Homozygous Children Research Articles

Transcranial Doppler in 150 Congolese children with sickle cell disease

IntroductionSickle Cell Disease (SCD) ranks among the most prevalent genetic disorders globally. The incidence in sub-Saharan African countries has been estimated to be 230.000/y with a high prevalence (1%) in the Democratic Republic of Congo (DRC). Stroke is a significant complication of Sickle Cell Disease (SCD), and carries a high risk of disability and mortality. Transcranial Doppler (TCD) is currently the non-invasive exploration recommended for the prevention of stroke in young SCD patients.ObjectiveTo determine the prevalence of pathological TCD in a population of young Congolese SCA patients and to assess its association with hematological parameters.Population and methodsThis cross sectional study was carried out on 150 Congolese SS homozygous children between the ages 2–16 years old (mean age: 8.5 ± 4.0 years) in stable condition, and followed from January 1 to December 31, 2013. TCD was performed using the STOP I method in the main cerebral arteries. The risk of stroke was absent when the average maximum speed during a cycle (TAMMV) in middle cerebral artery (MCA) was < 170 cm/s, but present when TAMMV was borderline or conditional for values between 170 and 199 cm/s and pathological for values ≥ 200 cm/s.ResultsThe prevalence of pathological TCD was 4% while the conditional TCD prevalence was 10%. The Mean blood velocity in MCA was 114.0 cm/s. There was a significant difference in the means of WBC (p = 0.003), Hb (p < 0.001), Hct (p < 0.001), MCV (p = 0.005) parameters when comparing normal and at risk TCD (conditional and abnormal). However, no significant association was found for the categorical corresponding parametersConclusionGlobally, 14% of patients were at risk of stroke, hence the interest in integrating TCD in the routine monitoring of children with SCD in order to prevent overt stroke by implementing a chronic blood transfusion program or the use of hydroxycarbamide.

Elexacaftor/tezacaftor/ivacaftor improves chronic rhinosinusitis detected by magnetic resonance imaging in children with cystic fibrosis on long-term therapy with lumacaftor/ivacaftor

Introduction: Previous studies using magnetic resonance imaging (MRI) demonstrated early onset and progression of chronic rhinosinusitis (CRS) from infancy to school age, and response to lumacaftor/ivacaftor (LUM/IVA) therapy in children with cystic fibrosis (CF). However, the effect of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on CRS detected by MRI in children with CF and at least one F508del mutation, and potential incremental effects of ELX/TEZ/IVA compared to LUM/IVA in F508del homozygous children have not been studied.Methods: 30 children with CF with at least one F508del mutation underwent three longitudinal paranasal sinus MRI before (MRI1), without (n = 16) or with LUM/IVA therapy (n = 14, MRI2), and with ELX/TEZ/IVA therapy (MRI3, mean age at therapy initiation 11.1 ± 3.4y, range 6–16y). MRI were evaluated using the CRS-MRI score.Results: After therapy initiation with ELX/TEZ/IVA, the prevalence and in maxillary and sphenoid sinuses the dominance of mucopyoceles decreased (35% vs. 0 %, p<0.001 and 26% vs. 8 %, p < 0.05, respectively). This leads to a reduction in mucopyocele subscore (-3.4 ± 1.9, p < 0.001), and sinus subscores in MRI3 (maxillary sinus: -5.3 ± 3.1, p < 0.001, frontal sinus: -1.0 ± 1.9, p < 0.01, sphenoid subscore: -2.8 ± 3.5, p < 0.001, ethmoid sinus: -1.7 ± 1.9, p < 0.001). The CRS-MRI sum score decreased after therapy initiation with ELX/TEZ/IVA by -9.6 ± 5.5 score points (p < 0.001). The strength in reduction of mucopyoceles subscore and CRS-MRI sum score was independent of a pretreatment with LUM/IVA from MRI1-MRI2 (p = 0.275–0.999).Conclusions: ELX/TEZ/IVA therapy leads to improvement of CRS in eligible children with CF. Our data support the role of MRI for comprehensive monitoring of CRS disease severity and response to therapy in children with CF.

