Atypical Alstrom syndrome with novel ALMS1 mutations precluded by current diagnostic criteria

We report on clinical and genetic studies in a non-consanguineous Irish sib-pair with infantile dilated cardiomyopathy and retinopathy. A diagnosis of Alström Syndrome (AS) was considered and diagnostic testing pursued. The Alströms gene (ALMS1) is very large (23 exons) and diagnostic testing of mutational hotspots (exon 6, 8 and 10) was negative. Furthermore the siblings were tall and did not have the typical phenotype of nystagmus, photophobia, obesity or hearing loss and so the AS diagnosis was removed. We then sought to identify the causative gene in this family using whole exome sequencing. Unexpectedly, the exome analysis identified novel compound heterozygous ALMS1 mutations in exon 5 (c.777delT:p.D260fs*26) and exon 20 (c.12145_12146insC:p.S4049fs*36) that segregated with the phenotype. Although the siblings show some clinical overlap with AS, their phenotype is not classical. It is plausible that their atypical presentation may be due to the location of the ALMS1 mutations outside the usual mutational hotspots. Our findings show how atypical cases of AS may be missed under the current diagnostic guidelines and support consideration of complete ALMS1 sequencing in children with two or more features, even if all of the core clinical features of AS are not present.     

Alström Syndrome: Mutation Spectrum of ALMS1

Alström Syndrome (ALMS), a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multisystem involvement including early cone‐rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis, and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of ALMS. Mutational analysis in a world‐wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with ALMS, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date.     

Coronary artery disease in Alström syndrome

Alström syndrome (ALMS) is a rare autosomal recessive condition, caused by mutations in the ALMS1 gene located on the short arm of chromosome 2. This gene codes for a protein linked with the centrosome, whose precise function is unknown. This condition was first described by Alström in 1959. ALMS is a multisystem condition that is characterised by childhood onset of blindness secondary to rod-cone retinal degeneration and dilated cardiomyopathy with heart failure, which often presents in infanthood and may recur later in life. Metabolic abnormalities including hypertriglyceridemia, liver steatosis, insulin resistance and type 2 diabetes mellitus are common, often occurring in association with obesity. Other abnormalities include endocrinological disturbances, such as thyroid disorder, growth hormone deficiency, hypogonadism and, in women, hyperandrogenism. This syndrome is also associated with sensorineural hearing loss, renal failure secondary to glomerulo-fibrosis, and fibrotic lung disease. Multiorgan fibrotic infiltration is the common feature in all cases. Considering the history of diabetes, hypertension, dyslipidemia, obesity and renal dysfunction in ALMS, it would be expected that this group of patients could develop coronary artery disease (CAD). But such cases have not been reported so far. We report a case of premature onset of CAD in one of the longest surviving patient with ALMS.     

SCYL1 variants cause a syndrome with lowγ-glutamyl-transferase cholestasis,acute liver failure,and neurodegeneration (CALFAN)

PurposeBiallelic mutations in SCYL1 were recently identified as causing a syndromal disorder characterized by peripheral neuropathy, cerebellar atrophy, ataxia, and recurrent episodes of liver failure. The occurrence of SCYL1 deficiency among patients with previously undetermined infantile cholestasis or acute liver failure has not been studied; furthermore, little is known regarding the hepatic phenotype.MethodsWe aimed to identify patients with SCYL1 variants within an exome-sequencing study of individuals with infantile cholestasis or acute liver failure of unknown etiology. Deep clinical and biochemical phenotyping plus analysis of liver biopsies and functional studies on fibroblasts were performed.ResultsSeven patients from five families with biallelic SCYL1 variants were identified. The main clinical phenotype was recurrent low γ-glutamyl-transferase (GGT) cholestasis or acute liver failure with onset in infancy and a variable neurological phenotype of later onset (CALFAN syndrome). Liver crises were triggered by febrile infections and were transient, but fibrosis developed. Functional studies emphasize that SCYL1 deficiency is linked to impaired intracellular trafficking.ConclusionSCYL1 deficiency can cause recurrent low-GGT cholestatic liver dysfunction in conjunction with a variable neurological phenotype. Like NBAS deficiency, it is a member of the emerging group of congenital disorders of intracellular trafficking causing hepatopathy.     

Genetic evaluation of patients with Alström syndrome in the Polish population

Alström syndrome (AS) is a rare syndromic form of obesity and type 2 diabetes (T2D) in children coexisting with retinal dystrophy and disorders of many organs caused by the mutations in ALMS1 gene. Aim of this study was to identify the causative mutations in ALMS1 in a group of 12 patients of Polish origin with clinical symptoms of AS, and their 21 first‐degree relatives. Using DNA sequencing, nine different mutations including three novel were identified. These mutations were not present in 212 Polish individuals with no symptoms of AS, subjected to whole‐exome sequencing and collected in a national registry. Looking for genotype–phenotype relationships, we confirmed a severe phenotype in a boy with homozygous mutation in exon 16, and a relationship between a presence of T2D and mutations in exon 19. Evaluation of the type of mutation and its clinical effects gives hope for earlier diagnosis of AS in future patients and more advanced therapeutic approaches for patients with already diagnosed AS.     

Clinical and molecular findings in 37 Turkish patients with isolated methylmalonic acidemia

Background/aim Isolated methylmalonic acidemia (MMA) is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 or mut– enzymatic subtype), a defect of its cofactor adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. While onset of the disease ranges from the neonatal period to adulthood, most cases present with lethargy, vomiting and ketoacidosis in the early infancy. Major secondary complications are; growth failure, developmental delay, interstitial nephritis with progressive renal failure, basal ganglia injury and cardiomyopathy. We aimed to demonstrate clinical and molecular findings based on long-term follow up in our patient cohort. Materials and methods The study includes 37 Turkish patients with isolated MMA who were followed up for long term complications 1 to 14 years. All patients were followed up regularly with clinical, biochemical and dietary monitoring to determine long term complications. Next Generation Sequencing technique was used for mutation screening in five disease-causing genes including; MUT , MMAA , MMAB , MMADHC , MCEE genes. Mutation screening identified 30 different types of mutations. Results While 28 of these mutations were previously reported, one novel MMAA mutation p.H382Pfs*24 (c.1145delA) and one novel MUT mutation IVS3+1G>T(c.752+1G>T) has been reported. The most common clinical complications were growth retardation, renal involvement, mental motor retardation and developmental delay. Furthermore, one of our patients developed cardiomyopathy, another one died because of hepatic failure and one presented with lactic acidosis after linezolid exposure. Conclusion We have detected two novel mutations, including one splice-site mutation in the MUT gene and one frame shift mutation in the MMAA gene in 37 Turkish patients. We confirm the genotype-phenotype correlation in the study population according to the long-term complications.     

TTR variants in patients with dilated cardiomyopathy: An investigation of the DCM Precision Medicine Study

PurposeThe cardiac phenotype of hereditary transthyretin amyloidosis (hTTR) usually presents as a restrictive or hypertrophic cardiomyopathy, and, although rarely observed as dilated cardiomyopathy (DCM), TTR is routinely included in DCM genetic testing panels. However, the prevalence and phenotypes of TTR variants in patients with DCM have not been reported.MethodsExome sequences of 729 probands with idiopathic DCM were analyzed for TTR and 35 DCM genes.ResultsRare TTR variants were identified in 2 (0.5%; 95% CI = 0.1%-1.8%) of 404 non-Hispanic White DCM probands; neither of them had features of hTTR. In 1 proband, a TTR His110Asn variant and a variant of uncertain significance in DSP were identified, and in the other proband, a TTR Val50Met variant known to cause hTTR and a likely pathogenic variant in FLNC were identified. The TTR Val142Ile variant was identified in 8 (3.0%) non-Hispanic Black probands, comparable with African/African American Genome Aggregation Database controls (OR = 1.01; 95% CI = 0.46-1.99).ConclusionAmong the 729 DCM probands, 2 had rare TTR variants identified without the features of hTTR, and both had other plausible genetic causes of DCM. Moreover, the frequency of TTR Val142Ile was comparable to a control sample. These findings suggest that hTTR variants may have a limited role in patients with DCM without TTR-specific findings.     

Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood

AimTo perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations.MethodA multi-gene panel of childhood-onset basal ganglia neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts.ResultsThree siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Brain magnetic resonance showed symmetric and bilateral cytotoxic lesions in the putamen and proliferation of the lenticular-striate arteries, latter spreading to the caudate and progressing to cavitation and volume loss. We identified a frameshift novel change (c.554_558delTTCTT; p.Tyr187AsnfsTer65) and a pathogenic missense change (c.371T>C; p.Ile124Thr) in the NDUFAF6 gene, which segregated with an autosomal recessive inheritance within the family. Patient mutations were associated with the absence of the NDUFAF6 protein and reduced activity and assembly of mature complex I in fibroblasts. By functional complementation assay, the mutant phenotype was rescued by the canonical version of the NDUFAF6. A literature review of 14 NDUFAF6 patients showed a consistent phenotype of an early childhood insidious onset neurological regression with prominent dystonia associated with basal ganglia degeneration and long survival.InterpretationNDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis. By genetic complementation, we could demonstrate the pathogenicity of novel genetic variants in NDUFAF6.     

ABCC8 mutation allele frequency in the Ashkenazi Jewish population and risk of focal hyperinsulinemic hypoglycemia

PurposeCongenital hyperinsulinism of infancy (OMIM# 256450) is a devastating disease most commonly caused by dominant or recessive mutations in either ABCC8 or KCNJ11, the genes that encode for the β-cell adenosine triphosphate-regulated potassium channel. A unique combination of a paternally inherited germline mutation and somatic loss-of-heterozygosity causes the focal form of the disease (Focal-congenital hyperinsulinism of infancy [Focal-CHI]), the incidence of which in genetically susceptible individuals is not known.MethodsWe genotyped 21,122 Ashkenazi Jewish individuals for two previously identified ABCC8 founder mutations and utilized a clinical database of 61 unrelated Ashkenazi patients with congenital hyperinsulinism of infancy to obtain an estimate of the risk of Focal-CHI in a genetically susceptible fetus.ResultsThe combined mutation carrier rate in Ashkenazi Jews was 1:52, giving an estimated frequency of homozygosity or compound heterozygosity of 1:10,816 in this population. The risk of Focal-CHI is 1:540 per pregnancy in offspring of carrier fathers.ConclusionWe recommend that these mutations be included in the genetic screening program for the Ashkenazi Jewish population. As the risk of Focal-CHI is not expected to be mutation specific, the data reported in this study are useful for counseling all families in which the father was found to carry a recessive ABCC8 or KCNJ11 mutation.     

Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation

PurposeNoonan syndrome (NS) is an autosomal-dominant disorder characterized by craniofacial dysmorphism, growth retardation, cardiac abnormalities, and learning difficulties. It belongs to the RASopathies, which are caused by germ-line mutations in genes encoding components of the RAS mitogen-activated protein kinase (MAPK) pathway. RIT1 was recently reported as a disease gene for NS, but the number of published cases is still limited.MethodsWe sequenced RIT1 in 310 mutation-negative individuals with a suspected RASopathy and prospectively in individuals who underwent genetic testing for NS. Using a standardized form, we recorded clinical features of all RIT1 mutation-positive patients. Clinical and genotype data from 36 individuals with RIT1 mutation reported previously were reviewed.ResultsEleven different RIT1 missense mutations, three of which were novel, were identified in 33 subjects from 28 families; codons 57, 82, and 95 represent mutation hotspots. In relation to NS of other genetic etiologies, prenatal abnormalities, cardiovascular disease, and lymphatic abnormalities were common in individuals with RIT1 mutation, whereas short stature, intellectual problems, pectus anomalies, and ectodermal findings were less frequent.ConclusionRIT1 is one of the major genes for NS. The RIT1-associated phenotype differs gradually from other NS subtypes, with a high prevalence of cardiovascular manifestations, especially hypertrophic cardiomyopathy, and lymphatic problems.Genet Med 18 12, 1226–1234.     

De novo p.G696S mutation in COL4A1 causes intracranial calcification and late-onset cerebral hemorrhage: A case report and review of the literature

BackgroundThe collagen type IV alpha 1 chain (COL4A1) is an essential component of the basement membrane in small vessels. Pathogenic variants in COL4A1 cause perinatal cerebral hemorrhages in an autosomal-dominant fashion. However, little is known about the long-term outcomes of patients with mildly affecting COL4A1 mutations.Case reportWe report a 17-year-old boy, who presented with recurrent intracranial hemorrhages in the periventricular white matter. He had been followed-up as a child with cerebral palsy bearing intracranial calcifications, developmental delay and epilepsy. Screening tests in infancy provided negative results for intrauterine infections. Severe motor and cognitive deficits persisted after admission. Carbazochrome was introduced on day 19 of admission, which appeared to prevent extension and reactivation of cerebral hemorrhages for over 6 months after discharge.ResultsTargeted sequencing of NOTCH3 and TREX1 excluded causal mutations in these genes. The whole-exome sequencing revealed that he carried a de novo mutation in COL4A1 (p.Gly696Ser). An overview of the literature for 345 cases with COL4A1 mutations supported evidence that p.Gly696Ser is associated with the unique phenotype of late-onset hemorrhage among patients with COL4A1-associated cerebral angiopathy.ConclusionsThis case first demonstrates that infants with COL4A1-associated leukoencephalopathy and calcifications have a risk for developing the rupture of small vessels in the cerebral white matter after 10 years of age.     

Study of phenotype evolution during childhood in Marfan syndrome to improve clinical recognition

PurposeBecause diagnosis of Marfan syndrome is difficult during infancy, we used a large cohort of children to describe the evolution of the Marfan syndrome phenotype with age.MethodsTwo hundred and fifty-nine children carrying an FBN1 gene mutation and fulfilling Ghent criteria were compared with 474 non-Marfan syndrome children.ResultsPrevalence of skeletal features changed with aging: prevalence of pectus deformity increased from 43% at 0–6 years to 62% at 15–17 years, wrist signs increased from 28 to 67%, and scoliosis increased from 16 to 59%. Hypermobility decreased from 67 to 47% and pes planus decreased from 73 to 65%. Striae increased from 2 to 84%. Prevalence of ectopia lentis remained stable, varying from 66 to 72%, similar to aortic root dilatation (varying from 75 to 80%). Aortic root dilatation remained stable during follow-up in this population receiving β-blocker therapy. When comparing Marfan syndrome children with non-Marfan syndrome children, height appeared to be a simple and discriminant criterion when it was >3.3 SD above the mean. Ectopia lentis and aortic dilatation were both similarly discriminating.ConclusionEctopia lentis and aortic dilatation are the best-discriminating features, but height remains a simple discriminating variable for general practitioners when >3.3 SD above the mean. Mean aortic dilatation remains stable in infancy when children receive a β-blocker.Genet Med 2014:16(3):246–250     

Clinical predictors of genetic testing outcomes in hypertrophic cardiomyopathy

PurposeGenetic testing for hypertrophic cardiomyopathy has been commercially available for almost a decade; however, low mutation detection rate and cost have hindered uptake. This study sought to identify clinical variables that can predict probands with hypertrophic cardiomyopathy in whom a pathogenic mutation will be identified.MethodsProbands attending specialized cardiac genetic clinics across Australia over a 10-year period (2002–2011), who met clinical diagnostic criteria for hypertrophic cardiomyopathy and who underwent genetic testing for hypertrophic cardiomyopathy were included. Clinical, family history, and genotype information were collected.ResultsA total of 265 unrelated individuals with hypertrophic cardiomyopathy were included, with 138 (52%) having at least one mutation identified. The mutation detection rate was significantly higher in the probands with hypertrophic cardiomyopathy with an established family history of disease (72 vs. 29%, P < 0.0001), and a positive family history of sudden cardiac death further increased the detection rate (89 vs. 59%, P < 0.0001). Multivariate analysis identified female gender, increased left-ventricular wall thickness, family history of hypertrophic cardiomyopathy, and family history of sudden cardiac death as being associated with greatest chance of identifying a gene mutation. Multiple mutation carriers (n = 16, 6%) were more likely to have suffered an out-of-hospital cardiac arrest or sudden cardiac death (31 vs. 7%, P = 0.012).ConclusionFamily history is a key clinical predictor of a positive genetic diagnosis and has direct clinical relevance, particularly in the pretest genetic counseling setting.Genet Med15 12, 972–977.     

Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

PurposeThe purpose of this document is to provide updated guidance for the genetic evaluation of cardiomyopathy and for an approach to manage secondary findings from cardiomyopathy genes. The genetic bases of the primary cardiomyopathies (dilated, hypertrophic, arrhythmogenic right ventricular, and restrictive) have been established, and each is medically actionable; in most cases established treatments or interventions are available to improve survival, reduce morbidity, and enhance quality of life.MethodsA writing group of cardiologists and genetics professionals updated guidance, first published in 2009 for the Heart Failure Society of America (HFSA), in a collaboration with the American College of Medical Genetics and Genomics (ACMG). Each recommendation was assigned to teams of individuals by expertise, literature was reviewed, and recommendations were decided by consensus of the writing group. Recommendations for family history, phenotype screening of at-risk family members, referral to expert centers as needed, genetic counseling, and cardiovascular therapies, informed in part by phenotype, are presented in the HFSA document.ResultsA genetic evaluation of cardiomyopathy is indicated with a cardiomyopathy diagnosis, which includes genetic testing. Guidance is also provided for clinical approaches to secondary findings from cardiomyopathy genes. This is relevant as cardiomyopathy is the phenotype associated with 27% of the genes on the ACMG list for return of secondary findings. Recommendations herein are considered expert opinion per current ACMG policy as no systematic approach to literature review was conducted.ConclusionGenetic testing is indicated for cardiomyopathy to assist in patient care and management of at-risk family members.     

Cholestasis as a dominating symptom of patients with CYP27A1 mutations: An analysis of 17 Chinese infants

BackgroundCYP27A1 is the disease-causing gene of cerebrotendinous xanthomatosis (CTX). As a treatable lipid storage disease, early treatment can improve the prognosis. However, CTX patients reported in the literature are mostly adult patients; the phenotype spectrum of CTX in the infantile population remains elusive.ObjectiveWe aimed to investigate the phenotype spectrum of infants who carried pathogenic or likely pathogenic variants in the CYP27A1 gene and were suspected of having CTX.MethodsFrom June 2014 to May 2020, infants with pathogenic or likely pathogenic variants in CYP27A1 gene were enrolled, who underwent next-generation sequencing or Sanger sequencing in Children's Hospital of Fudan University. Patient characteristics, clinical treatments and outcomes were extracted from electronic medical records.ResultsA total of 17 patients with an average onset age of 8 (1–42) days were found. The average diagnosis age was ten months. Cholestasis was the dominant symptom of these infants. Thirteen variants were detected, of which c.379C > T was a hotspot variant (26.5% alleles, 9/34). Cholestatic CTX is usually underestimated, but it could be severe or even fatal in infancy. For outcomes, 5 suffered from liver failure (36%, 5/14), 1 still showed cholestasis (7%, 1/14), 7 were asymptomatic (50%, 7/14), and 1 presented seizure and developmental delay in later childhood (7%, 1/14).ConclusionBased on this infantile cohort, we concluded that it is necessary to consider the possibility of CTX caused by CYP27A1 gene variants for infants with cholestasis.     

Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies

PurposeTo characterize the genetic architecture of left ventricular noncompaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases.MethodsWe performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM).ResultsWe observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology. In particular, MYH7 truncating variants (MYH7tv), generally considered nonpathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7tv heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater noncompaction compared with matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes.ConclusionLVNC is characterized by substantial genetic overlap with DCM/HCM but is also associated with distinct noncompaction and arrhythmia etiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological noncompaction.     

Congenital hyperinsulinism due to mutations in HNF1A

Congenital hyperinsulinism is a rare but significant cause of severe and persistent hypoglycaemia in infancy. Although a biphasic phenotype of congenital hyperinsulinism in infancy followed by Maturity-Onset Diabetes of the Young (MODY) in later life has been established for HNF4A, the existence of a similar phenotype for a related MODY gene, HNF1A, is less clear. We describe two cases of congenital hyperinsulinism in association with dominantly inherited variants in HNF1A. They presented in the early neonatal period with unequivocal biochemical evidence of congenital hyperinsulinism and persistence into childhood with ongoing need for medical therapy. Both cases inherited HNF1A variants from a parent with a diabetes phenotype consistent with MODY, without obesity, insulin resistance or other metabolic syndrome features. In the first case, a paternally inherited novel c.-230_-101del variant was found that deletes the minimal promoter region presumably required for HNF1A expression. In the second case, a maternally inherited missense variant (c.713G>T, p.(Arg238Met)) was identified. This variant is predicted to cause haploinsufficiency via aberrant splicing and has previously been associated with MODY but not congenital hyperinsulinism. Our cases further strengthen the evidence for HNF1A as a CHI-causing gene requiring long-term follow-up.     

A genome-first approach to aggregating rare genetic variants in LMNA for association with electronic health record phenotypes

Purpose“Genome-first” approaches, in which genetic sequencing is agnostically linked to associated phenotypes, can enhance our understanding of rare variants’ contributions to disease. Loss-of-function variants in LMNA cause a range of rare diseases, including cardiomyopathy.MethodsWe leveraged exome sequencing from 11,451 unselected individuals in the Penn Medicine Biobank to associate rare variants in LMNA with diverse electronic health record (EHR)–derived phenotypes. We used Rare Exome Variant Ensemble Learner (REVEL) to annotate rare missense variants, clustered predicted deleterious and loss-of-function variants into a “gene burden” (N = 72 individuals), and performed a phenome-wide association study (PheWAS). Major findings were replicated in DiscovEHR.ResultsThe LMNA gene burden was significantly associated with primary cardiomyopathy (p = 1.78E-11) and cardiac conduction disorders (p = 5.27E-07). Most patients had not been clinically diagnosed with LMNA cardiomyopathy. We also noted an association with chronic kidney disease (p = 1.13E-06). Regression analyses on echocardiography and serum labs revealed that LMNA variant carriers had dilated cardiomyopathy and primary renal disease.ConclusionPathogenic LMNA variants are an underdiagnosed cause of cardiomyopathy. We also find that LMNA loss of function may be a primary cause of renal disease. Finally, we show the value of aggregating rare, annotated variants into a gene burden and using PheWAS to identify novel ontologies for pleiotropic human genes.     

Effect of paracetamol use on the modification of the development of asthma by reactive oxygen species genes

BackgroundRecent studies have identified an increase in the prevalence of asthma associated with paracetamol use.ObjectiveTo identify the relationship among asthma, biomarkers, genes, and paracetamol use in preschool children.MethodsWe undertook a population-based, cross-sectional survey of 933 preschool children. Asthma status was classified according to medical history and asthmatic symptoms. History of paracetamol use in infancy was recorded. Impulse oscillometry, blood tests for eosinophils and total IgE, and genotyping of NAT2, Nrf2, and GSTP1 polymorphisms by TaqMan assay were conducted.ResultParacetamol use in infancy was associated with an increased risk of treatment for asthma within the previous 12 months. Paracetamol use together with a family history of asthma increased the risk of asthma diagnosis ever, current asthma, and treatment for asthma within the previous 12 months. Gene polymorphisms in NAT2 (rs4271002), Nrf2 (rd6726395), and GSTP1 (rd1695) increased the risk of treatment for asthma within the last 12 months. Eosinophils were significantly elevated in the group with paracetamol use and a family history of asthma; however, the serum total IgE level and IOS did not show any significant difference.ConclusionParacetamol use in infancy was significantly associated with increased risk of asthma. The association is more significant in genetically susceptible children, related to antioxidant genes, and the effect may be mediated by eosinophilic inflammation.     

Airway hyperresponsiveness in young children with respiratory symptoms: A five-year follow-up

BackgroundRecurrent wheezing in early life is transient in most children. The significance of airway hyperresponsiveness (AHR) in persistence of respiratory symptoms from infancy to early childhood is controversial.ObjectiveWe evaluated whether AHR in wheezy infants predicts doctor-diagnosed asthma (DDA) or AHR at the age of 6 years.MethodsSixty-one wheezy infants (age 6-24 months) were followed up to the median age of 6 years. Lung function and AHR with methacholine challenge test were assessed at infancy and 6 years. The exercise challenge test was performed at the age of 6 years. Atopy was assessed with skin prick tests.ResultsAt 6 years, 21 (34%) of the children had DDA. Children with DDA had higher logarithmic transformed dose-response slope (LOGDRS) to methacholine in infancy than children without DDA (0.047 vs 0.025; P = .033). Furthermore, AHR to methacholine in infancy and at 6 years were associated with each other (r = 0.324, P = .011). Children with exercise-induced bronchoconstriction (EIB) at 6 years were more reactive to methacholine in infancy than those without EIB (P = .019).ConclusionIncreased AHR in symptomatic infants was associated with increased AHR, DDA, and EIB at median the age of 6 years, suggesting early establishment of AHR.