Preliminary Evaluation Of Psychoeducational Support Interventions On Quality Of Life In Rural Breast Cancer Survivors After Primary Treatment

Although most cancer survivors are at risk for being lost in the transition from treatment to survivorship, rural breast cancer survivors face special challenges that might place them at particular risk. This small-scale preliminary study had 2 specific aims: (aim 1) establish the feasibility of rural breast cancer survivors participation in a longitudinal quality of life (QOL) intervention trial and (aim 2) determine the effects of the Breast Cancer Education Intervention (BCEI) on overall QOL. Fifty-three rural breast cancer survivors were randomized to either an experimental (n = 27) or a wait-control arm (n = 26). Participants in the experimental arm received the BCEI consisting of 3 face-to-face education and support sessions and 2 face-to-face and 3 telephone follow-up sessions, along with supplemental written and audiotape materials over a 6-month period. Breast Cancer Education Intervention modules and interventions are organized within a QOL framework. To address the possible effects of attention, wait-control participants received 3 face-to-face sessions and 3 telephone sessions during the first 6 months of participation in the study, but not the BCEI intervention. Research questions addressing aim 1 were as follows: (a) can rural breast cancer survivors be recruited into a longitudinal intervention trial, and (b) can their participation be retained. Research questions for aim 2 were as follows: (a) do participants who received the BCEI show improvement in overall QOL, and (b) is the QOL improvement sustained over time. Data were analyzed using repeated-measures general linear mixed models. Results demonstrated the ability to recruit and retain 53 rural breast cancer survivors, that the experimental arm showed improvement in overall QOL (P = .013), and that there were significant differences in overall QOL between the experimental and wait-control groups at both months 3 and 6. Thus, it appears that at least some rural breast cancer survivors can and will participate in a larger trial and will maintain their participation and that those that do participate experience significant QOL benefit. Copyright © 2009 Lippincott Williams & Wilkins

HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder

Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders. [Display omitted] We identified genetic variants of HNRNPC in 13 individuals with intellectual disability and global developmental delay. Through a meta-analysis of multiple cell types, we found that loss of HNRNPC affects alternative splicing, in particular of intellectual disability-associated genes. In vivo assays confirmed that neurodevelopment was affected by aberrant HNRNPC levels

Correction to: An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids (Genetics in Medicine, (2021), 23, 4, (740-750), 10.1038/s41436-020-01027-3)

In the original author list, Seth Perlman’s degrees were listed as MD, PhD. Dr Perlman’s degree is MD. The original version has been corrected

An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

Purpose: In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu). Methods: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients’ fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics. Results: All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients’ fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production. Conclusion: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly

Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 (H3K4) and has not been implicated in human disease. We identify five unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and two missense variants were identified in probands with neurodevelopmental symptoms including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models. Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles. Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder. Huang et al. report the first functional validation of candidate pathological variants in RBBP5. We present three truncating p.(K244Nfs*6), p.(W254*), p.(R307*) and two missense p.(T232I), p.(E296D) variants found de novo in affected individuals sharing phenotypes including microcephaly and short stature. RBBP5 is a core member of the COMPASS complex responsible for H3 lysine 4 methylation to activate developmental target genes (COMPASS complex adapted from Namitz et al., 2023). Differentiation of neural stem cells in humans and neuroblasts in Drosophila is conserved allowing for the study of neural development in the fly model organism (neural stem cell/neuroblast differentiation diagram adapted from Kim and Hirth, 2009). We used overexpression and rescue experiments to characterize the missense variants in the fly. Neural progenitor populations were evaluated in the larval brain and tissue specific phenotypes were quantified using adult eye and wing morphology studies. We identify that the truncating and missense variants are loss-of-function alleles. As additional patients are identified, the full phenotypic spectrum of RBBP5-related disorders will be elucidated. Created with Biorender.com. [Display omitted

Dominant negative variants in IKZF2 cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay

BackgroundHelios (encoded by IKZF2), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and immune function. Although predominantly recognised for its role in the development and function of T lymphocytes, particularly the CD4+ regulatory T cells (Tregs), the expression and function of Helios extends beyond the immune system. During embryogenesis, Helios is expressed in a wide range of tissues, making genetic variants that disrupt the function of Helios strong candidates for causing widespread immune-related and developmental abnormalities in humans.MethodsWe performed detailed phenotypic, genomic and functional investigations on two unrelated individuals with a phenotype of immune dysregulation combined with syndromic features including craniofacial differences, sensorineural hearing loss and congenital abnormalities.ResultsGenome sequencing revealed de novo heterozygous variants that alter the critical DNA-binding zinc fingers (ZFs) of Helios. Proband 1 had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios (p.Gly136_Ser191dup) and Proband 2 had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios (p.Gly153Arg). Functional studies confirmed that both these variant proteins are expressed and that they interfere with the ability of the wild-type Helios protein to perform its canonical function—repressing IL2 transcription activity—in a dominant negative manner.ConclusionThis study is the first to describe dominant negative IKZF2 variants. These variants cause a novel genetic syndrome characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay

Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1 beta subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder