Rare inherited variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES) in two families, each with three affected siblings. We also performed a two-stage follow-up case-control study in a Japanese population. WES of the six affected siblings identified six novel rare missense variations. Among these variations, CLN8 R24H was inherited in one family by three affected siblings from an affected father and thus co-segregated with ASD. In the first stage of the follow-up study, we genotyped the six novel rare missense variations identified by WES in 241 patients and 667 controls (the Niigata sample). Only CLN8 R24H had higher mutant allele frequencies in patients (1/482) compared with controls (1/1334). In the second stage, this variation was further genotyped, yet was not detected in a sample of 309 patients and 350 controls (the Nagoya sample). In the combined Niigata and Nagoya samples, there was no significant association (odds ratio = 1.8, 95% confidence interval = 0.1–29.6). These results suggest that CLN8 R24H plays a role in the genetic etiology of ASD, at least in a subset of ASD patients.

Aims:The oxytocin receptor (OXTR) is implicated in the pathophysiology of autism spectrum disorder (ASD). A recent study found a rare non-synonymous OXTR gene variation, rs35062132 (R376G), associated with ASD in a Japanese population. In order to investigate the association between rare nonsynonymous OXTR variations and ASD, we resequenced OXTR and performed association analysis with ASD in a Japanese population. Methods:We resequenced the OXTR coding region in 213 ASD patients. Rare non-synonymous OXTR variations detected by resequencing were genotyped in 213 patients and 667 controls.Results: We detected three rare non-synonymous variations: rs35062132 (R376G/C), rs151257822 (G334D), and g.8809426G>T (R150S). However, there was no significant association between these rare non-synonymous variations and ASD.Conclusions: Our present study does not support the contribution of rare non-synonymous OXTR variations to ASD susceptibility in the Japanese population.Key words: autism spectrum disorder, Japanese, nonsynonymous variation, OXTR, resequencing.A UTISM SPECTRUM DISORDER (ASD) is marked by social and communication deficits, and the presence of rigid and repetitive behaviors and interests. It is a complex disorder with a heritability of 0.8. 1The peptide hormone oxytocin (OXT) has a role in social functions, such as emotion recognition and feelings of attachment.2 OXT actions are mediated through the OXT receptor (OXTR), which belongs to the class I G-protein coupled receptor family. 3OXT-OXTR signaling has been implicated in ASD pathophysiology. 4 Thus, the OXTR gene is a potential candidate gene for ASD.Several studies have found common non-coding OXTR variations associated with ASD, 5-10 although a recent meta-analysis did not find any association between ASD and two of the most extensively investigated variations, rs53576 and rs2254298, located in intron 3.11 Almost all earlier studies investigated common, and not rare, variations. Recently, Ma et al. 12 demonstrated that a rare non-synonymous variation, rs35062132 (R376G), detected by resequencing of the OXTR coding region in 59 ASD patients and 30 control individuals, was associated with ASD in a Japanese population (132 patients and 248 controls). To confirm the association between rare non-synonymous OXTR variations and ASD, we resequenced the OXTR coding region in 213 ASD

Background: Atomoxetine (ATX) is used as a first-line, non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD), although no studies have systematically examined the relationship between plasma concentration and clinical efficacy. We conducted this non-randomized prospective interventional study to examine the relationship between plasma concentration of ATX and clinical efficacy. Methods: Forty-three ADHD pediatric patients received ATX, and the steady-state through plasma concentration of the last daily dose that was maintained for at least 4 weeks were determined by high-performance liquid chromatography. Results: The receiver operating characteristic curve suggested that when plasma concentration exceeded 64.60 ng/mL, scores on the ADHD-Rating Scale improved by 50% or more ( P = .14). Although 6 of the 8 final responders were unresponsive at the initial dose (.72 ± .04 mg/kg [mean ± standard deviation]), they responded after increasing the ATX dose to the final dose (1.52 ± .31 mg/kg). Excluding 7 outlier participants, the concentration was 83.3 ± 32.3 ng/mL in 7 responders and was significantly higher than 29.5 ± 23.9 ng/mL ( P < .01) for the 29 non-responders. Conclusions: These results suggest that a minimum effective plasma concentration of ATX is required to achieve sufficient clinical efficacy. We hypothesized a mechanism that results in the realization of a clinical effect when the plasma concentration exceeds a certain threshold in the potential response group, whereas will not improve even if the plasma concentration is increased in the unqualified non-responder group.

Aims: Rare heterozygous truncating variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare heterozygous truncating variations, we performed whole-exome sequencing (WES) in a mul-tiplex ASD family with four affected individuals (two siblings and two maternal cousins), and a follow-up case-control study in a Japanese population. Methods: WES was performed in four individuals (a proband, his affected and unaffected siblings, and their putative carrier mother) from the multiplex ASD family. Rare heterozygous truncating variations prioritized in WES were genotyped in 243 patients and 667 controls. Results: By WES of the multiplex family, we prioritized two rare heterozygous truncating variations, RPS24 Q191X and CD300LF P261fsX266. However, we did not identify these variations in patients or controls in the follow-up study. Conclusions: Our findings suggest that two rare heterozygous truncating variations (RPS24 Q191X and CD300LF P261fsX266) are risk candidates for ASD. A UTISM SPECTRUM DISORDER (ASD) is a neurodevelopmental disorder marked by social and communication deficits, and the presence of rigid and repetitive behaviors and interests. ASD is a complex disorder with an estimated heri-tability of 52.4%, mostly due to common variations, although rare variations also contribute substantially to ASD liability. 1 Whole-exome sequencing (WES) studies of proband-parent trios show that rare de novo mutations play an important role in the genetic etiology of ASD. 2-5 Similarly, WES of multiplex families suggest that rare inherited variations contribute to the genetic etiology of ASD. 6,7 In consanguineous families, homozygous and compound heterozygous variations co-segregate with ASD. 6 In 10 multiplex ASD families, the number of heterozygous truncating variations transmitted to the affected siblings was significantly higher than those not transmitted. 7 To further investigate the role of rare heterozy-gous truncating variations in the genetic etiology of ASD, we performed WES in a multiplex ASD family

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