Disease Status at Diagnosis in Danish Children with α 1 -antitrypsin Deficiency.

The aim of this cross-sectional study was to assess the state of disease at the time of diagnosis in Danish children with α 1 -antitrypsin deficiency as Denmark has a high prevalence of ZZ-homozygosity. Children either heterozygous, compound heterozygous, or homozygous for Z- and S-variants in the SERPINA1 -gene were included. Clinical characteristics, SERPINA1 -genotype, and blood serum (S) concentrations were recorded concurrently with genetic testing. Serum liver marker concentrations were compared using T tests and Wilcoxon-Mann-Whitney tests. Generalized estimating equation (GEE) linear regression models, both univariable and multivariable adjusted for age and sex, were applied to identify correlations with serum α 1 -antitrypsin (S-AAT). The relationship between S-AAT concentration and genotype was assessed using logistic regression with GEE. The study included 183 of 225 children genetically tested for alpha-1-antitrypsin deficiency (AATD). Of these, 36.6% were homozygous for the Z-variant. Of the heterozygotes, 89.7% had a ZM genotype and the remaining had either an MS genotype or were compound heterozygous. At diagnosis, ZZ-homozygous children had higher serum concentrations of liver enzymes and conjugated bilirubin, but lower concentrations of S-AAT compared with heterozygotes. Serum concentrations of conjugated bilirubin and liver enzymes were negatively associated with S-AAT. Children under 6 months of age had higher total S-bilirubin concentrations than children over 6 months of age. A low S-AAT concentration is a strong indicator of homozygosity, and homozygous children have higher enzymatic and cholestatic parameters compared with heterozygous children at diagnosis. This underlines the importance of measuring the S-AAT concentration in children with prolonged neonatal jaundice.

Low circulating PCSK9 levels in LPL homozygous children with chylomicronemia syndrome in a syrian refugee family in Lebanon.

Familial chylomicronemia syndrome is a rare autosomal recessive disorder of lipoprotein metabolism characterized by the presence of chylomicrons in fasting plasma and an important increase in plasma triglycerides (TG) levels that can exceed 22.58 mmol/l. The disease is associated with recurrent episodes of abdominal pain and pancreatitis, eruptive cutaneous xanthomatosis, lipemia retinalis, and hepatosplenomegaly. A consanguineous Syrian family who migrated to Lebanon was referred to our laboratory after perceiving familial chylomicronemia syndrome in two children. The LPL and PCSK9 genes were sequenced and plasma PCSK9 levels were measured. Sanger sequencing of the LPL gene revealed the presence of the p.(Val227Phe) pathogenic variant in exon 5 at the homozygous state in the two affected children, and at the heterozygous state in the other recruited family members. Interestingly, PCSK9 levels in homozygous carriers of the p.(Val227Phe) were ≈50% lower than those in heterozygous carriers of the variant (p-value = 0.13) and ranged between the 5th and the 7.5th percentile of PCSK9 levels in a sample of Lebanese children of approximately the same age group. Moreover, this is the first reported case of individuals carrying simultaneously an LPL pathogenic variant and PCSK9 variants, the L10 and L11 leucine insertion, which can lower and raise low-density lipoprotein cholesterol (LDL-C) levels respectively. TG levels fluctuated concomitantly between the two children, were especially high following the migration from a country to another, and were reduced under a low-fat diet. This case is crucial to raise public awareness on the risks of consanguineous marriages to decrease the emergence of inherited autosomal recessive diseases. It also highlights the importance of the early diagnosis and management of these diseases to prevent serious complications, such as recurrent pancreatitis in the case of familial hyperchylomicronemia.

WS15.06 Fat-soluble vitamin status in F508del homozygous children with cystic fibrosis following commencement of lumacaftor/ivacaftor

WS15.06 Fat-soluble vitamin status in F508del homozygous children with cystic fibrosis following commencement of lumacaftor/ivacaftor

A family screening of CD19 gene mutation by PCR-RFLP

Introduction and aim. Mutation(s) in the gene encoding the CD19 molecule affect CD19 protein expression and primary immunodeficiency (PID) occurs. The PCR-RFLP method, which is faster and cheaper than other mutation detection methods, is rarely used in the diagnosis of PID. The study aimed to genetically identify CD19 deficiency, which is a PID, using the PCR-RFLP method. Material and methods. A total of 8 patients and two healthy controls were included in the study and the relevant region genotypes in the CD19 gene were determined by performing PCR-RFLP analysis. Results. The index case, newborn baby and mother were also included in the study. It was determined that the index case (P6) was homozygous mutant, the newborn baby (P7) and mother (P8) had heterozygous genotype. Based on this situation, one child (P1) was found to be homozygous mutant, mother (P2), father (P3) and other children (P4 and P5) had heterozygous genotype in the family, which was determined to be related to the first case. Conclusion. In our study, it has been shown that PCR-RFLP is a method that can be used in the diagnosis of PID by determining genotypes using PCR-RFLP, and especially in terms of rapid genetic testing of family screenings.

Novel SCNN1A gene splicing-site mutation causing autosomal recessive pseudohypoaldosteronism type 1 (PHA1) in two Italian patients belonging to the same small town

IntroductionPseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease due to the peripheral resistance to aldosterone. Its clinical spectrum includes neonatal salt loss syndrome with hyponatremia and hypochloraemia, hyperkalemia, metabolic acidosis and increased plasmatic levels of aldosterone. Two genetically distinct forms of disease, renal and systemic, have been described, showing a wide clinical expressivity. Mutations in the genes encoding for the subunits of the epithelial sodium channels (ENaC) are responsible for generalized PHA1.Patients’ presentationWe hereby report on two Italian patients with generalized PHA1, coming from the same small town in the center of Sicily. The first patient is a male child, born from the first pregnancy of healthy consanguineous Sicilian parents. A novel SCNN1A (sodium channel epithelial subunit alpha) gene mutation, inherited from both heterozygous parents, was identified by next generation sequencing (NGS) in the homozygous child (and later, also in the heterozygous maternal aunt). A more detailed family history disclosed a possible related twenty-year-old girl, belonging to the same Sicilian small town, with referred neonatal salt loss syndrome associated to hyperkalemia, and subsequent normal growth and neurodevelopment. This second patient had a PHA1 clinical diagnosis when she was about 1 year old. The genetic investigation was, then, extended to her and to her family, revealing the same mutation in the homozygous girl and in the heterozygous parents.ConclusionsThe neonatologist should consider PHA1 diagnosis in newborns showing hyponatremia, hyperkalemia and metabolic acidosis, after the exclusion of a salting-loss form of adrenogenital syndrome. The increased plasmatic levels of aldosterone and aldosterone/renin ratio, associated to a poor response to steroid administration, confirmed the diagnosis in the first present patient. An accurate family history may be decisive to identify the clinical picture. A multidisciplinary approach and close follow-up evaluations are requested, in view of optimal management, adequate growth and development of patients. Next generation sequencing (NGS) techniques allowed the identification of the SCNN1A gene mutation either in both patients or in other heterozygous family members, enabling also primary prevention of disease. Our report may broaden the knowledge of the genetic and molecular bases of PHA1, improving its clinical characterization and providing useful indications for the treatment of patients. Clinical approach must be personalized, also in relation to long-term survival and potential multiorgan complications.

Il neonato che “sa di sale”

Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease due to the peripheral resistance to aldosterone. Clinical spectrum with neonatal onset includes salt loss, hyponatremia, hypochloraemia, hyperkalaemia, metabolic acidosis and increased plasmatic levels of aldosterone. Two forms of the disease - renal and systemic – have been described, which are genetically distinct and with wide clinical expressivity. The most severe generalized PHA1 is caused by mutations in the genes encoding for the subunits of the epithelial sodium channels (ENaC). The paper reports the case of a newborn of the first pregnancy of healthy and consanguineous Sicilian parents, with a clinical and hormonal picture compatible with the diagnosis of generalized PHA1. A novel SCNN1A gene mutation, inherited from both heterozygous, was identified by next generation sequencing (NGS) in the homozygous child. The neonatologist should consider a diagnosis of PHA1 in case of hyponatremia, hyperkalaemia and metabolic acidosis. The diagnostic suspicion was confirmed by the increased plasmatic levels of aldosterone and aldosterone/renin ratio, associated to a poor response to steroid administration. The treatment is based on high doses of sodium chloride, fludrocortisone and glucocorticoids, insulin and ion exchange resins. It may be useful to reduce potassium intake with the use of special formulas. The clinician must gradually balance the doses of drugs on the basis of electrolyte and hormone levels. A multi-disciplinary team and close follow-up evaluations are needed for optimal management of such patients. The present report may broaden the knowledge of the genetic and molecular bases of disease, by improving its clinical characterization and providing useful indications for the treatment of patients. Clinical approach must be personalized, also in relation to long survival and potential multi-organ complications.

Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX.

Multiple genes are known to be associated with osteogenesis imperfecta (OI), a phenotypically and genetically heterogenous bone disorder, marked predominantly by low bone mineral density and increased risk of fractures. Recently, mutations affecting MESD, which encodes for a chaperone required for trafficking of the low-density lipoprotein receptors LRP5 and LRP6 in the endoplasmic reticulum, were described to cause autosomal-recessive OI XX in homozygous children. In the present study, whole-exome sequencing of three stillbirths in one family was performed to evaluate the presence of a hereditary disorder. To further characterize the skeletal phenotype, fetal autopsy, bone histology, and quantitative backscattered electron imaging (qBEI) were performed, and the results were compared with those from an age-matched control with regular skeletal phenotype. In each of the affected individuals, compound heterozygous mutations in MESD exon 2 and exon 3 were detected. Based on the skeletal phenotype, which was characterized by multiple intrauterine fractures and severe skeletal deformity, OI XX was diagnosed in these individuals. Histological evaluation of MESD specimens revealed an impaired osseous development with an altered osteocyte morphology and reduced canalicular connectivity. Moreover, analysis of bone mineral density distribution by qBEI indicated an impaired and more heterogeneous matrix mineralization in individuals with MESD mutations than in controls. In contrast to the previously reported phenotypes of individuals with OI XX, the more severe phenotype in the present study is likely explained by a mutation in exon 2, located within the chaperone domain of MESD, that leads to a complete loss of function, which indicates the relevance of MESD in early skeletal development. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..

Glomerular Filtration Rate in Homozygous Sickle Cell Disease children in Steady State and Healthy Nigerian Children: A Comparative Study in north-eastern Nigeria

Glomerular Filtration Rate in Homozygous Sickle Cell Disease children in Steady State and Healthy Nigerian Children: A Comparative Study in north-eastern Nigeria

The influence of maternal and child FADS genotype on cord blood polyunsaturated fatty acid (PUFA) concentrations

AbstractOptimal maternal polyunsaturated fatty acid (PUFA) status is essential for foetal development. The desaturase enzymes, encoded by the fatty acid desaturase (FADS) genes, are involved in the endogenous synthesis of long chain (LC)PUFA and influence maternal LCPUFA concentrations. The minor allele of various FADS SNPs has been associated with increased maternal concentrations of the precursors linoleic acid (LA) and α-linolenic acid (ALA), and lower concentrations of the LCPUFA arachidonic acid (AA) and docosahexaenoic acid (DHA); however, there is limited research to date on the influence of FADS genotype on cord PUFA status. The aim of the current study was to investigate the influence of maternal and child genetic variation on cord blood PUFA status in a high fish-eating cohort.Cord blood samples collected from mother-child pairs (n = 1088) taking part in the Seychelles Child Development Study (SCDS) Nutrition Cohort 2 (NC2) were analysed for total serum PUFA. Maternal (n = 1088) and child genotype (n = 592) were determined for the FADS SNPs rs174537, rs174561, rs174575, and rs3834458. Regression analysis determined associations between maternal and child FADS genotype and cord PUFA status. In all regression models, the major allele homozygote genotype for each SNP was used as the reference group.Directions of significant associations were as predicted. In mothers, the minor allele homozygote genotype for SNPs rs174537, rs174561 and rs3834458 was associated with lower cord DHA and lower total n-3 PUFA when compared to the major allele homozygous genotype (p &lt; 0.05 for all). The heterozygous genotype was associated with increased concentrations of LA compared to the reference genotype for rs174561 (p = 0.021) and rs383448 (p = 0.023). In children, the heterozygous genotype was associated with lower AA concentrations and lower cord n-6:n-3 ratio for all SNPs (p &lt; 0.05 for all) compared to those with the major allele homozygous genotype. A lower cord AA:LA ratio was also observed for children heterozygous for rs174547, rs174561 and rs174575 (p &lt; 0.05 for all). Contrary to expected, there were no associations between cord PUFA concentrations and child minor allele homozygous genotype.The current study indicates that variation in maternal and child FADS genotype influences cord PUFA concentrations, despite the high intake of preformed dietary LCPUFA from fish in this population. The sample size for minor allele homozygous children was likely too small to observe any statistically significant associations in the current analysis. Further research is needed to determine whether increased dietary intake can compensate for lower PUFA status as a result of FADS genotype.

Diagnostic accuracy of microalbuminuria among sickle cell children with nephropathy

Objective: The aim of this study is to detect the diagnostic accuracy of microalbuminuria (MA) among sickle cell children with nephropathy.Materials and Methods: Five hundred and seven sickle cell homozygous children between 5 and 14 years of age group were enrolled after receiving written informed consent from the parents and/or caregiver. Children with preexisting kidney diseases, albuminuria, and taking any drugs that will affect renal function were excluded from the study. Sickle cell nephropathy (SCN) was diagnosed by using the National Kidney Foundation Kidney Disease Outcome Quality Initiative guidelines.Study Design: The study design involves diagnostic study Phase I.Statistical Analysis: Descriptive statistics were done using SPSS version 25.0 (IBM, NY, USA), and diagnostic statistics such as receiver operating characteristic curve (ROC) and others were done by Dxt version 1.0 software (BRTC, Vellore, India).Results: Of 507 patients, 268 (52.8%) were male and 239 (47.1%) were female. The mean age of the study population was 9.42 ± 2.56 years. Cutoff value of MA was ≥47 mg/day (sensitivity [Sn]: 73.9%, specificity [Sp]: 90.5% and area under curve was 0.841 [0.56, 0.91] with P = 0.001). Sn of MA was 76.1% (61.1%, 80.7%), Sp: 90.9% (87.8%, 93.5%), positive predictive value: 62.4% (52.2%, 71.8%), negative predictive value: 93.8% (91%–96%), likelihood ratio positive (LR+): 7.894 (5.672, 10.986), likelihood ratio negative (LR-): 0.312 (0.224, 0.436), odds ratio: 25.266 (14.277, 44.713) with diagnostic accuracy of 83.62%.Conclusions: MA can be used as a good screening tool for early detection of SCN. However, larger studies with a good level of evidence are awaited.

Frequency of null alleles in paternity cases from Mexico for the locus Penta E

We report three peculiar motherless paternity cases received in our lab at consecutive months, which involved four father-child mismatches for Penta E, the autosomal STR loci included in the Powerplex Fusion system. In all these cases, based on the residual Paternity Index (PI), the kinship was confirmed between the father and three children (PI > 1.6 × 10+6). In the first case, the homozygous father 16/16 did not match with two homozygous children 5/5 for the Penta E locus. Unexpectedly, the next week we detected another unique mismatch for Penta E between one homozygous father 9/9 and the homozygous child 17/17. Finally, four months later, in another motherless case, the father was 14/14 and the child was 16/16 for Penta E. Consequently, these four paternity test mismatches were faced as null alleles, which are described as variants in the primer-binding region that can lead to allele dropout resulting as false homozygous. Interestingly, allele nulls for Penta E are not described in the STRBase (https://strbase.nist.gov/NullAlleles.htm). According with these findings and our previous lab’s records (García-Aceves et al. 2018), we estimated a preliminary null allele frequency for Penta E in Mexico (7/3300; 0.21%). Because this estimate comes from motherless paternity cases and only one Mexican paternity testing laboratory, eventually this frequency needs to be confirmed. In brief, this report provides helpful information for reliable interpretation of paternity cases with unique mismatches for Penta E in Mexico, promoting research or simple modification of the corresponding primers by the supplier.

The P429L loss of function mutation of the human glycine transporter 2 associated with hyperekplexia.

Glycine transporter 2 (GlyT2) mutations across the entire sequence have been shown to represent the presynaptic component of the neurological disease hyperekplexia. Dominant, recessive and compound heterozygous mutations have been identified, most of them leading to impaired glycine uptake. Here, we identified a novel loss of function mutation of the GlyT2 resulting from an amino acid exchange of proline 429 to leucine in a family with both parents being heterozygous carriers. A homozygous child suffered from severe neuromotor deficits. We characterised the GlyT2P429L variant at the molecular, cellular and protein level. Functionality was determined by glycine uptake assays. Homology modelling revealed that the mutation localises to α-helix 5, presumably disrupting the integrity of this α-helix. GlyT2P429L shows protein trafficking through various intracellular compartments to the cellular surface. However, the protein expression at the whole cell level was significantly reduced. Although present at the cellular surface, GlyT2P429L demonstrated a loss of protein function. Coexpression of the mutant with the wild-type protein, reflecting the situation in the parents, did not affect transporter function, thus explaining their non-symptomatic phenotype. Nevertheless, when the mutant was expressed in excess compared with the wild-type protein, glycine uptake was significantly reduced. Thus, these data demonstrate that the proline residue at position 429 is structurally important for the correct formation of α-helix 5. The failure in functionality of the mutated GlyT2 is most probably due to structural changes localised in close proximity to the sodium-binding site of the transporter.

Estimation of vitamin D status in infants with obesity

Цель работы – определение показателей статуса витамина D, костного метаболизма, роли однонуклеотидного полиморфизма Bsm I гена VDR у детей первого года жизни с ожирением. Материалы и методы. Проведено комплексное клиническое и лабораторное обследование 120 детей в возрасте от 3 до 12 месяцев. Основную группу обследованных (n = 90) составили дети, показатели физического развития которых превышали возрастную норму. Контрольную группу (n = 30) составили дети, показатели физического развития которых находились в пределах линий стандартного отклонения. Всем детям проведено определение концентрации 25(OH)D и остеокальцина в сыворотке крови. Полиморфные варианты гена VDR – rs1544410 (Bsm I , A/G transition) определяли методом ПЦР-RLFP. Результаты. У детей основной группы отмечена достоверная разница по частоте установления дефицита витамина D. У детей первого года жизни на фоне ожирения определяли наиболее низкий уровень 25(OH)D в сыворотке крови. Нарастание дефицита витамина D сопровождалось достоверным снижением содержания остеокальцина в сыворотке крови. цУстановлены достоверные обратные корреляционные связи между уровнем 25(OH)D в сыворотке крови и индексом массы тела у детей первого года жизни с максимальными значениями у детей с ожирением. Проведен анализ ассоциации аллелей и генотипов Bsm I полиморфизма гена VDR с уровнем витамина D в сыворотке крови. Выводы. У детей первого года жизни дефицит витамина D отмечают достоверно чаще на фоне ожирения, чем у детей с избыточной массой тела, риском избыточной массы тела и лиц с физическим развитием, отвечающим возрастной норме. Среди обследованных детей интенсивность костного обмена по показателям остеокальцина в сыворотке крови была достоверно снижена при ожирении в сравнении с детьми, которые имели риск избыточной массы тела и нормальное физическое развитие. У гомозигот мутантного аллеля В достоверно чаще регистрируют дефицит витамина D с наиболее низким значением 25(OH)D в сыворотке крови, чем у гетерозигот и гомозигот аллеля b.

Novel mutations causing biotinidase deficiency in individuals identified by the newborn screening program in Minas Gerais, Brazil.

Biotinidase deficiency is an autosomal recessive inherited metabolic disorder caused by mutations in the BTD gene. Clinical manifestations can be treated and effectively prevented with pharmacological doses of biotin. Nine novel mutations in BTD are reported in 14 children diagnosed by the newborn screening program in Minas Gerais, Brazil, from June 2013 to December 2017. Serum BTD enzyme activity was determined for all cases and some parents. Two of the mutations are deletions and seven missense mutations located in the exonic region of the BTD gene, mostly in exon 4. Two newborns were profoundly biotinidase-deficient (one homozygous p.A534V [c.1601C > T] and another, double heterozygous for a novel mutation p.R211S [c.631C > A] co-inherited with an already described mutation p.T532 M [c.1595C > T]). Two mutations were associated with a partial deficiency of biotinidase (p.F361 V [c.1081 T > G] in two homozygous children, and p.S311 T [c.932G > C] in a compound heterozygous child who co-inherited a known severe mutation p.Y438X [c.1314 T > A]). The remaining five mutations were found in compound heterozygous children. Hence, a definitive conclusion about the degree of biotinidase deficiency is not possible yet. These results emphasize the importance of sequencing the BTD gene as an important tool to gain a better understanding of the correlation between biochemical phenotype and genotype.

Association of calcium and dairy product consumption with childhood obesity and the presence of a Brain Derived Neurotropic Factor-Antisense (BDNF-AS) polymorphism

Calcium and dairy products have multiple health benefits. The objective of this work was to evaluate the association between calcium/dairy intake, blood pressure, the BDNF-AS rs925946 polymorphism and nutritional status in a group of schoolchildren. As part of the GENYAL study to childhood obesity prevention, 221 children belonging to different areas of the Community of Madrid were enrolled. Anthropometric and dietary data were collected, and children were genotyped according to the rs925946 polymorphism. Adjusted logistic and linear models were used to describe the data. A significantly lower consumption of calcium in overweight versus normal weight children was observed (811.0±174.1; 859.0±195.9; 954.0±223.1mg; for obesity, overweight and normal weight, respectively, p=0.010). Moreover, an inverse association between blood pressures and calcium intake was detected (β=-0.006 (-0.011,-3e-4)), p=0.040. The number of dairy servings/day showed a protective effect against overweight (OR=0.48 (0.29, 0.75), p=0.001). Finally, common homozygous children (GG) showed an inverse association between the calcium intake and the BMI (β=-0.003 (-0.006,-0.001), p=0.004), which was not observed in children carrying the T allele (β=-1.3e-4 (-0.0022, 0.0024), p=0.93). Calcium and dairy were strongly associated with the nutritional status and blood pressure. The identification of differential effects of calcium/dairy consumption on the nutritional status according to genetics may contribute to the personalization of future nutritional advice. This study is registered at www.clinicaltrials.govNCT03419520.

Familial Hypercholesterolemia: Cascade Screening in Children and Relatives of the Affected.

Familial Hypercholesterolemia (FH) is an inherited disorder of lipid metabolism characterized by very high low density lipoprotein (LDL) cholesterol since birth, resulting in premature atherosclerosis and coronary artery disease (CAD). Cascade screening of children and family members of proven FH individuals can identify more subjects who have high LDL cholesterol or the family mutation and appropriate intervention can reduce their risk of atherosclerosis and prevent its complications. Cascade screening by molecular testing, was carried out in 133 family members, comprising 24 children, of 31 probands with FH having a pathogenic mutation in LDLR/ApoB gene. Lipid profiles were obtained in 44 family members including 11 children. Of 133 family members tested, 88 (66.1%) were identified to carry the family mutation. Twelve of these were children below 18 y of age and 76 were adults. CAD was present in 15 (11.2%) family members and 63(47.4%) family members, including nine children, were already on Lipid Lowering Therapy. Cascade screening led to identification of 88 new cases, with a pathogenic mutation, who were at a very high risk of developing premature CAD. The authors identified 12 children with family specific mutation, out of which 9 were initiated on low dose statin therapy. Four homozygous children were treated with high dose statins because of substantially increased risk of CAD. Cascade screening, therefore, proved to be a successful initiative towards primary prevention of CAD in India.

Evaluation of association of DRD2 TaqIA and -141C InsDel polymorphisms with food intake and anthropometric data in children at the first stages of development.

The reward sensation after food intake may be different between individuals and variants in genes related to the dopaminergic system may indicate a different response in people exposed to the same environmental factors. This study investigated the association of TaqIA (rs1800497) and -141C InsDel (rs1799732) variants in DRD2/ANKK1 gene with food intake and adiposity parameters in a cohort of children. The sample consisted of 270 children followed until 7 to 8 years old. DNA was extracted from blood and polymorphisms were detected by PCR-RFLP analysis. Food intake and nutritional status were compared among individuals with different SNP genotypes. Children carrying the A1 allele (TaqIA) had higher energy of lipid dense foods (LDF) when compared with A2/A2 homozygous children at 7 to 8 years old (GLM p=0.004; Mann Whitney p=0.005). No association was detected with -141C Ins/Del polymorphism. To our knowledge, this is the first association study of the DRD2 TaqIA and -141C Ins/Del polymorphism with food intake and anthropometric parameters in children. DRD2 TaqIA polymorphism has been associated with a reduction in D2 dopamine receptor availability. Therefore, the differences observed in LDF intake in our sample may occur as an effort to compensate the hypodopaminergic functioning.

Does the Novel KLF1 Gene Mutation Lead to a Delay in Fetal Hemoglobin Switch?

The Kruppel-like factor 1 (KLF1) gene is an essential transcription factor that is required for the proper maturation of the erythroid cells. Recent studies have reported that KLF1 variations are associated with increased fetal hemoglobin (HbF) levels. Here we report a novel KLF1 gene variation codon 211 A→G (c.632 A>G) in a family who was referred for hemoglobinopathy screening. Both parents were classical β-thalassemia trait (mother: HbA2 4.1%, HbF 8.6%; father: HbA2 5.5%, HbF 0.6%) codon 15 G→A heterozygous, and the child was β-thalassemia homozygous. Because the mother showed a high HbF level, the genetic determinants for raised HbF were screened. We detected a novel KLF1 gene variant in the mother and the child in the heterozygous state. The co-inheritance of this novel KLF1 variant might have increased the HbF levels in the mother and may have ameliorated the clinical manifestations of the 6-year-old untransfused β-thalassemia homozygous child. Identification of KLF1 gene variants may act as a novel target for increasing HbF levels in patients with β-hemoglobinopathies.