RESUMEN
Kabuki syndrome is a heterogeneous condition characterized by distinctive facial features, intellectual disability, growth retardation, skeletal abnormalities and a range of organ malformations. Although at least two major causative genes have been identified, these do not explain all cases. Here we describe a patient with a complex Kabuki-like syndrome that included nodular heterotopia, in whom testing for several single-gene disorders had proved negative. Exome sequencing uncovered a de novo c.931_932insTT variant in HNRNPK (heterogeneous nuclear ribonucleoprotein K). Although this variant was identified in March 2012, its clinical relevance could only be confirmed following the August 2015 publication of two cases with HNRNPK mutations and an overlapping phenotype that included intellectual disability, distinctive facial dysmorphism and skeletal/connective tissue abnormalities. Whilst we had attempted (unsuccessfully) to identify additional cases through existing collaborators, the two published cases were 'matched' using GeneMatcher, a web-based tool for connecting researchers and clinicians working on identical genes. Our report therefore exemplifies the importance of such online tools in clinical genetics research and the benefits of periodically reviewing cases with variants of unproven significance. Our study also suggests that loss of function variants in HNRNPK should be considered as a molecular basis for patients with Kabuki-like syndrome.
Asunto(s)
Anomalías Múltiples/genética , Discapacidades del Desarrollo/genética , Cara/anomalías , Enfermedades Hematológicas/genética , Discapacidad Intelectual/genética , Ribonucleoproteínas/genética , Enfermedades Vestibulares/genética , Anomalías Múltiples/fisiopatología , Secuencia de Bases , Discapacidades del Desarrollo/fisiopatología , Exoma , Cara/fisiopatología , Femenino , Mutación del Sistema de Lectura , Enfermedades Hematológicas/fisiopatología , Ribonucleoproteína Heterogénea-Nuclear Grupo K , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/fisiopatología , Enfermedades Vestibulares/fisiopatologíaRESUMEN
BACKGROUND: Genomic disorders are often caused by non-allelic homologous recombination between segmental duplications. Chromosome 16 is especially rich in a chromosome-specific low copy repeat, termed LCR16. METHODS AND RESULTS: A bacterial artificial chromosome (BAC) array comparative genome hybridisation (CGH) screen of 1027 patients with mental retardation and/or multiple congenital anomalies (MR/MCA) was performed. The BAC array CGH screen identified five patients with deletions and five with apparently reciprocal duplications of 16p13 covering 1.65 Mb, including 15 RefSeq genes. In addition, three atypical rearrangements overlapping or flanking this region were found. Fine mapping by high-resolution oligonucleotide arrays suggests that these deletions and duplications result from non-allelic homologous recombination (NAHR) between distinct LCR16 subunits with >99% sequence identity. Deletions and duplications were either de novo or inherited from unaffected parents. To determine whether these imbalances are associated with the MR/MCA phenotype or whether they might be benign variants, a population of 2014 normal controls was screened. The absence of deletions in the control population showed that 16p13.11 deletions are significantly associated with MR/MCA (p = 0.0048). Despite phenotypic variability, common features were identified: three patients with deletions presented with MR, microcephaly and epilepsy (two of these had also short stature), and two other deletion carriers ascertained prenatally presented with cleft lip and midline defects. In contrast to its previous association with autism, the duplication seems to be a common variant in the population (5/1682, 0.29%). CONCLUSION: These findings indicate that deletions inherited from clinically normal parents are likely to be causal for the patients' phenotype whereas the role of duplications (de novo or inherited) in the phenotype remains uncertain. This difference in knowledge regarding the clinical relevance of the deletion and the duplication causes a paradigm shift in (cyto)genetic counselling.
Asunto(s)
Anomalías Múltiples/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 16/genética , Discapacidad Intelectual/genética , Anomalías Múltiples/patología , Adulto , Anciano , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/patología , Labio Leporino/patología , Hibridación Genómica Comparativa , Epilepsia/patología , Duplicación de Gen , Trastornos del Crecimiento/patología , Humanos , Discapacidad Intelectual/patología , Microcefalia/patología , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de RiesgoRESUMEN
BACKGROUND: Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy. METHODS: To assess further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region. RESULTS: The 15q13.3 microdeletion in our series was associated with a highly variable intra- and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients. CONCLUSIONS: Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.
Asunto(s)
Aberraciones Cromosómicas , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 15/genética , Duplicación de Gen , Adolescente , Adulto , Niño , Preescolar , Trastornos de los Cromosomas/patología , Femenino , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Embarazo , SíndromeRESUMEN
BACKGROUND: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation. AIM: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome. RESULTS: We estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10(-5)). CONCLUSION: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.
Asunto(s)
Anomalías Múltiples , Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Discapacidades del Desarrollo , Anomalías Múltiples/epidemiología , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Niño , Preescolar , Inversión Cromosómica , Discapacidades del Desarrollo/epidemiología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Cara/patología , Femenino , Humanos , Lactante , Masculino , Hipotonía Muscular/epidemiología , Hipotonía Muscular/genética , Hipotonía Muscular/fisiopatología , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Prevalencia , Adulto Joven , Proteínas tauRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
This corrects the article DOI: 10.1038/leu.2017.177.
RESUMEN
Chronic lymphocytic leukaemia (CLL) consists of two biologically and clinically distinct subtypes defined by the abundance of somatic hypermutation (SHM) affecting the Ig variable heavy-chain locus (IgHV). The molecular mechanisms underlying these subtypes are incompletely understood. Here, we present a comprehensive whole-genome sequencing analysis of somatically acquired genetic events from 46 CLL patients, including a systematic comparison of coding and non-coding single-nucleotide variants, copy number variants and structural variants, regions of kataegis and mutation signatures between IgHVmut and IgHVunmut subtypes. We demonstrate that one-quarter of non-coding mutations in regions of kataegis outside the Ig loci are located in genes relevant to CLL. We show that non-coding mutations in ATM may negatively impact on ATM expression and find non-coding and regulatory region mutations in TCL1A, and in IgHVunmut CLL in IKZF3, SAMHD1,PAX5 and BIRC3. Finally, we show that IgHVunmut CLL is dominated by coding mutations in driver genes and an aging signature, whereas IgHVmut CLL has a high incidence of promoter and enhancer mutations caused by aberrant activation-induced cytidine deaminase activity. Taken together, our data support the hypothesis that differences in clinical outcome and biological characteristics between the two subgroups might reflect differences in mutation distribution, incidence and distinct underlying mutagenic mechanisms.
Asunto(s)
Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación/genética , Anciano , Anciano de 80 o más Años , Citidina Desaminasa/genética , Elementos de Facilitación Genéticos/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas/genética , Proteína 1 que Contiene Dominios SAM y HD/genética , Secuenciación Completa del Genoma/métodosRESUMEN
Learning disability (LD) is a very common, lifelong and disabling condition, affecting about 3% of the population. Despite this, it is only over the past 10-15 years that major progress has been made towards understanding the origins of LD. In particular, genetics driven advances in technology have led to the unequivocal demonstration of the importance of genome imbalance in the aetiology of idiopathic LD (ILD). In this review we provide an overview of these advances, discussing technologies such as multi-telomere FISH and array CGH that have already emerged as well as new approaches that show diagnostic potential for the future. The advances to date have highlighted new considerations such as copy number polymorphisms (CNPs) that can complicate the interpretation of genome imbalance and its relevance to ILD. More importantly though, they have provided a remarkable approximately 15-20% improvement in diagnostic capability as well as facilitating genotype/phenotype correlations and providing new avenues for the identification and understanding of genes involved in neurocognitive function.
Asunto(s)
Genoma Humano , Discapacidades para el Aprendizaje/genética , Aberraciones Cromosómicas , Mapeo Cromosómico , Cromosomas/ultraestructura , Genómica/métodos , Humanos , Hibridación Fluorescente in Situ , Internet , Hibridación de Ácido Nucleico , Polimorfismo GenéticoRESUMEN
Genome-wide array approaches and sequencing analyses are powerful tools for identifying genetic aberrations in cancers, including leukemias and lymphomas. However, the clinical and biological significance of such aberrations and their subclonal distribution are poorly understood. Here, we present the first genome-wide array based study of pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia (B-CLL) that uses the computational statistical tool OncoSNP. We show that quantification of the proportion of copy number alterations (CNAs) and copy neutral loss of heterozygosity regions (cnLOHs) in each sample is feasible. Furthermore, we (i) reveal complex changes in the subclonal architecture of paired samples at relapse compared with pre-treatment, (ii) provide evidence supporting an association between increased genomic complexity and poor clinical outcome (iii) report previously undefined, recurrent CNA/cnLOH regions that expand or newly occur at relapse and therefore might harbor candidate driver genes of relapse and/or chemotherapy resistance. Our findings are likely to impact on future therapeutic strategies aimed towards selecting effective and individually tailored targeted therapies.
Asunto(s)
Biomarcadores de Tumor/genética , Aberraciones Cromosómicas , Células Clonales/patología , Leucemia Linfocítica Crónica de Células B/genética , Recurrencia Local de Neoplasia/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Dosificación de Gen , Genoma Humano , Genómica , Humanos , Leucemia Linfocítica Crónica de Células B/terapia , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/terapia , Análisis de Secuencia por Matrices de Oligonucleótidos , PronósticoRESUMEN
The chromosome region 22q11.2 has long been recognized to be susceptible to genomic rearrangement. More recently, this genomic instability has been shown to extend distally (involving LCR22E-H) to the commonly deleted/duplicated region. To date, 21 index cases with 'distal' 22q11.2 duplications have been reported. We report on the clinical and molecular characterization of 16 individuals with distal 22q11.2 duplications identified by DNA microarray analysis. Two of the individuals have been partly described previously. The clinical phenotype varied among the patients in this study, although the majority displayed various degrees of developmental delay and speech disturbances. Other clinical features included behavioral problems, hypotonia, and dysmorphic facial features. Notably, none of the patients was diagnosed with a congenital heart defect. We found a high degree of inherited duplications. Additional copy number changes of unclear clinical significance were identified in 5 of our patients, and it is possible that these may contribute to the phenotypic expression in these patients as has been suggested recently in a 2-hit 'digenic' model for 16p12.1 deletions. The varied phenotypic expression and incomplete penetrance observed for distal 22q11.2 duplications makes it exceedingly difficult to ascribe pathogenicity for these duplications. Given the observed enrichment of the duplication in patient samples versus healthy controls, it is likely that distal 22q11.2 duplications represent a susceptibility/risk locus for speech and mild developmental delay.