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1.
Genet Med ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31316167

RESUMO

PURPOSE: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing. METHODS: In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups. RESULTS: The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups. CONCLUSIONS: Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.

2.
Genet Med ; 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31239556

RESUMO

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

3.
Am J Hum Genet ; 103(5): 752-768, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388402

RESUMO

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.

4.
Artigo em Inglês | MEDLINE | ID: mdl-29437797

RESUMO

Aquaporin-4, encoded by AQP4, is the major water channel in the central nervous system and plays an important role in the brain's water balance, including edema formation and clearance. Using genomic copy-number analysis and trio-exome sequencing, we investigated a male patient with intellectual disability, hearing loss, and progressive gait dysfunction and found a de novo missense change Ser111Thr in AQP4 as the only suspicious finding. Perinatally, signs of brain ischemia were detected in relation to acute collapse 2 h after birth that resolved a few days later. At the age of 3 mo, cardiac hypertrophy was detected that persisted through childhood but was completely resolved by age 16. In theory, this neurodevelopmental disorder with transient cardiomyopathy could be caused by a disturbance of cellular water balance. Ser111 is an extremely conserved residue in the short cytoplasmic loop between AQP4 transmembrane helix 2 and 3, present across all AQP isoforms from plants to mammals, and it does not appear to be a phosphorylation site. We found that the Ser111Thr change does not affect water permeability or protein stability, suggesting another and possibly regulatory role. Although causality remains unproven, this case study draws attention to AQP4 as a candidate gene for a unique developmental disorder and to a specific serine as a residue of possibly great functional importance in many AQPs.

5.
Eur J Hum Genet ; 26(1): 64-74, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29180823

RESUMO

Whole-gene duplications and missense variants in the HUWE1 gene (NM_031407.6) have been reported in association with intellectual disability (ID). Increased gene dosage has been observed in males with non-syndromic mild to moderate ID with speech delay. Missense variants reported previously appear to be associated with severe ID in males and mild or no ID in obligate carrier females. Here, we report the largest cohort of patients with HUWE1 variants, consisting of 14 females and 7 males, with 15 different missense variants and one splice site variant. Clinical assessment identified common clinical features consisting of moderate to profound ID, delayed or absent speech, short stature with small hands and feet and facial dysmorphism consisting of a broad nasal tip, deep set eyes, epicanthic folds, short palpebral fissures, and a short philtrum. We describe for the first time that females can be severely affected, despite preferential inactivation of the affected X chromosome. Three females with the c.329 G > A p.Arg110Gln variant, present with a phenotype of mild ID, specific facial features, scoliosis and craniosynostosis, as reported previously in a single patient. In these females, the X inactivation pattern appeared skewed in favour of the affected transcript. In summary, HUWE1 missense variants may cause syndromic ID in both males and females.

6.
Acta Ophthalmol ; 95(3): 240-246, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27775217

RESUMO

PURPOSE: Despite being the third most common ABCA4 variant observed in patients with Stargardt disease, the functional effect of the intronic ABCA4 variant c.5461-10T>C is unknown. The purpose of this study was to investigate the molecular effect of this variant. METHODS: Fibroblast samples from patients carrying the ABCA4 variant c.5461-10T>C were analysed by isolating total RNA, followed by real-time polymerase chain reaction (RT-PCR) using specific primers spanning the variant. For detection of ABCA4 protein, fibroblast samples were lysed and analysed by SDS-PAGE followed by immunoblotting using a monoclonal ABCA4 antibody. RESULTS: The ABCA4 variant c.5461-10T>C causes a splicing defect resulting in the reduction of full-length mRNA in fibroblasts from patients and the presence of alternatively spliced mRNAs where exon 39-40 is skipped. A reduced level of full-length ABCA4 protein is observed compared to controls not carrying the variant. CONCLUSIONS: This study describes the functional effect and the molecular mechanism of the pathogenic ABCA4 variant c.5461-10T>C. The variant is functionally important as it leads to splicing defects and a reduced level of ABCA4 protein.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Degeneração Macular/congênito , Mutação , RNA/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Células Cultivadas , Análise Mutacional de DNA , Eletrorretinografia , Éxons , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Immunoblotting , Íntrons , Degeneração Macular/diagnóstico , Degeneração Macular/genética , Degeneração Macular/metabolismo , Masculino , Linhagem , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Segmento Externo da Célula Bastonete , Tomografia de Coerência Óptica , Adulto Jovem
7.
J Clin Invest ; 126(8): 3080-8, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27400125

RESUMO

Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (EPHB4). Biochemical analysis determined that the mutant EPHB4 proteins are devoid of tyrosine kinase activity, indicating that loss of EPHB4 signaling contributes to LRHF pathogenesis. Further, inactivation of Ephb4 in lymphatic endothelial cells of developing mouse embryos led to defective lymphovenous valve formation and consequent subcutaneous edema. Together, these findings identify EPHB4 as a critical regulator of early lymphatic vascular development and demonstrate that mutations in the gene can cause an autosomal dominant form of LRHF that is associated with a high mortality rate.


