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Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterised by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next generation sequencing based assay. Comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. Review of the clinical and genetic features of SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants (p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)). Both SETD2 subgroups demonstrated a methylation episignature which was characterised by hypomethylation and hypermethylation events respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype–phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.

PURPOSEThe terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation, and to support variant classification within the ACMG/AMP framework.METHODSTerminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition (GenCC) members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated.RESULTSWe present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both sequence ontology (SO) and human phenotype ontology (HPO) ontologies. GenCC member groups intend to use or map to these terms in their respective resources.CONCLUSIONThe terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.

Background and ObjectivesATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process.MethodsUndiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term “ATP1A3” from 2004 to 2021.ResultsTwenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2–3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint.DiscussionOur study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone.

Next-generation sequencing has led to a dramatic improvement in molecular diagnoses of serious pediatric disorders caused by apparently de novo mutations (DNMs); by contrast, clinicians’ ability to counsel the parents about the risk of recurrence in a future child has lagged behind. Owing to the possibility that one of the parents could be mosaic in their germline, a recurrence risk of 1-2% is frequently quoted, but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk stratification, by combining deep-sequencing of multiple tissues in the mother-father-child trio with haplotyping to determine the parental origin of the DNM. In the first 58 couples analysed (total of 59 DNMs in 49 different genes), the risk for 35 (59%) DNMs was decreased below 0.1% but for 6 (10%) couples it was increased owing to parental mosaicism - that could be quantified in semen (recurrence risks of 5.6-12.1%) for the paternal cases. Deep-sequencing of the DNM efficiently identifies couples at greatest risk for recurrence and may qualify them for additional reproductive technologies. Haplotyping can further reassure many other couples that their recurrence risk is very low, but its implementation is more technically challenging and will require better understanding of how couples respond to information that reduces their risks.

Funder: NIHR Cambridge Biomedical Reserach Centre VHL Alliance UK, BACKGROUND: Von Hippel-Lindau (VHL) disease is an inherited tumour predisposition syndrome and a paradigm for the importance of early diagnosis and surveillance. However, there is limited information on the "real world" management of VHL disease. METHODS: A national audit of VHL disease in the United Kingdom. RESULTS: VHL disease was managed mostly via specialist clinics coordinated through regional clinical genetics services (but frequently involving additional specialties). Over the study period, 19 genetic centres saw 842 individuals (393 males, 449 females) with a clinical and/or molecular diagnosis of VHL disease and 74 individuals (35 male, 39 female) with a prior risk of 50% (affected parent). All centres offered retinal, central nervous system and abdominal surveillance to affected individuals and at-risk relatives though surveillance details differed between centres (but complied with international recommendations). Renal lesions detected on the first surveillance scan were, on average, larger than those detected during subsequent scans and the larger the diameter at detection the greater the likelihood of early intervention. CONCLUSIONS: In a state-funded health care system individuals with a rare inherited cancer predisposition syndrome are generally able to access appropriate surveillance and patient management is improved compared to historical data. The "real world" data from this study will inform the future development of VHL management protocols.

Rapid technological advances in genomic testing continue to increase our understanding of the genetic basis of a wide range of kidney disorders. Establishing a molecular diagnosis benefits the individual by bringing an end to what is often a protracted diagnostic odyssey, facilitates accurate reproductive counselling for families and, in the future, is likely to lead to the delivery of more targeted management and surveillance regimens. The selection of the most appropriate testing modality requires an understanding both of the technologies available and of the genetic architecture and heterogeneity of kidney disease. Whilst we are witnessing a far greater diagnostic yield with broader genetic testing, such approaches invariably generate variants of uncertain significance and secondary incidental findings, which are not only difficult to interpret but present ethical challenges with reporting and feeding back to patients and their families. Here, we review the spectrum of nephrogenetic disorders, consider the optimal approach to genetic testing, explore the clinical utility of obtaining a molecular diagnosis, reflect on the challenges of variant interpretation and look to the future of this dynamic field.

A proper interaction between muscle-derived collagen XXV and its motor neuron-derived receptors protein tyrosine phosphatases sigma and delta (PTP sigma/delta) is indispensable for intramuscular motor innervation. Despite this, thus far, pathogenic recessive variants in the COL25A1 gene had only been detected in a few patients with isolated ocular congenital cranial dysinnervation disorders. Here we describe five patients from three unrelated families with recessive missense and splice site COL25A1 variants presenting with a recognizable phenotype characterized by arthrogryposis multiplex congenita with or without an ocular congenital cranial dysinnervation disorder phenotype. The clinical features of the older patients remained stable over time, without central nervous system involvement. This study extends the phenotypic and genotypic spectrum of COL25A1 related conditions, and further adds to our knowledge of the complex process of intramuscular motor innervation. Our observations indicate a role for collagen XXV in regulating the appropriate innervation not only of extraocular muscles, but also of bulbar, axial, and limb muscles in the human.

Undiagnosed individuals withTwenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an

We report a patient with profound congenital hypotonia, central hypoventilation, poor visual behaviour with retinal hypopigmentation, and significantly decreased mitochondrial respiratory chain complex I activity in muscle, who died at 7 months of age having made minimal developmental progress. Biallelic predicted truncating P4HTM variants were identified following trio whole-genome sequencing, consistent with a diagnosis of hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy and eye abnormalities (HIDEA) syndrome. Very few patients with HIDEA syndrome have been reported previously and mitochondrial abnormalities were observed in three of four previous cases who had a muscle biopsy, suggesting the possibility that HIDEA syndrome represents a primary mitochondrial disorder. P4HTM encodes a transmembrane prolyl 4-hydroxylase with putative targets including hypoxia inducible factors, RNA polymerase II and activating transcription factor 4, which has been implicated in the integrated stress response observed in cell and animal models of mitochondrial disease, and may explain the mitochondrial dysfunction observed in HIDEA syndrome.

Structural eye disorders are increasingly recognised as having a genetic basis, although current genetic testing is limited in its success. De novo missense variants in WDR37 are a recently described cause of a multisystemic syndromic disorder featuring ocular coloboma. This study characterises the phenotypic spectrum of this disorder and reports 2 de novo heterozygous variants (p.Thr115Ile, p.Ser119Tyr) in three unrelated Caucasian individuals. All had a clinical phenotype consisting of bilateral iris and retinal coloboma, developmental delay and additional, variable multisystem features. The variants fall within a highly conserved region upstream of the WD-repeat domains, within an apparent mutation cluster. Consistent with the literature, intellectual disability, structural eye disorders, epilepsy, congenital heart disease, genitorenal anomalies and dysmorphic facial features were observed. In addition, a broader developmental profile is reported with a more specific musculoskeletal phenotype described in association with the novel variant (p.Thr115Ile). We further expand the phenotypic spectrum of WDR37-related disorders to include those with milder developmental delay and strengthen the association of ocular coloboma and musculoskeletal features. We promote the inclusion of WDR37 on gene panels for intellectual disability, epilepsy and structural eye disorders.

Rare diseases, particularly those with great phenotypic and genetic heterogeneity, remain a diagnostic challenge. Broadening the investigative approach through whole genome sequencing (WGS) is anticipated to improve diagnostic yield. Despite this, substantial numbers of patients remain undiagnosed through current 100,000 Genomes Project pipelines. In these cases, the causative mutation may not be prioritised due to lack of evidence associating the gene with a specific phenotype, or as a result of being inadvertently filtered out. A systematic approach to additional data analysis utilising both inheritance model filtering and ranking algorithm tools has been piloted in cases with no primary findings (NPF). Examples of diagnoses secured include a de novo TAB2mutation, causing a connective tissue phenotype with congenital heart disease and a paternally inherited COL7A1mutation, causing a variable penetrance skin blistering disorder, epidermolysis bullosa dystrophica. Identification of causative variants in WGS data remains challenging. Data led approaches to optimising additional review of cases with NPF have the prospect of improving both sensitivity and cost efficiency and may provide earlier diagnosis for individuals with rare disease, ending their diagnostic odyssey. Establishing a standardised approach to reanalysis will be particularly important as we approach the introduction of an NHS clinical sequencing service.

