RESUMEN
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5' splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.
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PURPOSE: Genome sequencing (GS)-specific diagnostic rates in prospective tightly ascertained exome sequencing (ES)-negative intellectual disability (ID) cohorts have not been reported extensively. METHODS: ES, GS, epigenetic signatures, and long-read sequencing diagnoses were assessed in 74 trios with at least moderate ID. RESULTS: The ES diagnostic yield was 42 of 74 (57%). GS diagnoses were made in 9 of 32 (28%) ES-unresolved families. Repeated ES with a contemporary pipeline on the GS-diagnosed families identified 8 of 9 single-nucleotide variations/copy-number variations undetected in older ES, confirming a GS-unique diagnostic rate of 1 in 32 (3%). Episignatures contributed diagnostic information in 9% with GS corroboration in 1 of 32 (3%) and diagnostic clues in 2 of 32 (6%). A genetic etiology for ID was detected in 51 of 74 (69%) families. Twelve candidate disease genes were identified. Contemporary ES followed by GS cost US$4976 (95% CI: $3704; $6969) per diagnosis and first-line GS at a cost of $7062 (95% CI: $6210; $8475) per diagnosis. CONCLUSION: Performing GS only in ID trios would be cost equivalent to ES if GS were available at $2435, about a 60% reduction from current prices. This study demonstrates that first-line GS achieves higher diagnostic rate than contemporary ES but at a higher cost.
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Secuenciación del Exoma , Exoma , Discapacidad Intelectual , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Masculino , Femenino , Exoma/genética , Secuenciación del Exoma/economía , Estudios de Cohortes , Pruebas Genéticas/economía , Pruebas Genéticas/métodos , Secuenciación Completa del Genoma/economía , Niño , Genoma Humano/genética , Variaciones en el Número de Copia de ADN/genética , Polimorfismo de Nucleótido Simple/genética , PreescolarRESUMEN
PURPOSE: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22-p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. METHODS: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. RESULTS: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. CONCLUSION: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene-disease validity for the purpose of diagnostic reporting.
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Discapacidad Intelectual , Trastornos del Neurodesarrollo , Haploinsuficiencia/genética , Heterocigoto , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Fenotipo , Complejo Represivo Polycomb 2/genética , Síndrome , Secuenciación del ExomaRESUMEN
OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.
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Cardiomiopatía Dilatada/congénito , Conectina/genética , Proteínas Musculares/genética , Músculo Esquelético/patología , Femenino , Humanos , Masculino , Mutación/genética , Fenotipo , Isoformas de Proteínas/genéticaRESUMEN
The devastating clinical presentation of X-linked lissencephaly with abnormal genitalia (XLAG) is invariably caused by loss-of-function mutations in the Aristaless-related homeobox (ARX) gene. Mutations in this X-chromosome gene contribute to intellectual disability (ID) with co-morbidities including seizures and movement disorders such as dystonia in affected males. The detection of affected females with mutations in ARX is increasing. We present a family with multiple affected individuals, including two females. Two male siblings presenting with XLAG were deceased prior to full-term gestation or within the first few weeks of life. Of the two female siblings, one presented with behavioral disturbances, mild ID, a seizure disorder, and complete agenesis of the corpus callosum (ACC), similar to the mother's phenotype. A novel insertion mutation in Exon 2 of ARX was identified, c.982delCinsTTT predicted to cause a frameshift at p.(Q328Ffs* 37). Our finding is consistent with loss-of-function mutations in ARX causing XLAG in hemizygous males and extends the findings of ID and seizures in heterozygous females. We review the reported phenotypes of females with mutations in ARX and highlight the importance of screening ARX in male and female patients with ID, seizures, and in particular with complete ACC.
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Estudios de Asociación Genética , Proteínas de Homeodominio/genética , Mutación , Fenotipo , Factores de Transcripción/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Encéfalo/patología , Niño , Preescolar , Análisis Mutacional de ADN , Exones , Femenino , Genes Ligados a X , Proteínas de Homeodominio/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Linaje , Factores de Transcripción/metabolismoRESUMEN
Mutations in ADNP were recently identified as a frequent cause of syndromic autism, characterized by deficits in social communication and interaction and restricted, repetitive behavioral patterns. Based on its functional domains, ADNP is a presumed transcription factor. The gene interacts closely with the SWI/SNF complex by direct and experimentally verified binding of its C-terminus to three of its core components. A detailed and systematic clinical assessment of the symptoms observed in our patients allows a detailed comparison with the symptoms observed in other SWI/SNF disorders. While the mutational mechanism of the first 10 patients identified suggested a gain of function mechanism, an 11th patient reported here is predicted haploinsufficient. The latter observation may raise hope for therapy, as addition of NAP, a neuroprotective octapeptide named after the first three amino acids of the sequence NAPVSPIQ, has been reported by others to ameliorate some of the cognitive abnormalities observed in a knockout mouse model. It is concluded that detailed clinical and molecular studies on larger cohorts of patients are necessary to establish a better insight in the genotype phenotype correlation and in the mutational mechanism.
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Trastorno Autístico/genética , Proteínas de Homeodominio/genética , Mutación , Proteínas del Tejido Nervioso/genética , Anomalías Múltiples/genética , Animales , Trastorno Autístico/etiología , Preescolar , ADN Helicasas/genética , ADN Helicasas/metabolismo , Cara/anomalías , Deformidades Congénitas de la Mano/genética , Haploinsuficiencia/genética , Humanos , Lactante , Discapacidad Intelectual/genética , Ratones Noqueados , Micrognatismo/genética , Cuello/anomalías , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oligopéptidos/farmacología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a novel syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals.
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Brittle cornea syndrome (BCS; MIM 229200) is an autosomal recessive generalized connective tissue disorder caused by mutations in ZNF469 and PRDM5. It is characterized by extreme thinning and fragility of the cornea that may rupture in the absence of significant trauma leading to blindness. Keratoconus or keratoglobus, high myopia, blue sclerae, hyperelasticity of the skin without excessive fragility, and hypermobility of the small joints are additional features of BCS. Transcriptional regulation of extracellular matrix components, particularly of fibrillar collagens, by PRDM5 and ZNF469 suggests that they might be part of the same pathway, the disruption of which is likely to cause the features of BCS. In the present study, we have performed molecular analysis of a cohort of 23 BCS affected patients on both ZNF469 and PRDM5, including those who were clinically reported previously [1]; the clinical description of three additional patients is reported in detail. We identified either homozygous or compound heterozygous mutations in ZNF469 in 18 patients while, 4 were found to be homozygous for PRDM5 mutations. In one single patient a mutation in neither ZNF469 nor PRDM5 was identified. Furthermore, we report the 12 novel ZNF469 variants identified in our patient cohort, and show evidence that ZNF469 is a single exon rather than a two exon gene.
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Síndrome de Ehlers-Danlos/genética , Exones , Matriz Extracelular/genética , Regulación de la Expresión Génica , Mutación , Factores de Transcripción/genética , Adolescente , Niño , Preescolar , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/terapia , Anomalías del Ojo , Femenino , Genotipo , Humanos , Inestabilidad de la Articulación/congénito , Anomalías CutáneasRESUMEN
Reproductive genetic carrier screening aims to offer couples information about their chance of having children with certain autosomal recessive and X-linked genetic conditions. We developed a gene list for use in "Mackenzie's Mission", a research project in which 10,000 couples will undergo screening. Criteria for selecting genes were: the condition should be life-limiting or disabling, with childhood onset, such that couples would be likely to take steps to avoid having an affected child; and/or be one for which early diagnosis and intervention would substantially change outcome. Strong evidence for gene-phenotype relationship was required. Candidate genes were identified from OMIM and via review of 23 commercial and published gene lists. Genes were reviewed by 16 clinical geneticists using a standard operating procedure, in a process overseen by a multidisciplinary committee which included clinical geneticists, genetic counselors, an ethicist, a parent of a child with a genetic condition and scientists from diagnostic and research backgrounds. 1300 genes met criteria. Genes associated with non-syndromic deafness and non-syndromic differences of sex development were not included. Our experience has highlighted that gene selection for a carrier screening panel needs to be a dynamic process with ongoing review and refinement.
