Parsing heterogeneity in attention-deficit hyperactivity disorder using EEG-based subgroups.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous condition for which multiple efforts to characterize brain state differences are underway. The objective of this study was to identify distinct subgroups of resting electroencephalography (EEG) profiles among children with and without ADHD and subsequently provide extensive clinical characterization of the subgroups. METHODS: Latent class analysis was used with resting state EEG recorded from a large sample of 781 children with and without ADHD (N = 620 ADHD, N = 161 Control), aged 6-18 years old. Behavioral and cognitive characteristics of the latent classes were derived from semistructured diagnostic interviews, parent completed behavior rating scales, and cognitive test performance. RESULTS: A five-class solution was the best fit for the data, of which four classes had a defining spectral power elevation. The distribution of ADHD and control subjects was similar across classes suggesting there is no one resting state EEG profile for children with or without ADHD. Specific latent classes demonstrated distinct behavioral and cognitive profiles. Those with elevated slow-wave activity (i.e. delta and theta band) had higher levels of externalizing behaviors and cognitive deficits. Latent subgroups with elevated alpha and beta power had higher levels of internalizing behaviors, emotion dysregulation, and intact cognitive functioning. CONCLUSIONS: There is population-level heterogeneity in resting state EEG subgroups, which are associated with distinct behavioral and cognitive profiles. EEG measures may be more useful biomarkers of ADHD outcome or treatment response rather than diagnosis.

Novel splice-affecting variants in CYP27A1 gene in two Chilean patients with Cerebrotendinous Xanthomatosis.

Cerebrotendinous Xanthomatosis (CTX), a rare lipid storage disorder, is caused by recessive loss-of-function mutations of the 27-sterol hydroxylase (CYP27A1), producing an alteration of the synthesis of bile acids, with an accumulation of cholestanol. Clinical characteristics include juvenile cataracts, diarrhea, tendon xanthomas, cognitive impairment and other neurological manifestations. Early diagnosis is critical, because treatment with chenodeoxycholic acid may prevent neurological damage. We studied the CYP27A1 gene in two Chilean CTX patients by sequencing its nine exons, exon-intron boundaries, and cDNA from peripheral blood mononuclear cells. Patient 1 is a compound heterozygote for the novel substitution c.256-1G > T that causes exon 2 skipping, leading to a premature stop codon in exon 3, and for the previously-known pathogenic mutation c.1183C > T (p.Arg395Cys). Patient 2 is homozygous for the novel mutation c.1185-1G > A that causes exon 7 skipping and the generation of a premature stop codon in exon 8, leading to the loss of the crucial adrenoxin binding domain of CYP27A1.

Association of RNASEL and 8q24 variants with the presence and aggressiveness of hereditary and sporadic prostate cancer in a Hispanic population.

To study the association between the polymorphisms Arg462Gln and Asp541Glu from the RNASEL gene (1q25), and the polymorphisms rs620861, rs1447295, rs6983267, rs7837328 from the chromosome 8q24 with the risk of presenting prostate cancer (PCa) and its clinical characteristics in a Hispanic (Chilean) population. The study was performed on 21 control patients and 83 patients diagnosed with PCa. Polymorphisms were analysed from blood samples through real-time PCR by using TaqMan probes, and the genetic analysis was performed with the SNPStats program. Also, a comparison was performed between clinical characteristics of PCa and the presence of the different polymorphism genotypes by using the Minitab software. There was a significant association between the genotype G/G from the polymorphism rs6983267 with an overall increased risk of PCa, in patients both with or without family history of PCa (OR = 4.47, 95% CI = 1.05-18.94, P = 0.034 and OR = 3.57, 95% CI = 0.96-13.35, P = 0.037, respectively). Regarding clinical parameters, patients carrying the genotype C/C from the polymorphism Asp541Glu had significantly higher prostate-specific antigen (PSA) levels than patients carrying the other genotypes (P = 0.034). Moreover, patients with the genotype G/G of rs6983267 had higher PSA levels (P = 0.024). The polymorphism rs6983267 from region 3 of the chromosome 8q24 appears to be a prominent risk factor for PCa and a biomarker for cancer aggressiveness in the group of patients who presented higher levels of PSA at the time of diagnosis.

