Dragana Josifova | King's College London (original) (raw)

Papers by Dragana Josifova

British Journal of Dermatology, 2019

Background Genotype-phenotype studies can identify subgroups of patients with specific clinical f... more Background Genotype-phenotype studies can identify subgroups of patients with specific clinical features or differing outcomes, which can help shape management. Objectives To characterize the frequency of different causative genotypes in congenital melanocytic naevi (CMN), and to investigate genotype-phenotype and genotype-outcome associations. Methods We conducted a large cohort study in which we undertook MC1R genotyping from blood, and high-sensitivity genotyping of NRAS and BRAF hotspots in 156 naevus biopsies from 134 patients with CMN [male 40%; multiple CMN 76%; projected adult size (PAS) > 20 cm, 59%]. Results Mosaic NRAS mutations were detected in 68%, mutually exclusive with BRAF mutations in 7%, with double wild-type in 25%. Two separate naevi were sequenced in five of seven patients with BRAF mutations, confirming clonality. Five of seven patients with BRAF mutations had a dramatic multinodular phenotype, with characteristic histology distinct from classical proliferative nodules. NRAS mutation was the commonest in all sizes of CMN, but was particularly common in naevi with PAS > 60 cm, implying more tolerance to that mutation early in embryogenesis. Facial features were less common in double wild-type patients. Importantly, the incidence of congenital neurological disease, and apparently of melanoma, was not altered by genotype; no cases of melanoma were seen in BRAF-mutant multiple CMN, however, this genotype is rare. Conclusions CMN of all sizes are most commonly caused by mutations in NRAS. BRAF is confirmed as a much rarer cause of multiple CMN, and appears to be commonly associated with a multinodular phenotype. Genotype in this cohort was not associated with differences in incidence of neurological disease in childhood. However, genotyping should be undertaken in suspected melanoma, for guidance of treatment. What's already known about this topic? • Multiple congenital melanocytic naevi (CMN) have been shown to be caused by NRAS mosaic mutations in 70-80% of cases, by BRAF mosaicism in one case report and by inference in some previous cases. • There has been debate about genotypic association with different sizes of CMN, and no data on genotype-outcome.

British Journal of Dermatology, 2015

mortality rate of patients with BP is still high, ranging from 13% to 38%. 1,2 Recently, we repor... more mortality rate of patients with BP is still high, ranging from 13% to 38%. 1,2 Recently, we reported the effectiveness of rituximab, a monoclonal anti-CD20 antibody, as first-line therapy for pemphigus. 3 Therefore, we have attempted to measure the utility of rituximab as first-line therapy for BP. From 2010 to 2012 we performed a retrospective casecontrol study in a referral centre in Taiwan, including patients with the generalized form of BP requiring systemic treatment. Diagnosis of BP was based on typical clinical presentations, characteristic histopathological findings, and the presence of autoantibodies on direct and/or indirect immunofluorescence studies. In the first-line combination therapy group (group R), the regimen included four weekly infusions of 500 mg rituximab (MabThera TM ; Roche, Basel, Switzerland), and corticosteroids, with a starting dose of prednisolone of 0Á5 mg kg À1 daily (Table 1). The dose of corticosteroids was tapered rapidly after disease was controlled. Each dose lasted for 3-4 weeks, with a total duration of < 6 months. As a comparison (group C), to ensure the similarity of severity, we included patients from the same period receiving a similar starting dose of prednisolone for at least 6 months (Table 1). We excluded those with localized or mild disease, which could be controlled by topical treatment or a short course of systemic treatment. All patients were followed for 1 year or until death. In both groups, the average age, BP Disease Area Index values, 4 blood eosinophil counts and the presence of comorbidities were similar (Table 2). More than 90% of patients in group R achieved complete remission (CR), a status of no established or new lesions for at least 2 months, 4 which was significantly higher than in group C (P = 0Á02). Notably, eight of the patients achieving CR in group R achieved CR off therapy (CRoff). Of these eight patients, four maintained CRoff during the follow-up period of > 2 years. The other four experienced disease recurrence. Nevertheless, relapses in these cases were mild and easily controlled. The mean duration of CRoff in these four patients was 27 weeks (range 22-35 weeks). The risk of infection was slightly lower in group R than in group C (31% vs. 53%), but it was not statistically significant (P = 0Á22). Urinary tract infection and pneumonia were the leading infections in groups R and C, respectively. The 1-year mortality rate of group R was much lower than that of group C (15% vs. 37%), but it was not significantly different (P = 0Á18). To date, only anecdotal reports have mentioned the use of rituximab in BP. 5,6 Our study is the first to use rituximab as a firstline treatment in BP, and demonstrates a significantly better rate of CR than conventional treatment. A recent review article reports infection and mortality rates of around 20%, and suggests that careful and close monitoring may be neccessary. 7 These results are consistent with ours. Indeed, infections are the most important cause of mortality in our study, as also reported in another study. 8 Nevertheless, our study provides a comparison and shows that first-line combination therapy has similar or even lower rates of infection and mortality than conventional treatment. This might result from rapid tapering and withdrawing systemic corticosteroids in group R (Table 2), as a lower dose of systemic corticosteroids may reduce the rate of mortality. 9 In conclusion, we demonstrate that first-line combination therapy with rituximab and corticosteroids is effective and relatively safe for moderate-to-severe BP. A large prospective study is needed to confirm our observations.

