Clinical and neurogenetic characterisation of autosomal recessive RBL2-associated progressive neurodevelopmental disorder.

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects of RBL2 mutations in detail, we identified and clinically characterized a cohort of 28 patients from 18 families carrying LOF variants in RBL2 , including fourteen new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were uniformly observed, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements and non-specific dysmorphic features. Common neuroimaging features were cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, Drosophila melanogaster , to investigate how disruption of the conserved RBL2 orthologueue Rbf impacts nervous system function and development. We found that Drosophila Rbf LOF mutants recapitulate several features of patients harboring RBL2 variants, including alterations in the head and brain morphology reminiscent of microcephaly, and perturbed locomotor behaviour. Surprisingly, in addition to its known role in controlling tissue growth during development, we find that continued Rbf expression is also required in fully differentiated post-mitotic neurons for normal locomotion in Drosophila , and that adult-stage neuronal re-expression of Rbf is sufficient to rescue Rbf mutant locomotor defects. Taken together, this study provides a clinical and experimental basis to understand genotype-phenotype correlations in an RBL2 -linked neurodevelopmental disorder and suggests that restoring RBL2 expression through gene therapy approaches may ameliorate aspects of RBL2 LOF patient symptoms.

Mean and volatility spillover in Asian economies: Evidence from trade war.

This study aims to assess the mean and volatility spillover due to trade war between US and China on the Asian markets using GARCH, evidencing that portfolio opportunity exists for the investors in these markets. These markets may offer diversification benefits to investors who fear the negative ramifications of stock markets of the economies in US and China. The study creates a composite variable to test the impact of trade war. The composition of the variable is based on Bilateral Tariffs, Trade policy and Economic policy uncertainty of US only. It means the study covers the US side only for creating a trade war variable. The findings of the study reveal no mean or volatility spillover exists. The study has implications for investors and policymakers.

Genomic analysis of multiplex consanguineous families reveals causes of neurodevelopmental disorders with epilepsy.

INTRODUCTION: Neurodevelopmental disorders (NDD) are a diverse group of disorders that affect the development of the nervous system. Epilepsy is a common phenotypic aspect of NDD. METHODS: We recruited eight consanguineous families from Pakistan which segregated recessively inherited NDD with epilepsy. Magnetic Resonance imaging (MRI) and Electroencephalogram (EEG) were completed. Exome sequencing was carried out for selected participants from each family. The exome data were analyzed for exonic and splice-site variants that had allele frequencies of less than 0.01 in public databases. RESULTS: Clinical investigations determined that developmental delay, intellectual disability and seizures were manifested by most patients in early childhood. EEG findings were abnormal in the participants of four families. MRI revealed demyelination orcerebral atrophic changes in multiple participants. We identified four novel homozygous variants including nonsense andmissense variants in OCLN, ALDH7A1, IQSEC2 and COL3A1, segregating with the phenotypes in the participants of four families. Previously reported homozygous variants of CNTNAP2, TRIT1 and NARS1 were found in individuals from three families. Clinical utility was observed in directing treatment in case of patients with an ALDH7A1 variant which included pyridoxine administration and enabling accurate counseling about the natural history and recurrence risk. CONCLUSION: Our results add to the clinical and molecular delineation of very rare NDD with epilepsy. The high success rate of exome sequencing is likely attributable to the expectation of homozygous variants in patients of consanguineous families, and in one case, the availability of positional mapping data that greatly aided the variant prioritization.

MRM2 variants in families with complex dystonic syndromes: evidence for phenotypic heterogeneity.

BACKGROUND: Dystonia involves repetitive movements and muscle contractions leading to abnormal postures. We investigated patients in two families, DYAF11 and M, exhibiting dystonic or involuntary movement disorders. METHODS: Clinical investigations were performed for all patients. Genetic analyses included genome-wide linkage analysis and exome sequencing followed by Sanger sequencing validation. MRM2-specific transcripts were analysed from participants' blood samples in Family DYAF11 after cloning of gene-specific cDNA. RESULTS: Four affected siblings in Family DYAF11 had progressive dystonic features. Two patients in Family M exhibited a neurodevelopmental disorder accompanied by involuntary movements. In Family DYAF11, linkage was detected to the telomere at chromosome 7p22.3, spanning <2 Mb. Exome sequencing identified a donor splice-site variant, c.8+1G>T in MRM2, which segregated with the phenotype, corresponding to the linkage data since all affected individuals were homozygous while the obligate unaffected carriers were heterozygous for the variant. In the MRM2 c.8+1G>T allele, an aberrant alternative acceptor splice-site located within exon 2 was used in a subset of the transcripts, creating a frameshift in the open reading frame. Exome sequencing in Family M revealed a rare missense variant c.242C>T, p.(Ala81Val), which affected a conserved amino acid. CONCLUSIONS: Our results expand the clinical and allelic spectrum of MRM2 variants. Previously, these descriptions were based on observations in a single patient, diagnosed with mitochondrial DNA depletion syndrome 17, in whom movement disorder was accompanied by recurrent strokes and epilepsy. We also demonstrate a subset of correctly spliced tt-ag MRM2 transcripts, raising the possibility to develop treatment by understanding the disease mechanism.