PurposeTo describe the presentation of Best Vitelliform Macular Dystrophy (BVMD) as a unilateral maculopathy with bilateral retinal pigment epithelium (RPE) reduced function secondary to molecular changes or variants in BEST1 gene.MethodsRetrospective case series.ResultsBoth patients exhibited unilateral anatomical changes during fundus examination caused by pathogenic variants in BEST1. These changes were also evident in fundus autofluorescence (FAF) and optical coherence tomography (OCT) images. However, both patients displayed evidence of global RPE dysfunction, which was confirmed by a reduced light peak-to-dark trough amplitude ratio (LP: DT ratio) on the electrooculogram (EOG).ConclusionAutosomal dominant variants in the BEST1 gene can manifest as unilateral disease. In such cases, it is important to conduct genetic testing promptly to confirm the presence of bestrophinopathy. When counseling the patient, it is essential to discuss the potential for future anatomical involvement in the unaffected eye.

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 been described in only 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 35 patients from 20 families carrying pLOF variants in RBL2, including 15 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 observed uniformly, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Disrupted sleep was also evident in some patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements, seizures and non-specific dysmorphic features. Neuroimaging features included 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 orthologue Rbf impacts nervous system function and development. We found that Drosophila Rbf LOF mutants recapitulate several features of patients harbouring RBL2 variants, including developmental delay, alterations in head and brain morphology, locomotor defects and perturbed sleep. Surprisingly, in addition to its known role in controlling tissue growth during development, we found 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, our 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 might ameliorate some symptoms caused by RBL2 pLOF. RBL2 dysfunction, which disrupts cell-cycle gene expression, has been linked to a severe neurodevelopmental disorder. Aughey et al. characterize a cohort of patients carrying loss-of-function mutations in RBL2, identifying novel molecular variants and clinical features, and gaining mechanistic insights through a fruit fly model.

Purpose: Nonerythrocytic alpha II-spectrin (SPTAN1) variants have been previously associated with intellectual disability and epilepsy. We conducted this study to delineate the phenotypic spec-trum of SPTAN1 variants.Methods: We carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Functional studies were performed on fibroblasts from 2 patients. Results: Statistically significant enrichment of rare (minor allele frequency < 1 x 10-5) probably damaging SPTAN1 variants was identified in families with hereditary ataxia (HA) or hereditary spastic paraplegia (HSP) (12/1142 cases vs 52/23,847 controls, p = 2.8 x 10-5). We identified 31 individuals carrying SPTAN1 heterozygous variants or deletions. A total of 10 patients presented with pure or complex HSP/HA. The remaining 21 patients had developmental delay and seizures. Irregular alpha II-spectrin aggregation was noted in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants.Conclusion: We found that SPTAN1 is a genetic cause of neurodevelopmental disorder, which we classified into 3 distinct subgroups. The first comprises developmental epileptic encepha-lopathy. The second group exhibits milder phenotypes of developmental delay with or without seizures. The final group accounts for patients with pure or complex HSP/HA.(c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