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Conferencias de Consenso como Asunto , Tamización de Portadores Genéticos/métodos , Australia , Tamización de Portadores Genéticos/estadística & datos numéricos , Predisposición Genética a la Enfermedad , Humanos , Sitios de Carácter CuantitativoRESUMEN
BACKGROUND: The natural history of aortic diseases in patients with TGFBR1 or TGFBR2 mutations reported by different investigators has varied greatly. In particular, the current recommendations for the timing of surgical repair of the aortic root aneurysms may be overly aggressive. METHODS AND RESULTS: The Montalcino Aortic Consortium, which includes 15 centers worldwide that specialize in heritable thoracic aortic diseases, was used to gather data on 441 patients from 228 families, with 176 cases harboring a mutation in TGBR1 and 265 in TGFBR2. Patients harboring a TGFBR1 mutation have similar survival rates (80% survival at 60 years), aortic risk (23% aortic dissection and 18% preventive aortic surgery), and prevalence of extra-aortic features (29% hypertelorism, 53% cervical arterial tortuosity, and 27% wide scars) when compared with patients harboring a TGFBR2 mutation. However, TGFBR1 males had a greater aortic risk than females, whereas TGFBR2 males and females had a similar aortic risk. Additionally, aortic root diameter prior to or at the time of type A aortic dissection tended to be smaller in patients carrying a TGFBR2 mutation and was ≤45 mm in 6 women with TGFBR2 mutations, presenting with marked systemic features and low body surface area. Aortic dissection was observed in 1.6% of pregnancies. CONCLUSIONS: Patients with TGFBR1 or TGFBR2 mutations show the same prevalence of systemic features and the same global survival. Preventive aortic surgery at a diameter of 45 mm, lowered toward 40 in females with low body surface area, TGFBR2 mutation, and severe extra-aortic features may be considered.
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Aorta Torácica , Enfermedades de la Aorta/genética , Heterocigoto , Mutación , Complicaciones Cardiovasculares del Embarazo/genética , Proteínas Serina-Treonina Quinasas/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Aorta Torácica/diagnóstico por imagen , Aorta Torácica/cirugía , Enfermedades de la Aorta/diagnóstico por imagen , Enfermedades de la Aorta/mortalidad , Enfermedades de la Aorta/cirugía , Australia/epidemiología , Europa (Continente)/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Japón/epidemiología , Estimación de Kaplan-Meier , Masculino , Fenotipo , Embarazo , Complicaciones Cardiovasculares del Embarazo/diagnóstico por imagen , Complicaciones Cardiovasculares del Embarazo/mortalidad , Complicaciones Cardiovasculares del Embarazo/cirugía , Prevalencia , Modelos de Riesgos Proporcionales , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo II de Factor de Crecimiento Transformador beta , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Estados Unidos/epidemiología , Procedimientos Quirúrgicos VascularesRESUMEN
Despite the high heritability of autism spectrum disorders (ASD), characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests or activities, a genetic diagnosis can be established in only a minority of patients. Known genetic causes include chromosomal aberrations, such as the duplication of the 15q11-13 region, and monogenic causes, as in Rett and fragile-X syndromes. The genetic heterogeneity within ASD is striking, with even the most frequent causes responsible for only 1% of cases at the most. Even with the recent developments in next-generation sequencing, for the large majority of cases no molecular diagnosis can be established. Here, we report ten patients with ASD and other shared clinical characteristics, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/SNF remodeling complex. We estimate this gene to be mutated in at least 0.17% of ASD cases, making it one of the most frequent ASD-associated genes known to date.