[Cerebrotendinous xanthomatosis: physiopathology, clinical manifestations and genetics]. / Xantomatosis cerebrotendinosa: aspectos fisiopatológicos, clínicos y genéticos.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease, caused by genetic deficiency of the 27-hydroxylase enzyme (encoded by CYP27A1). It plays a key role in cholesterol metabolism, especially in bile acid synthesis and in the 25-hydroxylation of vitamin D3 in the liver. Its deficiency causes reduced bile acid synthesis and tissue accumulation of cholestanol. Clinical manifestations are related to the presence of cholestanol deposits and include tendon xanthomas, premature cataracts, chronic diarrhea, progressive neurologic impairment and less frequently coronary heart disease, early onset osteoporosis and abnormalities in the optic disk and retina. An early diagnosis and treatment with quenodeoxycholic acid may prevent further complications, mainly neurological manifestations. This review summarizes cholesterol metabolism related to bile acid synthesis, physiopathology, biochemistry and treatment of cerebrotendinous xanthomatosis.

[Association between genetic polymorphisms of interleukin 6 (IL6), IL6R and IL18 with metabolic syndrome in obese Chilean children]. / Polimorfismos genéticos de interleuquina 6 (IL6), IL6R e IL18: asociación con componentes del síndrome metabólico en niños chilenos con obesidad.

BACKGROUND: Metabolic Syndrome (MS) is highly prevalent among obese children and adolescents and is considered a predictor for the development of type 2 diabetes mellitus and cardiovascular disease. Obesity is associated with an increase in circulating levels of interleukins 6 (IL6) and 18 (IL18), which in turn would depend on polymorphisms of IL6, IL6R and IL18 genes. AIM: To evaluate the association between genetic polymorphisms of IL6 (rs1800795, rs1800796 and rs1800797), IL6R (rs2228145) and IL18 (rs360719, rs187238 and rs204355) and MS and/or its components in a sample of Chilean obese children. PATIENTS AND METHODS: These polymorphisms were genotyped in 259 obese children aged 10 ± 2 years with a body mass index of 26.1 ± 4.1 kg/m². Sixty eight had metabolic syndrome (26.3%). The association of their alleles, genotypes and haplotypes with the MS and its components was assessed. RESULTS: IL6, IL6R and IL18 variants showed no association with SM nor with any of the phenotypes that compose it. However, IL18 haplotypes (rs360719-rs187238-rs204355) TCT and CGT were associated with triglycerides ≤ 110 mg/dL and HDL < 40 mg/dL, respectively. CONCLUSIONS: IL6 and IL6R variants are not associated with MS or with any of its phenotypes. Although an association between IL18 haplotypes and certain MS component has been detected herein, it is necessary to replicate our findings in independent studies due to the low frequency of these allele combinations detected in our sample.

Emerging therapeutic drug monitoring technologies: considerations and opportunities in precision medicine.

In recent years, the development of sensor and wearable technologies have led to their increased adoption in clinical and health monitoring settings. One area that is in early, but promising, stages of development is the use of biosensors for therapeutic drug monitoring (TDM). Traditionally, TDM could only be performed in certified laboratories and was used in specific scenarios to optimize drug dosage based on measurement of plasma/blood drug concentrations. Although TDM has been typically pursued in settings involving medications that are challenging to manage, the basic approach is useful for characterizing drug activity. TDM is based on the idea that there is likely a clear relationship between plasma/blood drug concentration (or concentration in other matrices) and clinical efficacy. However, these relationships may vary across individuals and may be affected by genetic factors, comorbidities, lifestyle, and diet. TDM technologies will be valuable for enabling precision medicine strategies to determine the clinical efficacy of drugs in individuals, as well as optimizing personalized dosing, especially since therapeutic windows may vary inter-individually. In this mini-review, we discuss emerging TDM technologies and their applications, and factors that influence TDM including drug interactions, polypharmacy, and supplement use. We also discuss how using TDM within single subject (N-of-1) and aggregated N-of-1 clinical trial designs provides opportunities to better capture drug response and activity at the individual level. Individualized TDM solutions have the potential to help optimize treatment selection and dosing regimens so that the right drug and right dose may be matched to the right person and in the right context.