Assuntos
Hidropisia Fetal/genética , Hidropisia Fetal/metabolismo , Mutação , Receptor EphB4/genética , Receptor EphB4/metabolismo , Animais , Células Endoteliais/metabolismo , Exoma , Feminino , Deleção de Genes , Genes Dominantes , Células HEK293 , Heterozigoto , Humanos , Vasos Linfáticos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único
8.
Ophthalmic Genet ; 37(2): 183-93, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26333019

RESUMO

PURPOSE: To describe the genotype and phenotype of patients with autosomal recessive bestrophinopathy (ARB), and heterozygous carriers. METHODS: The members of three unrelated ARB families were investigated. Molecular genetic analysis was performed on 11 members of these families. Ten members were examined clinically; including visual acuity, slit-lamp examination, biomicroscopy, fundus photography, and Goldmann applanation tonometry. Measurements were also made of the anterior chamber depth and axial length, and optical coherence tomography (OCT), electrooculography (EOG), and full-field electroretinography (full-field ERG) were performed. Multifocal electroretinography (mfERG) was performed on eight members of these families. RESULTS: Two novel combinations of missense mutations in the BEST1 gene were identified: p.R141H/p.M325T in three patients with ARB in two unrelated Norwegian families, and p.R141H/p.I201T was found in an ARB patient in a Swedish family. All four patients with ARB had clinical and electrophysiological features of ARB. All the heterozygous carriers of the p.R141H mutation were clinically normal, and showed normal OCT, EOG and full-field ERG findings, but had mildly abnormal mfERG results. Only one heterozygous carrier of the p.M325T mutation was studied and he was clinically normal, showing normal OCT and full-field ERG results, but subnormal EOG and mfERG findings. The heterozygous carrier of the p.I201T mutation was clinically normal, showing normal OCT, EOG and full-field ERG results, but subnormal mfERG results. CONCLUSIONS: We have shown that the two novel combinations of compound heterozygous mutations p.R141H/p.M325T and p.R141H/p.I201T in the BEST1 gene can also lead to the ARB phenotype.


Assuntos
Canais de Cloreto/genética , Oftalmopatias Hereditárias/genética , Proteínas do Olho/genética , Mutação de Sentido Incorreto , Doenças Retinianas/genética , Adolescente , Adulto , Bestrofinas , Criança , Análise Mutacional de DNA , Eletrorretinografia , Oftalmopatias Hereditárias/patologia , Feminino , Genes Recessivos , Estudos de Associação Genética , Humanos , Masculino , Microscopia Acústica , Pessoa de Meia-Idade , Linhagem , Doenças Retinianas/patologia , Lâmpada de Fenda , Tomografia de Coerência Óptica , Tonometria Ocular , Acuidade Visual/fisiologia , Adulto Jovem
9.
J Clin Invest ; 125(8): 3051-62, 2015 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-26168268

RESUMO

Here we report inherited dysregulation of protein phosphatase activity as a cause of intellectual disability (ID). De novo missense mutations in 2 subunits of serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) were identified in 16 individuals with mild to severe ID, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. PP2A comprises catalytic (C), scaffolding (A), and regulatory (B) subunits that determine subcellular anchoring, substrate specificity, and physiological function. Ten patients had mutations within a highly conserved acidic loop of the PPP2R5D-encoded B56δ regulatory subunit, with the same E198K mutation present in 6 individuals. Five patients had mutations in the PPP2R1A-encoded scaffolding Aα subunit, with the same R182W mutation in 3 individuals. Some Aα cases presented with large ventricles, causing macrocephaly and hydrocephalus suspicion, and all cases exhibited partial or complete corpus callosum agenesis. Functional evaluation revealed that mutant A and B subunits were stable and uncoupled from phosphatase activity. Mutant B56δ was A and C binding-deficient, while mutant Aα subunits bound B56δ well but were unable to bind C or bound a catalytically impaired C, suggesting a dominant-negative effect where mutant subunits hinder dephosphorylation of B56δ-anchored substrates. Moreover, mutant subunit overexpression resulted in hyperphosphorylation of GSK3ß, a B56δ-regulated substrate. This effect was in line with clinical observations, supporting a correlation between the ID degree and biochemical disturbance.


Assuntos
Agenesia do Corpo Caloso , Corpo Caloso , Transtornos Mentais , Mutação de Sentido Incorreto , Proteína Fosfatase 2 , Adolescente , Adulto , Agenesia do Corpo Caloso/enzimologia , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Substituição de Aminoácidos , Criança , Pré-Escolar , Corpo Caloso/enzimologia , Corpo Caloso/patologia , Feminino , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Lactente , Masculino , Transtornos Mentais/enzimologia , Transtornos Mentais/genética , Transtornos Mentais/patologia , Pessoa de Meia-Idade , Fosforilação/genética , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína
11.
Eur J Hum Genet ; 23(9): 1165-70, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25424711

RESUMO

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.


Assuntos
Blefarofimose/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Éxons , Cardiopatias Congênitas/genética , Histona Acetiltransferases/genética , Deficiência Intelectual/genética , Instabilidade Articular/genética , Rim/anormalidades , Mutação , Patela/anormalidades , Transtornos Psicomotores/genética , Escroto/anormalidades , Anormalidades Urogenitais/genética , Blefarofimose/diagnóstico , Blefarofimose/patologia , Pré-Escolar , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/patologia , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/patologia , Análise Mutacional de DNA , Diagnóstico Diferencial , Exoma , Facies , Feminino , Expressão Gênica , Estudos de Associação Genética , Genótipo , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Instabilidade Articular/diagnóstico , Instabilidade Articular/patologia , Rim/patologia , Masculino , Patela/patologia , Fenótipo , Transtornos Psicomotores/diagnóstico , Transtornos Psicomotores/patologia , Escroto/patologia , Índice de Gravidade de Doença , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/patologia
12.
Am J Med Genet C Semin Med Genet ; 166C(3): 290-301, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25099957

RESUMO

Recently, de novo aberrations in PHF6 were identified in females with intellectual disability and with a distinct phenotype including a characteristic facial gestalt with bitemporal narrowing, prominent supraorbital ridges, synophrys, a short nose and dental anomalies, tapering fingers with brachytelephalangy, clinodactyly and hypoplastic nails, short toes with hypoplastic nails, and linear skin hyperpigmentation. In adolescent or older patients, this phenotype overlaps but is not identical with Borjeson-Forssman-Lehmann syndrome in males, caused by X-linked recessive mutations in PHF6. In younger girls there seems to be a striking phenotypic overlap with Coffin-Siris syndrome, which is characterized by intellectual disability, sparse hair and hypoplastic nails. This review will summarize and characterize the female phenotype caused by de novo aberrations in PHF6 and will discuss the overlapping and distinguishing features with Coffin-Siris syndrome.


Assuntos
Anormalidades Múltiplas/etiologia , Proteínas de Transporte/genética , Epilepsia/etiologia , Face/anormalidades , Dedos/anormalidades , Transtornos do Crescimento/etiologia , Deformidades Congênitas da Mão/etiologia , Hipogonadismo/etiologia , Deficiência Intelectual/etiologia , Retardo Mental Ligado ao Cromossomo X/etiologia , Micrognatismo/etiologia , Pescoço/anormalidades , Obesidade/etiologia , Anormalidades Múltiplas/genética , Criança , Epilepsia/genética , Feminino , Estudos de Associação Genética , Transtornos do Crescimento/genética , Deformidades Congênitas da Mão/genética , Humanos , Hipogonadismo/genética , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Micrognatismo/genética , Unhas Malformadas/genética , Obesidade/genética , Linhagem , Adulto Jovem
13.
Am J Med Genet A ; 164A(7): 1622-6, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24678003

RESUMO

MEIS2 is a homeodomain-containing transcription factor of the TALE superfamily that has been proven important for development. We confirm and extend a recent single clinical report stating that deletions in MEIS2 can cause cleft palate [Crowley et al. (2010); Am J Med Genet 152A:1326-1327]. Here we report on five additional patients with 15q14 deletions of sizes 0.6, 0.6, 1.0, 1.9, and 4.8 Mb, respectively, all involving MEIS2. In addition, we present a family with four affected individuals and an intragenic 58 kb direct duplication disrupting MEIS2. In total, 7/9 cases had clefting, from mild (submucous cleft palate) to severe (cleft lip and palate), and 3/9 cases had ventricular septal defects. All cases had delayed motor development and most had learning disability, at worst in the mild intellectual disability range. The cases had overlapping facial features (broad forehead, finely arched eyebrows, mildly shortened philtrum, and tented upper lip) but individually they were not considered to be dysmorphic. Our results show that MEIS2 is a gene needed for palate closure. In syndromic cases of cleft palate, MEIS2 should be considered among the candidate genes, for example, in cases without 22q11.2 deletions.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Estudos de Associação Genética , Haploinsuficiência , Proteínas de Homeodomínio/genética , Transtornos de Aprendizagem/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Fenda Labial/diagnóstico , Fissura Palatina/diagnóstico , Hibridização Genômica Comparativa , Facies , Feminino , Humanos , Transtornos de Aprendizagem/diagnóstico , Masculino , Fenótipo , Análise de Sequência de DNA , Adulto Jovem
14.
Eur J Hum Genet ; 21(12): 1344-8, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23572028

RESUMO

Classical Beckwith-Wiedemann syndrome (BWS) was diagnosed in two sisters and their male cousin. The children's mothers and a third sister were tall statured (178, 185 and 187 cm) and one had mild BWS features as a child. Their parents had average heights of 173 cm (mother) and 180 cm (father). This second generation tall stature and third generation BWS correlated with increased methylation of the maternal H19/IGF2-locus. The results were obtained by bisulphite treatment and subclone Sanger sequencing or next generation sequencing to quantitate the degree of CpG-methylation on three locations: the H19 promoter region and two CTCF binding sites in the H19 imprinting control region (ICR1), specifically in ICR1 repeats B1 and B7. Upon ICR1 copy number analysis and sequencing, the same maternal point variant NCBI36:11:g.1979595T>C that had been described previously as a cause of BWS in three brothers, was found. As expected, this point variant was on the paternal allele in the non-affected grandmother. This nucleotide variant has been shown to affect OCTamer-binding transcription factor-4 (OCT4) binding, which may be necessary for maintaining the unmethylated state of the maternal allele. Our data extend these findings by showing that the OCT4 binding site mutation caused incomplete switching from paternal to maternal ICR1 methylation imprint, and that upon further maternal transmission, methylation of the incompletely demethylated variant ICR1 allele was further increased. This suggests that maternal and paternal ICR1 alleles are treated differentially in the female germline, and only the paternal allele appears to be capable of demethylation.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Variação Estrutural do Genoma/genética , Adolescente , Alelos , Sítios de Ligação/genética , Criança , Cromossomos Humanos Par 11/genética , Metilação de DNA/genética , Feminino , Impressão Genômica/genética , Humanos , Fator de Crescimento Insulin-Like II/genética , Masculino , Mutação/genética , Fator 3 de Transcrição de Octâmero/genética , RNA Longo não Codificante/genética
15.
Am J Hum Genet ; 91(2): 252-64, 2012 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-22840365

RESUMO

We previously reported on nonrecurrent overlapping duplications at Xp11.22 in individuals with nonsyndromic intellectual disability (ID) harboring HSD17B10, HUWE1, and the microRNAs miR-98 and let-7f-2 in the smallest region of overlap. Here, we describe six additional individuals with nonsyndromic ID and overlapping microduplications that segregate in the families. High-resolution mapping of the 12 copy-number gains reduced the minimal duplicated region to the HUWE1 locus only. Consequently, increased mRNA levels were detected for HUWE1, but not HSD17B10. Marker and SNP analysis, together with identification of two de novo events, suggested a paternally derived intrachromosomal duplication event. In four independent families, we report on a polymorphic 70 kb recurrent copy-number gain, which harbors part of HUWE1 (exon 28 to 3' untranslated region), including miR-98 and let-7f-2. Our findings thus demonstrate that HUWE1 is the only remaining dosage-sensitive gene associated with the ID phenotype. Junction and in silico analysis of breakpoint regions demonstrated simple microhomology-mediated rearrangements suggestive of replication-based duplication events. Intriguingly, in a single family, the duplication was generated through nonallelic homologous recombination (NAHR) with the use of HUWE1-flanking imperfect low-copy repeats, which drive this infrequent NAHR event. The recurrent partial HUWE1 copy-number gain was also generated through NAHR, but here, the homologous sequences used were identified as TcMAR-Tigger DNA elements, a template that has not yet been reported for NAHR. In summary, we showed that an increased dosage of HUWE1 causes nonsyndromic ID and demonstrated that the Xp11.22 region is prone to recombination- and replication-based rearrangements.


Assuntos
Cromossomos Humanos X/genética , Variações do Número de Cópias de DNA/genética , Rearranjo Gênico/genética , Deficiência Intelectual/genética , Ubiquitina-Proteína Ligases/genética , Mapeamento Cromossômico , Cromossomos Artificiais Bacterianos/genética , Hibridização Genômica Comparativa , Biologia Computacional , Replicação do DNA/genética , Duplicação Gênica/genética , Humanos , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único/genética , Recombinação Genética/genética , