Functional Assessment In Vivo of the Mouse Homolog of the Human Ala-9-Ser NHE6 Variant.

Christianson syndrome (CS) is an X-linked neurogenetic disorder resulting from loss-of-function (LoF) mutations in SLC9A6, which encodes the endosomal Na+/H+ exchanger 6 (NHE6). NHE6 regulates proton efflux from endosomes and, thus, participates in regulating cargo processing and trafficking. LoF mutations in NHE6 cause aberrant acidification of endosomes. While CS arises in males generally due to clear LoF mutations, other potentially hypomorphic variants have emerged, yet most of these variants have not been evaluated for functional effects, particularly in vivo Here we characterize an SLC9A6 variant that has been previously reported in patients, yet now also appears in exome datasets of largely control individuals-c.25G>T, p.A9S. By heterologous expression in cell lines, we show that human NHE6A9S is expressed and localizes in a manner comparable to control NHE6. By genome editing, we generated the equivalent NHE6 mutation in mouse-p.A11S-and determined that male NHE6A11S mice have normal brain size at 6 months of age and do not show cerebellar degeneration or defective neuronal arborization. Neurons from male NHE6A11S mice also did not demonstrate an abnormality in intraendosomal pH compared with controls. These findings are in contrast to findings in NHE6-null mice previously reported and indicate that the NHE6A11S variant functions at a level equivalent to control NHE6 for many of the assays performed. These data stand in support of the population genetic data, which are also evaluated here, indicating that the A9S variant is unlikely to confer disease susceptibility with high penetrance.

Observation-centered approach to ASD assessment in Tanzania.

Abstract In many lower-income countries, there is a paucity of assessment services for autism spectrum disorders (ASD)., Guidelines will be provided for conducting cross-cultural assessments in the context of limited validated resources in Tanzania. By examining behavioral, social, and adaptive differences we were able to provide differential diagnostic evaluations aligning with best practice standards for 41 children in Tanzania age 2-21 years. We describe the utility of a flexible, behavioral observation instrument, the Childhood Autism Rating Scales, Second Edition (CARS2), to gather diagnostic information in a culturally sensitive manner. We observed that the ASD group was characterized by significantly higher scores on the CARS2, F  =  21.09, p < .001, η(2)  =  .37, than the general delay comparison group. Additional recommendations are provided for making cultural adaptations to current assessment instruments for use in a country without normed instruments, such as Tanzania.

Risk assessment models in genetics clinic for array comparative genomic hybridization: Clinical information can be used to predict the likelihood of an abnormal result in patients.

Array comparative genomic hybridization (aCGH) testing can diagnose chromosomal microdeletions and duplications too small to be detected by conventional cytogenetic techniques. We need to consider which patients are more likely to receive a diagnosis from aCGH testing versus patients that have lower likelihood and may benefit from broader genome wide scanning. We retrospectively reviewed charts of a population of 200 patients, 117 boys and 83 girls, who underwent aCGH testing in Genetics Clinic at Rhode Island hospital between 1 January/2008 and 31 December 2010. Data collected included sex, age at initial clinical presentation, aCGH result, history of seizures, autism, dysmorphic features, global developmental delay/intellectual disability, hypotonia and failure to thrive. aCGH analysis revealed abnormal results in 34 (17%) and variants of unknown significance in 24 (12%). Patients with three or more clinical diagnoses had a 25.0% incidence of abnormal aCGH findings, while patients with two or fewer clinical diagnoses had a 12.5% incidence of abnormal aCGH findings. Currently, we provide families with a range of 10-30% of a diagnosis with aCGH testing. With increased clinical complexity, patients have an increased probability of having an abnormal aCGH result. With this, we can provide individualized risk estimates for each patient.