On genome-wide association studies for family-based designs: an integrative analysis approach combining ascertained family samples with unselected controls.

Large numbers of control individuals with genome-wide genotype data are now available through various databases. These controls are regularly used in case-control genome-wide association studies (GWAS) to increase the statistical power. Controls are often "unselected" for the disease of interest and are not matched to cases in terms of confounding factors, making the studies more vulnerable to confounding as a result of population stratification. In this communication, we demonstrate that family-based designs can integrate unselected controls from other studies into the analysis without compromising the robustness of family-based designs against genetic confounding. The result is a hybrid case-control family-based analysis that achieves higher power levels than population-based studies with the same number of cases and controls. This strategy is widely applicable and works ideally for all situations in which both family and case-control data are available. The approach consists of three steps. First, we perform a standard family-based association test that does not utilize the between-family component. Second, we use the between-family information in conjunction with the genotypes from unselected controls in a Cochran-Armitage trend test. The p values from this step are then calculated by rank ordering the individual Cochran-Armitage trend test statistics for the genotype markers. Third, we generate a combined p value with the association p values from the first two steps. Simulation studies are used to assess the achievable power levels of this method compared to standard analysis approaches. We illustrate the approach by an application to a GWAS of attention deficit hyperactivity disorder parent-offspring trios and publicly available controls.

Brain growth rate abnormalities visualized in adolescents with autism.

Autism spectrum disorder is a heterogeneous disorder of brain development with wide ranging cognitive deficits. Typically diagnosed before age 3, autism spectrum disorder is behaviorally defined but patients are thought to have protracted alterations in brain maturation. With longitudinal magnetic resonance imaging (MRI), we mapped an anomalous developmental trajectory of the brains of autistic compared with those of typically developing children and adolescents. Using tensor-based morphometry, we created 3D maps visualizing regional tissue growth rates based on longitudinal brain MRI scans of 13 autistic and seven typically developing boys (mean age/interscan interval: autism 12.0 ± 2.3 years/2.9 ± 0.9 years; control 12.3 ± 2.4/2.8 ± 0.8). The typically developing boys demonstrated strong whole brain white matter growth during this period, but the autistic boys showed abnormally slowed white matter development (P = 0.03, corrected), especially in the parietal (P = 0.008), temporal (P = 0.03), and occipital lobes (P = 0.02). We also visualized abnormal overgrowth in autism in gray matter structures such as the putamen and anterior cingulate cortex. Our findings reveal aberrant growth rates in brain regions implicated in social impairment, communication deficits and repetitive behaviors in autism, suggesting that growth rate abnormalities persist into adolescence. Tensor-based morphometry revealed persisting growth rate anomalies long after diagnosis, which has implications for evaluation of therapeutic effects.

[Mitochondrial DNA heteroplasmy of the m.3243A>G mutation in maternally inherited diabetes and deafness]. / Heteroplasmia de la mutación del ADN mitocondrial m.3243A>G en la diabetes y sordera de herencia materna.

Maternally Inherited Diabetes and Deafness (MIDD) is caused by mutations in mitochondrial DNA (mtDNA), mainly m.3243A>G. Severity, onset and clinical phenotype of MIDD patients are partially determined by the proportion of mutant mitochondrial DNA copies in each cell and tissue (heteroplasmy). The identification of MIDD allows a corred treatment with insulin avoiding drugs that may interfere with mitochondrial electrón chain transpon. We estimated the degree of heteroplasmy of the mutation m.3243A>G from blood, saliva, hair root and a muscle biopsy using quantitative PCR (qPCR) in a femóle adult patient. For this purpose, PCR producís were inserted in a vector creating plasmids with 3243A or G. Mutant and wild-type vectors were mixed in different proportions to créate a calibration curve used to interpólate heteroplasmy percentages with qPCR threshold cycles. The proportions of m.3243A>G heteroplasmy were 62% (muscle), 14% (saliva), 6% (blood leukocytes) and 3% in hair root. Quantitative analysis of heteroplasmy showed marked variations in different tissues (highest in muscle and lowest in blood). Given the relatively high heteroplasmy found in saliva, this type of biológical sample may represent an adequate non-invasive way for assessing the presence of m.3243A>G mutations in epidemiologic studies.