New technological methods, such as rapidly developing molecular approaches, often provide new tools for scientific advances. However, these new tools are often not utilized equally across different research areas, possibly leading to disparities in progress between these areas. Here, we use empirical evidence from the scientific literature to test for potential discrepancies in the use of genetic tools to study parasiticvsnon-parasitic organisms across three distinguishable molecular periods, the allozyme, nucleotide and genomics periods. Publications on parasites constitute only a fraction (

Alpine ecosystems are frequently characterized by an abundance of wing-reduced insect species, but the drivers of this biodiversity remain poorly understood. Insect wing reduction in these environments has variously been attributed to altitude, temperature, isolation, habitat stability or decreased habitat size. We used fine-scale ecotypic and genomic analyses, along with broad-scale distributional analyses of ecotypes, to unravel the ecological drivers of wing reduction in the wing-dimorphic stonefly Zelandoperla fenestrata complex. Altitudinal transects within populations revealed dramatic wing reduction over very fine spatial scales, tightly linked to the alpine treeline. Broad biogeographical analyses confirm that the treeline has a much stronger effect on these ecotype distributions than altitude per se. Molecular analyses revealed parallel genomic divergence between vestigial-winged (high altitude) and full-winged (low altitude) ecotypes across distinct streams. These data thus highlight the role of the alpine treeline as a key driver of rapid speciation, providing a new model for ecological diversification along exposure gradients.

The use of genetic information is now fundamental in parasite taxonomy and systematics, for resolving parasite phylogenies, discovering cryptic species, and elucidating patterns of gene flow among parasite populations. The accumulation of available gene sequences per geographical area or per parasite taxonomic group is likely proportional to species richness, but not without some biases. Certain areas and certain taxonomic groups receive more research effort than others, possibly causing a deficit in the relative number of parasite species being characterized genetically in some areas or taxonomic groups. Here, we use data on the number of parasite records per country or helminth family from the London Natural History Museum host-parasite database, and matching data on the number of gene sequences available from the National Center for Biotechnology Information (NCBI) GenBank database, to determine how available gene sequences scale with species richness across countries or parasitic helminth families. Our quantitative analysis identified countries/regions of the world and helminth families that have received the most effort in genetic research. More importantly, it allowed us to generate lists (based on residuals from the statistical model) of the 20 countries/regions and the 20 helminth families with the largest deficit in available gene sequences relative to their helminth species richness. We propose these lists as useful guides toward future allocation of effort to maximise advances in parasite biodiscovery, systematics and population structure.

Comparing the genetic structure of host populations with that of their parasites can shed light on the efficiency and independence of their respective dispersal mechanisms. The degree of congruence between host and parasite genetic structure should reflect to what extent they share dispersal mechanisms. Here, we contrast the genetic structure of the acanthocephalan parasite Profilicollis novaezelandensis with that of its intermediate host, the hairy-handed shore crab Hemigrapsus crenulatus, along the east coast of New Zealand’s South Island. We expected no congruence in their phylogeographic patterns because of the very different modes of dispersal used by the crabs (planktonic drift) and the acanthocephalans (bird-mediated dispersal). Based on analysis of cytochrome oxidase subunit I gene sequences, we found no significant genetic structure among isolated populations of the crab and those of their parasite, along a roughly 600 km stretch of coastline. Surprisingly, based on a distance-based co-evolutionary analysis statistical tool (PACo), we observed an overall significant level of congruence between host and parasite population-level phylogenies. The most parsimonious interpretation is that statistical significance does not translate into biological significance, with the result likely due to chance, possibly because bird movements that disperse parasites coincidentally match patterns of crab dispersal by ocean currents in parts of our study area. In this system, the connectivity among different localities and the apparent genetic mixing among populations may have implications for host–parasite co-evolution.

Unilateral multicystic dysplastic kidney (MCDK) has an incidence of approximately 1 in 4300 births.1 They are usually isolated, and the natural course is of complete involution with compensatory contralateral renal hypertrophy.2 Associated genitourinary abnormalities occur, most commonly vesicoureteric reflux (VUR), with a reported incidence of 19.7%.3 Most of the identified VUR is not clinically significant and is likely to resolve spontaneously.4 Our local neonatal unit guideline recommended undertaking a micturating cystourethrogram (MCUG) if there was renal pelvic dilatation in the contralateral kidney. Our aim was to audit our clinical practice and evaluate the outcomes. Data were analysed over a 15-year period, from 2000 to …

2005 has seen the birth of the product KIWIN(TM)--an educational technology for nursing students in New Zealand involving web-based technology supported by Pocket PCs in the field. Nursing students use the technology to collect clinically relevant data at the point-of-care and transmit to a secure central server for storage using cradle synchronisation, WiFi or cellular wireless modalities. Later retrieval via the Internet enables collation of details, refinement of work, and construction with print-off of care reports to meet academic requirements. This demonstration will showcase the development to the international community. Critique and review will be welcomed.