Maya Yaari

Low CD38 expression in lymphoblastoid cells and haplotypes are both associated with autism in a family-based study.

Background: Impairments in social processes characterize one of the core deficits in autism spectrum disorders (ASD) and accumulating evidence suggests that oxytocin neurotransmission is implicated in mediating social adaptation in ASD. Using a mouse model, CD38, a transmembrane protein expressed in immune cells but also in brain, was found to be critical for social behavior via regulation of oxytocin secretion. This prompted us to both examine CD38 expression in human lymphoblastoid cell lines (LBC) as well as to test association between SNPs across the CD38 gene and ASD. Methods: LBCs were derived from 44 ASD lines and 40 “unaffected” parents. Family‐based association (UNPHASED) was examined by genotyping 11 tagging SNPs spanning the CD38 gene identified using HapMap data in 170 trios. An additional SNP (rs3796863) associated in a study by Munesue et al. with ASD was also genotyped. Results: A highly significant reduction in CD38 expression was observed in immortalized lymphocytes derived from ASD subjects compared to their “unaffected” parents (F = 17.2, P = 0.00024, df = 1). Haplotype analysis showed significant association (permutation corrected) between three and seven locus haplotypes and DSM IV ASD in low functioning (IQ<70) subjects. Conclusions: The current report supports a role for CD38 in conferring risk for ASD. Notably, our study shows that this gene is not only associated with low functioning ASD but that CD38 expression is markedly reduced in LBC derived from ASD subjects compared to “unaffected” parents, strengthening the connection between oxytocin and ASD.

All-trans Retinoic Acid Upregulates Reduced CD38 Transcription in Lymphoblastoid Cell Lines from Autism Spectrum Disorder.

Deficits In social behavior In mice lacking the CD38 gene have been attributed to Impaired secretion of oxytocin. In humans, similar deficits in social behavior are associated with autistic spectrum disorder (ASD), for which genetic variants of CD38 have been pinpointed as provisional risk factors. We sought to explore, in an in vitro model, the feasibility of the theory that restoring the level of CD38 in ASD patients could be of potential clinical benefit. CD38 transcription is highly sensitive to several cytokines and vitamins. One of these, all-trans retinoic acid (ATRA), a known inducer of CD38, was added during cell culture and tested on a large sample of N = 120 lymphoblastoid cell (LBC) lines from ASD patients and their parents. Analysis of CD38 mRNA levels shows that ATRA has an upmodulatory potential on LBC derived from ASD patients as well as from their parents. The next crucial issue addressed in our study was the relationship between levels of CD38 expression and psychological parameters. The results obtained indicate a positive correlation between CD38 expression levels and patient scores on the Vineland Adaptive Behavior Scale. In addition, analysis of the role of genetic polymorphisms in the dynamics of the molecule revealed that the genotype of a single-nucleotide polymorphism (rs6449182; C>G variation) in the CpG island of intron 1, harboring the retinoic-acid response element, exerts differential roles in CD38 expression in ASD and in parental LBC. In conclusion, our results provide an empirical basis for the development of a pharmacological ASD treatment strategy based on retinoids.

Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression

Recent work has led to the identification of several susceptibility genes for autism spectrum disorder (ASD) and an increased appreciation of the importance of rare and de novo mutations. Some of the mutations may be very hard to detect using current strategies, especially if they are located in regulatory regions. We present a new approach to identify functional mutations that exploit the fact that many rare mutations disrupt the expression of genes from a single parental chromosome. The method incorporates measurement of the relative expression of the two copies of a gene across the genome using single nucleotide polymorphism arrays. Allelic expression has been successfully used to study common regulatory polymorphisms; however, it has not been implemented as a screening tool for rare mutation. We tested the potential of this approach by screening for monoallelic expression in lymphoblastoid cell lines derived from a small ASD cohort. After filtering regions shared across multiple samples, we identified genes showing monoallelic expression in specific ASD samples. Validation by quantitative sequencing demonstrated that the genes (or only part of them) are monoallelic expressed. The genes included both previously suspected risk factors for ASD and novel candidates. In one gene, named autism susceptibility candidate 2 (AUTS2), we identified a rare duplication that is likely to be the cause of monoallelic expression. Our results demonstrate the ability to identify rare regulatory mutations using genome-wide allelic expression screens, capabilities that could be expanded to other diseases, especially those with suspected involvement of rare dominantly acting mutations.

Stability of early risk assessment for autism spectrum disorder in preterm infants

Stability and change in early autism spectrum disorder risk were examined in a cohort of 99 preterm infants (⩽34 weeks of gestation) using the Autism Observation Scale for Infants at 8 and 12 months and the Autism Diagnostic Observation Schedule—Toddler Module at 18 months. A total of 21 infants were identified at risk by the Autism Observation Scale for Infants at 8 months, and 9 were identified at risk at 12 months, including 4 children who were not previously identified. At 18 months, eight children were identified at risk for autism spectrum disorder using the Autism Diagnostic Observation Schedule—Toddler Module, only half of whom had been identified using the original Autism Observation Scale for Infants cutoffs. Results are discussed in relation to early trajectories of autism spectrum disorder risk among preterm infants as well as identifying social-communication deficiencies associated with the early preterm behavioral phenotype.

Social impairments among children perinatally exposed to oxytocin or oxytocin receptor antagonist

• The perinatal effects of Oxytocin (OT) and Tractocile (OT antagonist) were examined within the same sample.

Developmental assessment of preterm infants: Chronological or corrected age?

The aim of this study is to examine the effect of age correction on the developmental assessment scores of preterm infants, using for the first time, the Mullen scales of early learning (MSEL) test. Participants included 110 preterm infants (born at a gestational age of ≤ 34 weeks) at ages 1, 4, 8, 12, 18, 24 and 36 months. The corrected age-based MSEL composite score and each of the five MSEL scale scores were significantly higher than chronological age-based scores at all ages. These corrected scores were significantly higher than the chronological scores regardless of gestational age whether weight was, or adequate or small for gestational age. Larger differences between corrected and chronological age-based scores significantly correlated with earlier gestational age and with lower birth weight between 1 and 24 months but not at 36 months. Using chronological age-based scores yielded significantly more infants identified with developmental delays than using corrected age-based scores. The findings indicate that clinicians and researchers, as well as family members, should be aware of and acknowledge the distinction between corrected and chronological ages when evaluating preterm infants in research and clinical practices.

Maternal resolution of preterm birth from 1 to 18 months

ABSTRACT Preterm birth can be traumatic for some mothers, involving feelings of grief over the hoped-for full-term pregnancy. In this longitudinal study, we interviewed 50 mothers of preterm infants, using the reaction to diagnosis interview when their child was 1 month and 18 months old. We examined change and stability in resolution status over time. Additionally, we explored possible predictors of resolution trajectories between 1 and 18 months. Findings indicated that resolution at 1 month was not yet common. The rate of resolution at 18 months was 62.6%, compared with 38.2% at 1 month. Prenatal precursors of preterm birth, lower medical neonatal risk, and lower maternal stress at 1 month significantly differentiated mothers who attained resolution as early as at 1 month from those who were unresolved at 1 and 18 months. Lower maternal stress at 1 month was the only predictor that significantly differentiated initially unresolved mothers who later attained resolution from those who remained unresolved at 18 months. Discussion focuses on maternal stress, which may mark a subgroup of mothers of preterm infants who are at risk of being unresolved through the first 18 months, and who may benefit from resolution-focused intervention.

The Mullen scales of early learning: ceiling effects among preschool children

Two cognitive tests were administered to typically developing children (36–67 months): the Mullen Scales of Early Learning (MSEL), which is appropriate for very young children and thus often used in research with atypical samples (e.g., children with Autism Spectrum Disorder), and the Kaufman Assessment Battery for Children (K-ABC). This was done in order to re-examine possible MSEL ceiling effects in a new sample and achieve a more in-depth understanding of these ceiling effects, if indeed present. Results indicated that among children ranging in age from 51 to 68 months, MSEL scores were significantly lower than K-ABC scores, and that with increasing age the number of children who completed the MSEL without establishing a ceiling level increased. Our results indicated that the MSEL scores are affected by ceiling effects and, therefore, the test underestimates cognitive abilities among older and more cognitively able children.

Cognitive and social-communication abilities among young children conceived by assisted reproductive technologies

Abstract Assisted reproductive technologies (ART) lack biological filters that are part of the natural fertilization process and thus might enable the presence of abnormal genetic materials. Whereas the findings regarding neonatal and neurological risks among ART-conceived children are rather consistent, data regarding cognitive and social-emotional developmental outcomes are inconsistent. The aim of this study was to examine the association between ART and cognitive and social-communication outcomes among pre-school children. The results indicated that the cognitive and social-communicative abilities of the ART-conceived children were similar to those of the spontaneously conceived children; however, according to parental reports, children in the ART group had higher communicative skills and better motor abilities than spontaneously conceived children. These results should be interpreted with caution as we used measures that assess global cognitive abilities that may not be sensitive to more subtle differences of higher cognitive and social-communication abilities in infancy that may become more prominent later in life. Although infertile couples and professionals in the field of ART can be reassures by the current findings, further research is needed as well as follow-up evaluation of this population during school age.