APOA5 Q97X mutation identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family.

BACKGROUND: Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family. METHODS: We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives. RESULTS: A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls. CONCLUSION: The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family.

Does Modulation of an Epigenetic Clock Define a Geroprotector?

There is growing interest in the development of interventions (e.g., drugs, diets, dietary supplements, behavioral therapies, etc.) that can enhance health during the aging process, prevent or delay multiple age-related diseases, and ultimately extend lifespan. However, proving that such 'geroprotectors' do what they are hypothesized to do in relevant clinical trials is not trivial. We briefly discuss some of the more salient issues surrounding the design and interpretation of clinical trials of geroprotectors, including, importantly, how one defines a geroprotector. We also discuss whether emerging surrogate endpoints, such as epigenetic clocks, should be treated as primary or secondary endpoints in such trials. Simply put, geroprotectors should provide overt health and disease prevention benefits but the time-dependent relationships between epigenetic clocks and health-related phenomena are complex and in need of further scrutiny. Therefore, studies that enable understanding of the relationships between epigenetic clocks and disease processes while simultaneously testing the efficacy of a candidate geroprotector are crucial to move the field forward.

Psychometric Properties of a New Stress-Related Personality Scale: The Virtual Inventory of Behavior and Emotions (VIBE).

BACKGROUND: Personality traits are important factors with regard to the tendency to experience and response to stress. This study introduces and tests a new stress-related personality scale called the Virtual Inventory of Behavior and Emotions (VIBE). METHODS: Two samples totaling 5512 individuals (with 66% between the ages of 18 and 34) completed the VIBE along with other measures of personality, stress, mood, and well-being. RESULTS: Exploratory factor analyses revealed a four-factor structure for the instrument with dimensions labeled: 1) stressed; 2) energetic; 3) social; and 4) disciplined. Confirmatory factor analytic procedures on the final 23-item version showed good psychometric properties and data fit while machine learning analyses demonstrated the VIBE's ability to distinguish between groups with similar patterns of response. Strong convergent validity was suggested through robust correlations between the dimensions of the VIBE and other established rating scales. CONCLUSION: Overall, the data suggest that the VIBE is a promising tool to help advance understanding of the relations between stress, personality, and related constructs.

Association between eating behavior scores and obesity in Chilean children.

BACKGROUND: Inadequate eating behavior and physical inactivity contribute to the current epidemic of childhood obesity. The aim of this study was to assess the association between eating behavior scores and childhood obesity in Chilean children. DESIGN AND METHODS: We recruited 126 obese, 44 overweight and 124 normal-weight Chilean children (6-12 years-old; both genders) according to the International Obesity Task Force (IOTF) criteria. Eating behavior scores were calculated using the Child Eating Behavior Questionnaire (CEBQ). Factorial analysis in the culturally-adapted questionnaire for Chilean population was used to confirm the original eight-factor structure of CEBQ. The Cronbach's alpha statistic (>0.7 in most subscales) was used to assess internal consistency. Non-parametric methods were used to assess case-control associations. RESULTS: Eating behavior scores were strongly associated with childhood obesity in Chilean children. Childhood obesity was directly associated with high scores in the subscales "enjoyment of food" (P < 0.0001), "emotional overeating" (P < 0.001) and "food responsiveness" (P < 0.0001). Food-avoidant subscales "satiety responsiveness" and "slowness in eating" were inversely associated with childhood obesity (P < 0.001). There was a graded relation between the magnitude of these eating behavior scores across groups of normal-weight, overweight and obesity groups. CONCLUSION: Our study shows a strong and graded association between specific eating behavior scores and childhood obesity in Chile.

Characterizing Emotional State Transitions During Prolonged Use of a Mindfulness and Meditation App: Observational Study.