AIMS:To identify differential expression of shorter non-coding RNA (ncRNA) genes associated with autism spectrum disorders (ASD). BACKGROUND:ncRNA are functional molecules that derive from non-translated DNA sequence. The HUGO Gene Nomenclature Committee (HGNC) have approved ncRNA gene classes with alignment to the reference human genome. One subset is microRNA (miRNA), which are highly conserved, short RNA molecules that regulate gene expression by direct post-transcriptional repression of messenger RNA. Several miRNA genes are implicated in the development and regulation of the nervous system. Expression of miRNA genes in ASD cohorts have been examined by multiple research groups. Other shorter classes of ncRNA have been examined less. A comprehensive systematic review examining expression of shorter ncRNA gene classes in ASD is timely to inform the direction of research. METHODS:We extracted data from studies examining ncRNA gene expression in ASD compared with non-ASD controls. We included studies on miRNA, piwi-interacting RNA (piRNA), small NF90 (ILF3) associated RNA (snaR), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), transfer RNA (tRNA), vault RNA (vtRNA) and Y RNA. The following electronic databases were searched: Cochrane Library, EMBASE, PubMed, Web of Science, PsycINFO, ERIC, AMED and CINAHL for papers published from January 2000 to May 2022. Studies were screened by two independent investigators with a third resolving discrepancies. Data was extracted from eligible papers. RESULTS:Forty-eight eligible studies were included in our systematic review with the majority examining miRNA gene expression alone. Sixty-four miRNA genes had differential expression in ASD compared to controls as reported in two or more studies, but often in opposing directions. Four miRNA genes had differential expression in the same direction in the same tissue type in at least 3 separate studies. Increased expression was reported in miR-106b-5p, miR-155-5p and miR-146a-5p in blood, post-mortem brain, and across several tissue types, respectively. Decreased expression was reported in miR-328-3p in bloods samples. Seven studies examined differential expression from other classes of ncRNA, including piRNA, snRNA, snoRNA and Y RNA. No individual ncRNA genes were reported in more than one study. Six studies reported differentially expressed snoRNA genes in ASD. A meta-analysis was not possible because of inconsistent methodologies, disparate tissue types examined, and varying forms of data presented. CONCLUSION:There is limited but promising evidence associating the expression of certain miRNA genes and ASD, although the studies are of variable methodological quality and the results are largely inconsistent. There is emerging evidence associating differential expression of snoRNA genes in ASD. It is not currently possible to say whether the reports of differential expression in ncRNA may relate to ASD aetiology, a response to shared environmental factors linked to ASD such as sleep and nutrition, other molecular functions, human diversity, or chance findings. To improve our understanding of any potential association, we recommend improved and standardised methodologies and reporting of raw data. Further high-quality research is required to shine a light on possible associations, which may yet yield important information.

We investigated whether Father Christmas has a distinguishable facial phenotype by performing a cross-sectional cohort study examining the facial feature vectors of all publicly available photographs obtained from a google image search of individuals meeting our eligibility criteria presenting as Father Christmas compared with other adult and elderly bearded men. Facial feature vectors were determined using the open-source OpenFace facial recognition system and assessed by support vector machines (SVM). SVM classifiers were trained to distinguish between the facial feature vectors from our groups. Accuracy, precision, and recall results were calculated and the area under the curve (AUC) of the receiver operating characteristic (ROC) were reported for each classifier. SVM classifiers were able to distinguish the face of Father Christmas from other adult men with a high degree of accuracy and could discriminate Father Christmas from elderly bearded men but with lower accuracy. Father Christmas appears to have a distinct facial phenotype when compared to adult men and elderly bearded men. This will be reassuring to children who may be keen to recognise him but raises some interesting questions about the careful use of two-dimensional facial analysis, particularly when employed to explore the relationships between genotype and facial phenotype in a clinical dysmorphology setting.

PurposeThis study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants.MethodsIndividuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope.ResultsWe reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies.ConclusionSOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies.

PURPOSEInfantile esotropia is associated with maldevelopment of cortical visual motion processing, manifested as directional asymmetry of motion visual evoked potentials (mVEPs). The purpose of this study was to determine whether early surgery at or before age 11 months could promote the development of cortical visual motion processing in human infants, compared with standard surgery at age 11 to 18 months.METHODSSixteen children with a constant, infantile esotropia >or=30 prism diopters and onset before age 6 months were recruited prospectively. Eight of them underwent early surgery at <or=11 months of age, and eight underwent standard surgery at 11 to 18 months of age. Seven age-matched normal subjects served as the control. At 2 to 2.5 years of age, mVEPs were measured during monocular viewing of a grating that shifted between two positions with a lateral displacement of 90 degrees at 10 Hz. Nasotemporal mVEP asymmetry was assessed by an amplitude asymmetry index and by the presence of a significant interocular phase difference.RESULTSThe mean asymmetry index and interocular phase difference in the early surgery group were comparable to that in age-matched control subjects, and they were significantly lower than those in the standard surgery group.CONCLUSIONSEarly surgery for infantile esotropia promotes the development of cortical visual motion processing, whereas standard surgery is associated with abnormal mVEPs. The results provide additional evidence that early strabismus repair is beneficial for cortical development in human infants.