It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used ...next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain-containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (-7), deletions of 7q (7q-), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with -7 and 7q- developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.
BackgroundSilver-Russell syndrome (SRS) is an imprinting disorder characterised by prenatal and postnatal growth restriction, but its clinical features are non-specific and its differential diagnosis ...is broad. Known molecular causes of SRS include imprinting disturbance, single nucleotide variant (SNV), CNV or UPD affecting several genes; however, up to 40% of individuals with a clinical diagnosis of SRS currently receive no positive molecular diagnosis.MethodsTo determine whether whole-genome sequencing (WGS) could uncover pathogenic variants missed by current molecular testing, we analysed data of 72 participants recruited to the 100,000 Genomes Project within the clinical category of SRS.ResultsIn 20 participants (27% of the cohort) we identified genetic variants plausibly accounting for SRS. Coding SNVs were identified in genes including CDKN1C, IGF2, IGF1R and ORC1. Maternal-effect variants were found in mothers of five participants, including two participants with imprinting disturbance and one with multilocus imprinting disorder. Two regions of homozygosity were suggestive of UPD involving imprinted regions implicated in SRS and Temple syndrome, and three plausibly pathogenic CNVs were found, including a paternal deletion of PLAGL1. In 48 participants with no plausible pathogenic variant, unbiased analysis of SNVs detected a potential association with STX4.ConclusionWGS analysis can detect UPD, CNV and SNV and is potentially a valuable addition to diagnosis of SRS and related growth-restricting disorders.
Patients with rare diseases face unique challenges in obtaining a diagnosis, appropriate medical care and access to support services. Whole genome and exome sequencing have increased identification ...of causal variants compared to single gene testing alone, with diagnostic rates of approximately 50% for inherited diseases, however integrated multi-omic analysis may further increase diagnostic yield. Additionally, multi-omic analysis can aid the explanation of genotypic and phenotypic heterogeneity, which may not be evident from single omic analyses.
This scoping review took a systematic approach to comprehensively search the electronic databases MEDLINE, EMBASE, PubMed, Web of Science, Scopus, Google Scholar, and the grey literature databases OpenGrey / GreyLit for journal articles pertaining to multi-omics and rare disease, written in English and published prior to the 30th December 2018. Additionally, The Cancer Genome Atlas publications were searched for relevant studies and forward citation searching / screening of reference lists was performed to identify further eligible articles. Following title, abstract and full text screening, 66 articles were found to be eligible for inclusion in this review. Of these 42 (64%) were studies of multi-omics and rare cancer, two (3%) were studies of multi-omics and a pre-cancerous condition, and 22 (33.3%) were studies of non-cancerous rare diseases. The average age of participants (where known) across studies was 39.4 years. There has been a significant increase in the number of multi-omic studies in recent years, with 66.7% of included studies conducted since 2016 and 33% since 2018. Fourteen combinations of multi-omic analyses for rare disease research were returned spanning genomics, epigenomics, transcriptomics, proteomics, phenomics and metabolomics.
This scoping review emphasises the value of multi-omic analysis for rare disease research in several ways compared to single omic analysis, ranging from the provision of a diagnosis, identification of prognostic biomarkers, distinct molecular subtypes (particularly for rare cancers), and identification of novel therapeutic targets. Moving forward there is a critical need for collaboration of multi-omic rare disease studies to increase the potential to generate robust outcomes and development of standardised biorepository collection and reporting structures for multi-omic studies.
Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause neurodevelopmental disorders (NDDs). Here, we report on five individuals with mutations in SMARCD1; ...the individuals present with developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. Trio exome sequencing proved the mutations to be de novo in four of the five individuals. Mutations in other SWI/SNF components cause Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, or other syndromic and non-syndromic NDDs. Although the individuals presented here have dysmorphisms and some clinical overlap with these syndromes, they lack their typical facial dysmorphisms. To gain insight into the function of SMARCD1 in neurons, we investigated the Drosophila ortholog Bap60 in postmitotic memory-forming neurons of the adult Drosophila mushroom body (MB). Targeted knockdown of Bap60 in the MB of adult flies causes defects in long-term memory. Mushroom-body-specific transcriptome analysis revealed that Bap60 is required for context-dependent expression of genes involved in neuron function and development in juvenile flies when synaptic connections are actively being formed in response to experience. Taken together, we identify an NDD caused by SMARCD1 mutations and establish a role for the SMARCD1 ortholog Bap60 in the regulation of neurodevelopmental genes during a critical time window of juvenile adult brain development when neuronal circuits that are required for learning and memory are formed.
The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely ...uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBA5, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBA5 variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort. The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development. Furthermore, the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity. The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.Ala371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg55His, but also affects splicing by facilitating exon 2 skipping, thus also being in effect a loss-of-function allele. Using an in vitro thioester formation assay and cellular analyses, we show that the p.Ala371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1. Finally, we show that the CNS-specific knockout of Ufm1 in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function. Taken together, our data imply that the combination of a hypomorphic p.Ala371Thr variant in trans with a loss-of-function allele in UBA5 underlies a severe infantile-onset encephalopathy.
Variants in the chromodomain helicase DNA‐binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASDs) and overgrowth and CHD8 is one of the ...causative genes for OGID (overgrowth and ID). We investigated 25 individuals with CHD8 protein truncating variants (PTVs), including 10 previously unreported patients and found a male to female ratio of 2.7:1 (19:7) and a pattern of common features: macrocephaly (62.5%), tall stature (47%), developmental delay and/or intellectual disability (81%), ASDs (84%), sleep difficulties (50%), gastrointestinal problems (40%), and distinct facial features. Most of the individuals in this cohort had moderate‐to‐severe ID, some had regression of speech (37%), seizures (27%) and hypotonia (27%) and two individuals were non‐ambulant. Our study shows that haploinsufficiency of CHD8 is associated with a distinctive OGID syndrome with pronounced autistic traits and supports a sex‐dependent penetrance of CHD8 PTVs in humans.
Variants in the chromodomain helicase DNA‐binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASD) and overgrowth and CHD8 is one of the causative genes for OGID (overgrowth and ID). We investigated 25 individuals with CHD8 protein truncating variants (PTVs), including 10 previously unreported patients and found a male to female ratio of 2.7:1 (19:7) and a pattern of common features: macrocephaly (62.5%), tall stature (47%), developmental delay and/or intellectual disability (DD/ID, 81%), autism spectrum disorders (ASD, 84%), sleep difficulties (50%), gastrointestinal problems (40%), and distinct facial features. Most of the individuals in this cohort had moderate‐to‐severe intellectual disability, some had regression of speech (37%), seizures (27%) and hypotonia (27%) and two individuals were also non‐ambulant. Our study shows that haploinsufficiency of CHD8 is associated with a distinctive OGID syndrome with pronounced autistic traits and supports a sex‐dependent penetrance of CHD8 PTVs in humans.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multisystemic vascular dysplasia, characterized by arteriovenous malformations (AVMs), mucocutaneous telangiectasia and ...nosebleeds. HHT is caused by a heterozygous null allele in ACVRL1, ENG, or SMAD4, which encode proteins mediating bone morphogenetic protein (BMP) signaling. Several missense and stop-gain variants identified in GDF2 (encoding BMP9) have been reported to cause a vascular anomaly syndrome similar to HHT, however none of these patients met diagnostic criteria for HHT. HHT families from UK NHS Genomic Medicine Centres were recruited to the Genomics England 100,000 Genomes Project. Whole genome sequencing and tiering protocols identified a novel, heterozygous GDF2 sequence variant in all three affected members of one HHT family who had previously screened negative for ACVRL1, ENG, and SMAD4. All three had nosebleeds and typical HHT telangiectasia, and the proband also had severe pulmonary AVMs from childhood. In vitro studies showed the mutant construct expressed the proprotein but lacked active mature BMP9 dimer, suggesting the mutation disrupts correct cleavage of the protein. Plasma BMP9 levels in the patients were significantly lower than controls. In conclusion, we propose that this heterozygous GDF2 variant is a rare cause of HHT associated with pulmonary AVMs.
Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance ...is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1‐associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly‐acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound‐heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss‐of‐function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS‐like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.‐38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1‐4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.
IntroductionSport-related concussion is one of the most common injuries in adolescent rugby players with evidence of prolonged recovery in some concussed athletes. Concussion is a complex ...pathophysiological process that can affect a variety of subsystems with multifactorial presentation. Most research on adolescents recovery after concussion focuses on neurocognitive functioning and symptom outcomes over the short term. There is a need to explore concussion recovery over time across multiple subsystems in adolescent rugby players.Methods and analysisThis prospective study will use sensorimotor and oculomotor outcomes in adolescent male and female rugby players aged 16–18 years. Players will be recruited from school or club rugby teams across the province of Ulster. Baseline assessment will be undertaken at the start of the playing season and will include questionnaires, Quantified Y Balance Test and Pupillary Light Reflex. Players who sustain a concussive event will be reassessed on all outcomes at 3 days, 7 days, 14 days, 23 days, 90 days, 180 days and 365 days postconcussion. For serial outcome data, we will examine response curves for each participant and make comparisons between known groups. We will use logistic regression to explore any association between demographic variables and recovery. The strength of the predictive model will be determined using R2, p values and ORs, with 95% CIs.Ethics and disseminationEthical approval has been granted for this study from Ulster University Research Ethics Committee (REC/14/0060). This study will be published in an open-access research journal on completion.Trial registration numberACTRN12622000931774p.
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