BACKGROUND: The increasing demand for mental health care, a lack of mental health care providers, and unequal access to mental health care services have created a need for innovative approaches to mental health care. Digital device apps, including digital therapeutics, that provide recommendations and feedback for dealing with stress, depression, and other mental health issues can be used to adjust mood and ultimately show promise to help meet this demand. In addition, the recommendations delivered through such apps can also be tailored to an individual's needs (ie, personalized) and thereby potentially provide greater benefits than traditional "one-size-fits-all" recommendations. OBJECTIVE: This study aims to characterize individual transitions from one emotional state to another during the prolonged use of a digital app designed to provide a user with guided meditations based on their initial, potentially negative, emotional state. Understanding the factors that mediate such transitions can lead to improved recommendations for specific mindfulness and meditation interventions or activities (MMAs) provided in mental health apps. METHODS: We analyzed data collected during the use of the Stop, Breathe & Think (SBT) mindfulness app. The SBT app prompts users to input their emotional state before and immediately after engaging with MMAs recommended by the app. Data were collected from more than 650,000 SBT users engaging in nearly 5 million MMAs. We limited the scope of our analysis to users with 10 or more MMA sessions that included at least 6 basal emotional state evaluations. Using clustering techniques, we grouped emotions recorded by individual users and then applied longitudinal mixed effect models to assess the associations between individual recommended MMAs and transitions from one group of emotions to another. RESULTS: We found that basal emotional states have a strong influence on transitions from one emotional state to another after MMA engagement. We also found that different MMAs impact these transitions, and many were effective in eliciting a healthy transition but only under certain conditions. In addition, we observed gender and age effects on these transitions. CONCLUSIONS: We found that the initial emotional state of an SBT app user determines the type of SBT MMAs that will have a favorable effect on their transition from one emotional state to another. Our results have implications for the design and use of guided mental health recommendations for digital device apps.

Correction: Association Between Improvement in Baseline Mood and Long-Term Use of a Mindfulness and Meditation App: Observational Study.

[This corrects the article DOI: 10.2196/12617.].

Rethinking a right hemisphere deficit in ADHD.

INTRODUCTION: Early observations from lesion studies suggested right hemisphere (RH) dysfunction in ADHD. However, a strictly right-lateralized deficit has not been well supported. An alternatively view suggests increased R > L asymmetry of brain function and abnormal interhemispheric interaction. If true, RH pathology in ADHD should reflect interhemispherically networked and overactivated functioning. The authors evaluated these assertions. METHOD: Four elements of lateralized brain function were measured: LH specialized, RH specialized, LH with interhemispheric processing (LH/IH), and RH with interhemispheric processing (RH/IH). Next, the authors tested their association with cognitive ability, psychiatric comorbidity, and sibling correlations in 79 children with ADHD. RESULTS: RH/IH processing was uniquely associated with other outcome measures. There were no associations for independent RH or LH function alone. CONCLUSION: Interhemispherically networked RH processing is critical in ADHD. In addition, lack of association between LH specialized processing and cognitive ability (especially for verbal cognitive tasks) supports increased RH mediation of task processing.

Mindfulness and attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a disorder characterized by attentional difficulties. Mindfulness is a receptive attention to present experience. Both ADHD and mindfulness are associated with attention and personality. This study tests whether individuals with ADHD have lower mindfulness scores than controls and, if true, whether personality contributes to these differences. One hundred and five adults (half with ADHD) were assessed for mindfulness, using the Kentucky Inventory of Mindfulness Skills, and personality, using the Tridimensional Character Inventory. Individuals with ADHD report themselves as less mindful than non-ADHD controls and more novelty-seeking, less self-directed, and more self-transcendent. Mindfulness is negatively associated with ADHD and positively associated with self-directedness and self-transcendence. Analyses of subscales of mindfulness suggest that ADHD is associated most with the "Acting in Awareness" dimension, perhaps because of shared items reflecting attentional variability. The current findings support that a large portion of variability in trait mindfulness can be explained by ADHD status and personality traits of self-directedness and self-transcendence. It further suggests that interventions that increase mindfulness might improve symptoms of ADHD and increase self-directedness and/or self-transcendence.

Social functioning difficulties in ADHD: association with PDD risk.

Although social difficulties are a common feature of Attention-Deficit Hyperactivity Disorder (ADHD), little is known about the diversity of social problems, their etiology, or their relationship to disorders of social behavior, such as autism or Pervasive Developmental Disorder (PDD). In 379 children and adolescents with ADHD, social functioning was assessed using the Child Behavior Checklist (Achenbach, 1991). Factor analysis and structural equation modeling revealed two factors that we labeled Peer Rejection and Social Immaturity. A factor reflecting ;PDD risk' was defined from eight items of a separate screening instrument for PDD and examined for its association with these two social factors. There was a significant association with both factors, but the association was much stronger for the Social Immaturity (Standardized Beta [beta ] = .51) than Peer Rejection (beta = .29) factors. Social Immaturity was also associated with a greater number of hyperactive symptoms while high Peer Rejection was associated with increased aggression and lower IQ in the ADHD children.

Association Between Improvement in Baseline Mood and Long-Term Use of a Mindfulness and Meditation App: Observational Study.

BACKGROUND: The use of smartphone apps to monitor and deliver health care guidance and interventions has received considerable attention recently, particularly with regard to behavioral disorders, stress relief, negative emotional state, and poor mood in general. Unfortunately, there is little research investigating the long-term and repeated effects of apps meant to impact mood and emotional state. OBJECTIVE: We aimed to investigate the effects of both immediate point-of-intervention and long-term use (ie, at least 10 engagements) of a guided meditation and mindfulness smartphone app on users' emotional states. Data were collected from users of a mobile phone app developed by the company Stop, Breathe & Think (SBT) for achieving emotional wellness. To explore the long-term effects, we assessed changes in the users' basal emotional state before they completed an activity (eg, a guided meditation). We also assessed the immediate effects of the app on users' emotional states from preactivity to postactivity. METHODS: The SBT app collects information on the emotional state of the user before and after engagement in one or several mediation and mindfulness activities. These activities are recommended and provided by the app based on user input. We considered data on over 120,000 users of the app who collectively engaged in over 5.5 million sessions with the app during an approximate 2-year period. We focused our analysis on users who had at least 10 engagements with the app over an average of 6 months. We explored the changes in the emotional well-being of individuals with different emotional states at the time of their initial engagement with the app using mixed-effects models. In the process, we compared 2 different methods of classifying emotional states: (1) an expert-defined a priori mood classification and (2) an empirically driven cluster-based classification. RESULTS: We found that among long-term users of the app, there was an association between the length of use and a positive change in basal emotional state (4% positive mood increase on a 2-point scale every 10 sessions). We also found that individuals who were anxious or depressed tended to have a favorable long-term emotional transition (eg, from a sad emotional state to a happier emotional state) after using the app for an extended period (the odds ratio for achieving a positive emotional state was 3.2 and 6.2 for anxious and depressed individuals, respectively, compared with users with fewer sessions). CONCLUSIONS: Our analyses provide evidence for an association between both immediate and long-term use of an app providing guided meditations and improvements in the emotional state.

ATM allelic variants associated to hereditary breast cancer in 94 Chilean women: susceptibility or ethnic influences?

Besides BRCA1 and BRCA2, two genes accounting for a small proportion of breast cancer cases, ATM has been widely proposed as a low-penetrance susceptibility gene. Several nucleotide changes have been proposed to be associated with breast cancer, still remaining a high controversy in this sense. We screened the ATM gene in 94 breast cancer patients selected from 78 high-risk families, not presenting a mutation in BRCA1 or BRCA2. We found three novel allelic variants: IVS64 + 51delT and p.L752L, not showing association with hereditary breast cancer, and p.L694L found in one family in two breast cancer patients. Two amino acid substitutions p.S707P and p.F858L, previously reported to be associated with breast cancer, were present in our study in cases and controls, lacking of association with breast cancer. A positive association of c.5557G>A (p.D1853N) was found (OR 2.52, P = 0.008), when analyzed alone and in combination with an intronic variant IVS24-9delT (OR 3.97; P = 0.0003). We postulate that our discrepancies with other reports related to the associated ATM alleles to hereditary breast cancer, as well as discrepancies in the literature between other groups, could be explained by the diversity in the ethnic origins of families gathered in a sole study, and the selection of the control group. In relation to this issue, and based on genetic markers, we found that the Chilean group of breast cancer families in this study has a stronger European genetic component than our control sample selected randomly from the Chilean population.