Purpose: Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11–13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients’ phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype. Methods: Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2, 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant. Results: All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990–1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints. Conclusion: This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families. Genet Med 19 1, 45–52.

The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.1 microdeletion syndrome have been reported in the literature; however, the size of the deletions and their breakpoints vary, making it difficult to identify the candidate genes. Recent reports pointed to 4 genes ( XPO1 , USP34 , BCL11A , and REL ) that were included, alone or in combination, in the smallest deletions causing the syndrome. Here, we describe 8 new patients with the 2p15p16.1 deletion and review all published cases to date. We demonstrate functional deficits for the above 4 candidate genes using patients’ lymphoblast cell lines (LCLs) and knockdown of their orthologs in zebrafish. All genes were dosage sensitive on the basis of reduced protein expression in LCLs. In addition, deletion of XPO1 , a nuclear exporter, cosegregated with nuclear accumulation of one of its cargo molecules (rpS5) in patients’ LCLs. Other pathways associated with these genes (e.g., NF-κB and Wnt signaling as well as the DNA damage response) were not impaired in patients’ LCLs. Knockdown of xpo1a , rel , bcl11aa , and bcl11ab resulted in abnormal zebrafish embryonic development including microcephaly, dysmorphic body, hindered growth, and small fins as well as structural brain abnormalities. Our multifaceted analysis strongly implicates XPO1 , REL , and BCL11A as candidate genes for 2p15p16.1 microdeletion syndrome.

Although mice locate resources using turbulent airborne odor plumes, the stochasticity and intermittency of fluctuating plumes create challenges for interpreting odor cues in natural environments. Population activity within the olfactory bulb (OB) is thought to process this complex spatial and temporal information, but how plume dynamics impact odor representation in this early stage of the mouse olfactory system is unknown. Limitations in odor detection technology have made it difficult to measure plume fluctuations while simultaneously recording from the mouse's brain. Thus, previous studies have measured OB activity following controlled odor pulses of varying profiles or frequencies, but this approach only captures a subset of features found within olfactory plumes. Adequately sampling this feature space is difficult given a lack of knowledge regarding which features the brain extracts during exposure to natural olfactory scenes. Here we measured OB responses to naturally fluctuating odor plumes using a miniature, adapted odor sensor combined with wide-field GCaMP6f signaling from the dendrites of mitral and tufted (MT) cells imaged in olfactory glomeruli of head-fixed mice. We precisely tracked plume dynamics and imaged glomerular responses to this fluctuating input, while varying flow conditions across a range of ethologically-relevant values. We found that a consistent portion of MT activity in glomeruli follows odor concentration dynamics, and the strongest responding glomeruli are the best at following fluctuations within odor plumes. Further, the reliability and average response magnitude of glomerular populations of MT cells are affected by the flow condition in which the animal samples the plume, with the fidelity of plume following by MT cells increasing in conditions of higher flow velocity where odor dynamics result in intermittent whiffs of stronger concentration. Thus, the flow environment in which an animal encounters an odor has a large-scale impact on the temporal representation of an odor plume in the OB. Additionally, across flow conditions odor dynamics are a major driver of activity in many glomerular networks. Taken together, these data demonstrate that plume dynamics structure olfactory representations in the first stage of odor processing in the mouse olfactory system.

Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (RELN, SHANK2, DLG1, SCN10A, KMT2C and ASH1L). All are shared among the three children, except ASH1L, which is only present in the most severely affected child. The compound heterozygous variants in RELN, and the maternally inherited variant in SHANK2, are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. DLG1 is also involved in synapse functions, and KMT2C and ASH1L are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs.

Long-term outcomes of perinatal exposure to maternal antiretroviral therapy in HIV-exposed uninfected (HEU) children are unknown. However, both HIV antiretroviral therapy and autism spectrum disorder (ASD) have been associated with mitochondrial alterations. Leukocyte mitochondrial DNA (mtDNA) content can serve as a marker for mitochondrial dysfunction. In this cross-sectional, nested case-control study, HEU children with ASD were matched approximately 1:3 on age, sex, and ethnicity to HEU children without ASD, HIV-unexposed uninfected (HUU) controls, and HUU children with ASD. Leukocyte mtDNA content was measured using quantitative PCR. Among 299 HEU in this study, 14 (4.7%) were diagnosed with ASD, which is higher than the general population prevalence estimates. HEU children without ASD and HUU children with ASD had higher mtDNA content than HUU controls. HEU children with ASD had significantly higher mtDNA content than all other study groups. Our results suggest a clear association between elevated leukocyte mtDNA content and both HEU and ASD status. This may implicate mitochondrial dysfunction as a contributor to the high ASD prevalence observed in our cohort.