Neuromuscular Disorders, May 1, 2013

Infantile-onset X-linked spinal muscular atrophy (SMAX2) is a rare lethal disorder linked to muta... more Infantile-onset X-linked spinal muscular atrophy (SMAX2) is a rare lethal disorder linked to mutations in the UBA1 (previously UBE1) gene, encoding ubiquitin-activating enzyme 1 that has an important role in the ubiquitin-proteasome pathway. Published pathological reports are scarce. Here we report a male infant who presented from birth with predominantly truncal hypotonia following an antenatal history of reduced fetal movements. He had a myopathic face, profound weakness, multiple contractures and areflexia. Creatine kinase was moderately raised. Brain MRI showed non-specific symmetrical periventricular white matter changes. Neurophysiology revealed evidence of motor and sensory involvement and muscle biopsy showed marked inflammatory changes with subtle features suggestive of acute denervation. UBA1 sequencing revealed a novel hemizygous missense mutation (c.1670A&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;T; p.Glu557Val). He died from progressive respiratory failure at 4 months. On post mortem assessment, in addition to severe ventral motor neuron pathology, there was widespread involvement of the sensory system, as well as developmental and degenerative cerebellar abnormalities. In contrast to typical SMN1-associated SMA, the thalamus was unaffected. These findings indicate that SMAX2 is more accurately classified as a motor sensory neuronopathy rather than a pure anterior horn cell disorder. Ubiquitin-proteasome pathway defects may not only cause neurodegeneration but also affect normal neuronal development.

Best practice & research. Clinical obstetrics & gynaecology, 2017

From genomic imbalances associated with developmental abnormalities of the female genital tract t... more From genomic imbalances associated with developmental abnormalities of the female genital tract to the molecular mechanisms underpinning endometriosis and uterine leiomyomatosis, new technologies have allowed the exploration of the genetic contribution and mapping the molecular pathways underpinning common and rare gynaecological conditions. While some of these conditions have historically been considered sporadic, recent research has demonstrated their potentially heritable nature linked to single genes or copy number variants. The phenotypic variability including non-penetrance indicates their multifactorial, complex aetiology encompassing genetic, epigenetic and environmental influences. Although genetic tests are not routinely conducted in gynaecological practice, there is an increasing body of evidence suggesting that, in appropriate cases, molecular investigations such as array CGH analysis may be an important part of the diagnostic algorithm. The subtlety of clinical features...

Nature, Feb 23, 2017

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damag... more The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimat...

Journal of Neurology, Neurosurgery & Psychiatry, 2015

In 1987 Summers et al 1 described a 14-year-old girl with neurogenic bulbospinal muscular atrophy... more In 1987 Summers et al 1 described a 14-year-old girl with neurogenic bulbospinal muscular atrophy and sensorineural deafness. They discussed the overlap of clinical features in Brown-Vialetto-Van Laere syndrome (BVVLS) and Madras motor neuron disease (MMND) described by Jagganathan.2 The patient was considered to have BVVLS and was among the first 20 cases described in the literature. At that time no diagnostic test was available but recently mutations in the riboflavin transporter genes have been identified in BVVLS and, indeed, there is hope that riboflavin therapy may be helpful. Twenty-eight years previously, a 14-year-old girl presented with a 2-year history of slowly progressive bulbospinal weakness associated with sensorineural deafness. Distal upper limb muscles were markedly wasted, the voice was nasal in quality, but the leg muscles were less involved. Ventilatory function was abnormal (forced vital capacity (FVC) 60% predicted) and there was slight oxygen desaturation in sleep. Since diagnosis she has been closely followed at the Royal London Hospital. She and her mother recently agreed to genetic testing. Screening of the SLC52A3 gene in the patient revealed heterozygous c.193C>T (Arg65Trp) mutation in exon 2 and heterozygous c.1238T>C (Val413Ala) mutation in exon 5. The patient's mother had …

