Commentary: Sex difference differences? A reply to Constantino Dr Meng-Chuan Lai

Messinger et al. found a 3.18 odds ratio of male to female ASD recurrence in 1241 prospectively followed high-risk (HR) siblings. Among high-risk siblings (with and without ASD), as well as among 583 low-risk controls, girls exhibited higher performance on the Mullen Scales of Early Learning, as well as lower restricted and repetitive behavior severity scores on the Autism Diagnostic Observation Schedule (ADOS) than boys. That is, female-favoring sex differences in developmental performance and autism traits were evident among low-risk and non-ASD high-risk children, as well as those with ASD. Constantino (Mol Autism) suggests that sex differences in categorical ASD outcomes in Messinger et al. should be understood as a female protective effect. We are receptive to Constantino's (Mol Autism) suggestion, and propose that quantitative sex differences in autism-related features are keys to understanding this female protective effect

Play and Developmental Outcomes in Infant Siblings of Children with Autism

We observed infant siblings of children with autism later diagnosed with ASD (ASD siblings; n = 17), infant siblings of children with autism with and without other delays (Other Delays and No Delays siblings; n = 12 and n = 19, respectively) and typically developing controls (TD controls; n = 19) during a free-play task at 18 months of age. Functional, symbolic, and repeated play actions were coded. ASD siblings showed fewer functional and more non-functional repeated play behaviors than TD controls. Other Delays and No Delays siblings showed more non-functional repeated play than TD controls. Group differences disappeared with the inclusion of verbal mental age. Play as an early indicator of autism and its relationship to the broader autism phenotype is discussed

Behavioral Profiles of Affected and Unaffected Siblings of Children with Autism: Contribution of Measures of Mother–Infant Interaction and Nonverbal Communication

We investigated whether deficits in social gaze and affect and in joint attention behaviors are evident within the first year of life among siblings of children with autism who go on to be diagnosed with autism or ASD (ASD) and siblings who are non-diagnosed (NoASD-sib) compared to low-risk controls. The ASD group did not differ from the other two groups at 6 months of age in the frequency of gaze, smiles, and vocalizations directed toward the caregiver, nor in their sensitivity to her withdrawal from interaction. However, by 12 months, infants in the ASD group exhibited lower rates of joint attention and requesting behaviors. In contrast, NoASD-sibs did not differ from comparison infants on any variables of interest at 6 and 12 months

Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11–q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3×10−5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10−4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10−39), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts

Common genetic variants on 5p14.1 associate with autism spectrum disorders

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10−8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10−8 to 2.1 × 10−10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs

The Effect of Comprehension Feedback and Listener Age on Speech Complexity

Forty college-aged participants told a story and gave verbal walking directions to either a same-age peer or a 75-year-old adult. The listeners gave some participants comprehension feedback and gave other participants mixed comprehension and noncomprehension feedback. Analyses examined length of utterance immediately preceding or following feedback cues. Participants did not globally simplify their speech when talking to the older compared with the young adult. However, speech was sensitive to comprehension feedback from both listeners, and listener age affected speech complexity by influencing the magnitude of this fine tuning effect. Participants simplified their speech more in response to feedback cues from the older than the young listener. Taken together, these results suggest that fine tuning applies to conversations between adults and speech accommodations may be further “fine tuned” based on other factors such as listener age

B-lymphoblastic leukemia/lymphoma arising in treated plasma cell myeloma: A rare second malignancy

Plasma cell myeloma (PCM) is a neoplasm of plasma cells, end-stage post germinal center B cells, which shows a variable clinical spectrum from asymptomatic to aggressive; the nature of the disease is generally progressive. Rarely, leukemia arises treated plasma cell myeloma. Acute myeloid leukemia/Myelodysplastic syndrome (AML/MDS) is most common, but rare cases of B lymphoblastic leukemia/lymphoma (B-ALL) have been described. The diagnosis of transformation or secondary B-ALL is supported by ancillary studies such as flow cytometry, immunohistochemistry, and molecular studies. Once the diagnosis of a B-ALL is made, consideration should is given as to whether the malignancy is a clonally related transformation of the original PCM or treatment related second leukemia. We present a case of B-ALL after PCM which does not appear to show a clonal relationship with the original PCM suggesting a treatment related B-ALL