1) after several years of 0 N fertilizer and were grazed with weekly rotational stocking. Surface runoff losses of N were minimal. During these two periods, some years had precipitation up to 50% greater than the long-term average, which increased subsurface flow and NO(3)-N transport. Average annual NO(3)-N transported in subsurface flow from the four watersheds during the two 5-yr periods ranged from 11.3 to 22.7 kg N ha(-1), which was similar to or less than the mineral-N received in precipitation. Flow and transport variations were greater among seasons than among watersheds. Flow-weighted seasonal NO(3)-N concentrations in subsurface flow did not exceed 7 mg L(-1). Variations in NO(3)-N leached from pastures were primarily due to variable precipitation rather than the effects of continuous, weekly rotational, or frequent rotational stocking practices. This suggests that there was no difference among these grazing practices in terms of NO(3)-N leaching.

Sir Richard Doll Lecture. Developmental origins of chronic disease.

Coronary heart disease, type 2 diabetes, breast cancer and many other chronic diseases are unnecessary. Their occurrence is not mandated by genes passed down to us through thousands of years of evolution. Chronic diseases are not the inevitable lot of humankind. They are the result of the changing pattern of human development. We could readily prevent them, had we the will to do so. Prevention of chronic disease, and an increase in healthy ageing require improvement in the nutrition of girls and young women. Many babies in the womb in the Western world today are receiving unbalanced and inadequate diets. Many babies in the developing world are malnourished because their mothers are chronically malnourished. Protecting the nutrition and health of girls and young women should be the cornerstone of public health. Not only will this prevent chronic disease, but it will produce new generations who have better health and well-being through their lives.

Growth in childhood predicts hip fracture risk in later life.

UNLABELLED: The incidence of hip fracture was estimated in 6,370 women born in Helsinki between 1934 and 1944. Women in the lowest quarter of adiposity gain had an 8.2-fold increase in hip fracture risk compared with those in the highest quarter (p < 0.001). These data point to a relationship between childhood growth and fracture risk during later life. INTRODUCTION: Previous findings show that discordance between childhood increase in height and weight is associated with an increased risk of osteoporotic fractures during later life. METHODS: We studied 6,370 women born in Helsinki between 1934 and 1944. Each woman's birth weight and length at birth was recorded, as well as her height and weight through childhood. We identified the occurrence of hip fracture through the National Finnish Hospital discharge register. RESULTS: There were 49 hip fractures in the 6,370 women over 187,238 person-years of follow-up. Hip fracture was associated with increasing Z-scores for height between 1 and 12 years, not matched by a corresponding increase in weight. Therefore, reduction in the Z-score for body mass index was associated with increased risk of hip fracture. Women in the lowest quarter of change in Z-scores for body mass index had an 8.2-fold increase in hip fracture risk (95% CI 1.9 to 35), compared with those in the highest quarter (p < 0.001). CONCLUSION: Thinness in childhood is a risk factor for hip fracture in later life. This could be a direct effect of low fat mass on bone mineralization, or represent the influence of altered timing of pubertal maturation.

Sex differences in birth size and intergenerational effects of intrauterine exposure to Ramadan in Saudi Arabia.

OBJECTIVES: In Europe, boys and girls have different body proportions at birth. We examined newborn babies in Saudi Arabia to determine the sex differences and whether fetal growth differed if the mother was in utero during Ramadan. METHODS: We examined body size at birth among 967 babies (479 boys and 488 girls) born in Unizah, a small city in Saudi Arabia. RESULTS: Large head circumference was the strongest single predictor of male sex. In a simultaneous regression, female sex was predicted by small head circumference (P < 0.001), low birth weight (P = 0.002), and large chest circumference (P = 0.008). The mothers of boys were heavier in pregnancy than the mothers of girls and had a higher body mass index, 31.7 kg/m(2) compared to 30.2 (P < 0.001). The mothers of girls, however, were taller than the mothers of boys, 158.6 cm compared to 157.4 (P = 0.001). Compared to babies whose mothers were not in utero during Ramadan boys whose mothers were in mid gestation during Ramadan were 1.2 cm longer (P = 0.005) while girls had a 0.4 week shorter gestation period (P = 0.04). CONCLUSION: Our findings are consistent with other evidence that boys are more ready than girls to trade off visceral development in utero to protect somatic and brain growth. They also support the hypothesis that boys are more responsive to their mother's current diet than girls, who respond more to their mother's life time nutrition and metabolism. They provide the first evidence that changes in the life style of pregnant women during Ramadan affect more than one generation.

Prenatal growth, postnatal growth and trait anxiety in late adulthood - the Helsinki Birth Cohort Study.

OBJECTIVE: Trait anxiety may predispose to anxiety disorders and cardiovascular events. We tested whether prenatal growth or postnatal growth from birth to 11 years of age and in adulthood predict trait anxiety in late adulthood. METHOD: Women (n = 951) and men (n = 753) reported trait anxiety using the Spielberger Trait Anxiety Scale at an average age of 63.4 years and growth was estimated from records. RESULTS: Higher trait anxiety was predicted by smaller body size at birth, in infancy and in adulthood. Moreover, faster growth particularly from seven to 11 years of age and slower growth between 11 and 63 years predicted higher trait anxiety. CONCLUSION: We found a pattern of pre- and postnatal growth that predisposed to higher trait anxiety in late adulthood. This pattern resembles that found to increase the risk of cardiovascular events and, thus, points to a shared common origin in a suboptimal prenatal and childhood developmental milieu.

Depressive symptoms in adulthood and intrauterine exposure to pre-eclampsia: the Helsinki Birth Cohort Study.

OBJECTIVE: We studied whether pre-eclampsia predicts depressive symptoms in offspring. DESIGN: Retrospective longitudinal cohort study. SETTING: Participants in the Helsinki Birth Cohort 1934-44 Study. POPULATION: We classed 788 women and men born at term after a normotensive, hypertensive or pre-eclamptic pregnancy, by using the mother's blood pressure and urinary protein measurements, at maternity clinics and birth hospitals. METHODS: Linear and logistic regression analyses. We made adjustments for the mother's age and body mass index (BMI) at delivery, the participant's body size at birth/length of gestation, sex and childhood socio-economic status, age and educational attainment at testing. MAIN OUTCOME MEASURES: Beck depression inventory (BDI) scores completed twice, at the ages of 60 and 63 years. RESULT: Participants born after a primiparous pregnancy complicated by pre-eclampsia had over 30% (P < 0.04) higher depressive symptom scores in adulthood compared with those born after a primiparous normotensive pregnancy. We found no evidence of the association between pre-eclampsia and depression among participants born after multiparous pregnancies. Gestational hypertension and depressive symptoms were not significantly associated. The models adjusting for mother's age and BMI at delivery, the participant's body size at birth/length of gestation, sex, childhood socio-economic status, age and educational attainment at testing did not change the results. CONCLUSION: Pre-eclampsia is associated with later depressive symptoms in individuals born at term and after a primiparous pregnancy. These findings are compatible with the adverse fetal 'programming' by a suboptimal prenatal environment.

DNA sequence and analysis of human chromosome 9.

Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6-8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.

The DNA sequence and analysis of human chromosome 6.

Chromosome 6 is a metacentric chromosome that constitutes about 6% of the human genome. The finished sequence comprises 166,880,988 base pairs, representing the largest chromosome sequenced so far. The entire sequence has been subjected to high-quality manual annotation, resulting in the evidence-supported identification of 1,557 genes and 633 pseudogenes. Here we report that at least 96% of the protein-coding genes have been identified, as assessed by multi-species comparative sequence analysis, and provide evidence for the presence of further, otherwise unsupported exons/genes. Among these are genes directly implicated in cancer, schizophrenia, autoimmunity and many other diseases. Chromosome 6 harbours the largest transfer RNA gene cluster in the genome; we show that this cluster co-localizes with a region of high transcriptional activity. Within the essential immune loci of the major histocompatibility complex, we find HLA-B to be the most polymorphic gene on chromosome 6 and in the human genome.

Interaction between prenatal growth and high-risk genotypes in the development of type 2 diabetes.

AIMS/HYPOTHESIS: Early environmental factors and genetic variants have been reported to be involved in the pathogenesis of type 2 diabetes. The aim of this study was to investigate whether there is an interaction between birthweight and common variants in the TCF7L2, HHEX, PPARG, KCNJ11, SLC30A8, IGF2BP2, CDKAL1, CDKN2A/2B and JAZF1 genes in the risk of developing type 2 diabetes. METHODS: A total of 2,003 participants from the Helsinki Birth Cohort Study, 311 of whom were diagnosed with type 2 diabetes by an OGTT, were genotyped for the specified variants. Indices for insulin sensitivity and secretion were calculated. RESULTS: Low birthweight was associated with type 2 diabetes (p = 0.008) and impaired insulin secretion (p = 0.04). Of the tested variants, the risk variant in HHEX showed a trend towards a low birthweight (p = 0.09) and the risk variant in the CDKN2A/2B locus was associated with high birthweight (p = 0.01). The TCF7L2 risk allele was associated with increased risk of type 2 diabetes. Pooling across all nine genes, each risk allele increased the risk of type 2 diabetes by 14%. [corrected] Risk variants in the HHEX, CDKN2A/2B and JAZF1 genes interacted with birthweight, so that the risk of type 2 diabetes was highest in those with lower birthweight (p

Childhood growth and future risk of the metabolic syndrome in normal-weight men and women.

AIM: The aim of this study was to examine the effects of early growth on the risk of developing the metabolic syndrome in normal-weight individuals. METHODS: We examined 2003 subjects born in Helsinki, Finland, between 1934 and 1944, focusing on 588 individuals who were normal weight (body mass index [BMI] less than or equal to 25 kg/m(2)). These subjects had a median of seven measurements of height and weight from birth to 2 years, and eight measurements from 2 to 11 years of age. The metabolic syndrome was defined according to the 2005 criteria of the International Diabetes Federation. RESULTS: Individuals with the metabolic syndrome were heavier, had higher mean BMI and higher body fat percentages than those without the syndrome. No differences were seen in body size at birth and at 2 years but, by the age of 7 years, those men who later developed the metabolic syndrome were thinner (P=0.01). Changes in BMI during infancy were predictive of the syndrome, with an OR of 0.57 (95% CI: 0.36-0.90) per one S.D. increase in BMI from birth to 2 years. In women, these associations paralleled those in men, but did not reach statistical significance. CONCLUSION: Among normal-weight men, those who developed the metabolic syndrome in adulthood had smaller gains in BMI during infancy and were thinner at age 7 years. These results support findings that early growth may play an important role in the development of the metabolic syndrome.

Role of childhood growth on the risk of metabolic syndrome in obese men and women.

AIM: Although obesity is the key characteristic of the metabolic syndrome, not all obese individuals develop the syndrome. Our aim was to identify characteristics of early growth that protect these individuals from the metabolic syndrome. METHODS: We examined 2003 subjects born in Helsinki, Finland, between 1934 and 1944. We focused on the 499 who were obese (BMI> or =30 kg/m(2)), 400 of whom had the metabolic syndrome according to IDF 2005 criteria. The subjects had a median of seven measurements of height and weight from birth to two years of age, and eight measurements from two to 11 years of age. RESULTS: Among obese individuals, those with the metabolic syndrome had a higher mean body mass index (BMI) and larger waist circumference than those who did not. The two groups were similar in body size at birth but, by two years of age, those who later developed the metabolic syndrome were lighter and thinner, and remained so up to age 11 years. The period when BMI changes were predictive of the syndrome was from birth to seven years. OR was 0.72 (95% CI: 0.57-0.92) per 1 S.D. increase in BMI from birth to two years and 0.63 (95% CI: 0.49-0.81) per 1 S.D. increase in BMI from two to seven years. CONCLUSION: Among obese individuals, those who develop the metabolic syndrome were lighter and thinner from the age of two to 11 years compared with those who did not. These findings support the importance of early childhood growth in determining the metabolic consequences of obesity.

Childhood growth and cardiovascular reactivity to psychological stressors in late adulthood.

OBJECTIVE: Specific childhood growth patterns relate to risk of cardiovascular (CV) disease later in life, but the underlying mechanisms are unclear. We studied whether CV reactivity, a predictor of CV disease risk, is associated with childhood growth trajectories. METHODS: A total of 144 (77 women and 67 men) participants of the Helsinki Birth Cohort Study born 1934-1944, whose height and weight were recorded repeatedly during the first 11 years, underwent the Trier Social Stress Test at the average age of 63 years. Beat-to-beat blood pressure was monitored via noninvasive finger photoplethysmograph (Finometer), and CV reactivity scores were determined as the mean increment from baseline. RESULTS: In both women and men, systolic blood pressure (SBP) reactivity increased by 3.8 mmHg (95% CI 0.8-6.9) and diastolic BP (DBP) reactivity by 1.4 mmHg (95% CI 0.0-2.8) for every standard deviation increase in gain in body mass index (kg m(-2)) between 7 and 11 years. By contrast, effects of height gain were dissimilar between sexes. In women, higher DBP reactivity was associated with a slow gain in height between 0 and 2 years, whilst in men higher SBP reactivity was associated with a slow gain in height between 2 and 7 years, which was preceded by a more rapid gain in height between 0 and 2 years. Adjusting for adult body size, body size at birth or childhood socio-economic status did not change the results. CONCLUSIONS: We found that growth during childhood is associated with CV reactivity to stress later in adulthood. Early life programming of CV reactivity may partly underlie the link between early growth and CV disease.

Identification of the novel allele, HLA-B*14:56, in a Brazilian individual.

Novel allele, HLA-B*14:56, generated by a gene conversion event was identified in a Brazilian individual.

Single molecule real-time DNA sequencing of HLA genes at ultra-high resolution from 126 International HLA and Immunogenetics Workshop cell lines.

The hyperpolymorphic HLA genes play important roles in disease and transplantation and act as genetic markers of migration and evolution. A panel of 107 B-lymphoblastoid cell lines (B-LCLs) was established in 1987 at the 10th International Histocompatibility Workshop as a resource for the immunogenetics community. These B-LCLs are well characterised and represent diverse ethnicities and HLA haplotypes. Here we have applied Pacific Biosciences' Single Molecule Real-Time (SMRT) DNA sequencing to HLA type 126 B-LCL, including the 107 International HLA and Immunogenetics Workshop (IHIW) cells, to ultra-high resolution. Amplicon sequencing of full-length HLA class I genes (HLA-A, -B and -C) and partial length HLA class II genes (HLA-DRB1, -DQB1 and -DPB1) was performed. We typed a total of 931 HLA alleles, 895 (96%) of which were consistent with the typing in the IPD-IMGT/HLA Database (Release 3.27.0, January 20, 2017), with 595 (64%) typed at a higher resolution. Discrepant types, including novel alleles (n = 10) and changes in zygosity (n = 13), as well as previously unreported types (n = 34) were observed. In addition, patterns of linkage disequilibrium were distinguished by four-field resolution typing of HLA-B and HLA-C. By improving and standardising the HLA typing of these B-LCLs, we have ensured their continued usefulness as a resource for the immunogenetics community in the age of next generation DNA sequencing.

A novel allele, HLA-B*51:220, identified in an individual from south of Brazil.

Novel allele, HLA-B*51:220 generated by a gene conversion event was identified in a Brazilian individual.