American journal of medical genetics. Part A, Jan 22, 2015

Interstitial deletions of chromosome 3p14p12 are a rare chromosome rearrangement. Twenty-six pati... more Interstitial deletions of chromosome 3p14p12 are a rare chromosome rearrangement. Twenty-six patients have been reported in the literature to date, however, a specific clinical phenotype has not yet been delineated. We describe three patients (two new) with overlapping chromosome 3p14p12 deletions and review the clinical and molecular data of 11 well-characterized, published cases. These patients had a number of features in common, such as short stature, failure to thrive, facial dysmorphism, congenital heart defects, urogenital abnormalities, neurological problems, hearing loss, and global developmental delay, suggesting that the interstitial chromosome 3p14p12 deletion gives rise to a multiple congenital anomaly syndrome. Some of the patients show clinical overlap with other complex syndromes such as CHARGE syndrome. Genotype-phenotype analysis revealed candidate genes for parts of the clinical features suggesting that the 3p14 deletion is a contiguous gene syndrome. © 2015 Wiley ...

Molecular Genetics & Genomic Medicine, 2017

Background Microdeletions of 2q23.1 disrupting MBD5 and loss of function mutations of MBD5 cause ... more Background Microdeletions of 2q23.1 disrupting MBD5 and loss of function mutations of MBD5 cause MBD5-Associated Neurodevelopmental disorders (MAND). Nearly all reported patients have been isolated cases of de novo origin. Methods This study investigates three families with inherited MBD5 mutations from three different Regional Genetics Centres in the UK. Results Two of the parents in the study had MBD5 deletions in a mosaic form. The parent with an MBD5 deletion in an apparently nonmosaic form has a psychiatric disorder in the absence of developmental delay or dysmorphism. Conclusions Inherited forms of MBD5 deletions are rare, but do occur, especially in a mosaic form. The phenotypic spectrum of MAND may be wider than previously thought.

American Journal of Neuroradiology, 2021

BACKGROUND AND PURPOSE: Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation o... more BACKGROUND AND PURPOSE: Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, Ear abnormalities and deafness (CHARGE) syndrome is an autosomal dominant genetic disorder with evolving clinical diagnostic criteria. Recently, a number of additional anomalies have been described in this syndrome, which may aid in early diagnosis, particularly in incomplete phenotypes or atypical cases. The persistent trigeminal artery is an embryonic carotid-vertebral anastomosis, rarely seen in the healthy population, with a reported prevalence of 0.4%. Because we had observed the persistent trigeminal artery in patients with CHARGE syndrome, this study aimed to explore the prevalence of the persistent trigeminal artery in this syndrome. MATERIALS AND METHODS: A retrospective study was performed at our tertiary center. MR imaging studies, clinical records, and genetic results were reviewed for patients diagnosed with CHARGE syndrome between 2006 and 2019. The prevalence of the persistent trigeminal artery in patients with CHARGE syndrome was recorded and compared with other established diagnostic criteria. RESULTS: Twenty-five patients with CHARGE syndrome were included. The persistent trigeminal artery was demonstrated on MR imaging in 14/25 (56%) patients and was seen more frequently than 4 of 9 other established diagnostic criteria in our cohort. When individual major or minor diagnostic criteria were absent, the persistent trigeminal artery was still demonstrated on MR imaging in 52%-67% of these patients with CHARGE syndrome. CONCLUSIONS: The prevalence of the persistent trigeminal artery in CHARGE syndrome of 56% is higher than that of some other established diagnostic criteria and much higher than that in the general population. The persistent trigeminal artery may be a useful addition to the expanding phenotype of CHARGE syndrome, supplementing other diagnostic criteria. Radiologists should be aware of this novel finding demonstrable on MR imaging.

American journal of human genetics, Jan 5, 2017

Inherited retinal disease is a common cause of visual impairment and represents a highly heteroge... more Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also ide...

Developmental Medicine & Child Neurology, 2006

Nature Communications, 2021

Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked ... more Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understan...

Nature, 2020

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological varian... more Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and mediating genes for more than half such disorders remain to be discovered 1. We implemented whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants, in the coding and non-coding regions of the genome. In a pilot study for the 100,000 Genomes Project, we generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 patients with detailed phenotypic data. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed aetiological. Using WGS of UK Biobank 2 , we showed that rare alleles can explain the presence of some individuals in the tails of a quantitative red blood cell (RBC) trait. Finally, we identified 4 novel non-coding variants which cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare. Rare diseases affect approximately 1 in 20 people, but only a minority of patients receive a genetic diagnosis 3. Approximately 10,000 rare diseases are known, but fewer than half have a resolved genetic aetiology 1. Even when the aetiology is known, the prospects for diagnosis are severely diminished by fragmentary phenotyping and the restriction of testing to disease-specific panels of genes. On average, a molecular cause is determined after three misdiagnoses and 16 physician visits over several years 4. Recent development of WGS technology allows systematic, comprehensive genetic testing in integrated health systems concurrent with aetiological discovery in the coding and non-coding genome.

Genetics in Medicine, 2019

To provide a detailed electroclinical description and expand the phenotype of PIGT-CDG, to perfor... more To provide a detailed electroclinical description and expand the phenotype of PIGT-CDG, to perform genotype-phenotype correlation, and to investigate the onset and severity of the epilepsy associated with the different genetic subtypes of this rare disorder. Furthermore, to use computerassisted facial gestalt analysis in PIGT-CDG and to the compare findings with other glycosylphosphatidylinositol (GPI) anchor deficiencies. Methods: We evaluated 13 children from eight unrelated families with homozygous or compound heterozygous pathogenic variants in PIGT. Results: All patients had hypotonia, severe developmental delay, and epilepsy. Epilepsy onset ranged from first day of life to two years of age. Severity of the seizure disorder varied from treatable seizures to severe neonatal onset epileptic encephalopathies. The facial gestalt of patients resembled that of previously published PIGT patients as they were closest to the center of the PIGT cluster in the clinical face phenotype space and were distinguishable from other gene-specific phenotypes. Conclusion: We expand our knowledge of PIGT. Our cases reaffirm that the use of genetic testing is essential for diagnosis in this group of disorders. Finally, we show that computer-assisted facial gestalt analysis accurately assigned PIGT cases to the multiple congenital anomalies-hypotonia-seizures syndrome phenotypic series advocating the additional use of next-generation phenotyping technology.

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The Journal of biological chemistry, Jan 9, 2018

The complex disorder Cantu syndrome (CS) arises from gain-of-function mutations in either or , th... more The complex disorder Cantu syndrome (CS) arises from gain-of-function mutations in either or , the genes encoding the Kir6.1 and SUR2 subunits of ATP-sensitive potassium (K) channels, respectively. Recent reports indicate that such mutations can increase channel activity by multiple molecular mechanisms. In this study, we determined the mechanism by which K function is altered by several substitutions in distinct structural domains of SUR2: D207E in the intracellular L0-linker and Y985S, G989E, M1060I, and R1154Q/R1154W in TMD2. We engineered substitutions at their equivalent positions in rat SUR2A (D207E, Y981S, G985E, M1056I, and R1150Q/R1150W) and investigated functional consequences using macroscopic rubidium (Rb) efflux assays and patch-clamp electrophysiology. Our results indicate that D207E increases K channel activity by increasing intrinsic stability of the open state, whereas the cluster of Y981S/G985E/M1056I substitutions, as well as R1150Q/R1150W, augmented Mg-nucleotide...

American journal of human genetics, Jan 12, 2018

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result... more Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor ty...

Nature neuroscience, Jan 16, 2018

In the version of this article initially published, the consortium authorship and corresponding a... more In the version of this article initially published, the consortium authorship and corresponding authors were not presented correctly. In the PDF and print versions, the Whole Genome Sequencing for Psychiatric Disorders (WGSPD) consortium was missing from the author list at the beginning of the paper, where it should have appeared as the seventh author; it was present in the author list at the end of the paper, but the footnote directing readers to the Supplementary Note for a list of members was missing. In the HTML version, the consortium was listed as the last author instead of as the seventh, and the line directing readers to the Supplementary Note for a list of members appeared at the end of the paper under Author Information but not in association with the consortium name itself. Also, this line stated that both member names and affiliations could be found in the Supplementary Note; in fact, only names are given. In all versions of the paper, the corresponding author symbols we...

Circulation, Nov 28, 2017

Background -Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basi... more Background -Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis (PVOD/PCH). Here, we determined the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods -Whole genome sequencing was performed on DNA from patients with idiopathic and heritable PAH, as well as PVOD/PCH recruited to the NIHR BioResource - Rare Diseases Study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of < 1:10,000 in control data sets and predicted to be deleterious (by CADD, PolyPhen-2 and SIFT predictions...

Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de n... more Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with published data on 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the affected individual, the relatedness of their parents and the age of both father and mother. We identified 94 genes enriched for damaging de novo mutation at genome-wide significance (P < 7 × 10−7), including 14 genes for which compelling data for causation was previously lacking. We have characterised the phenotypic diversity among these genetic disorders. We demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42% of our co...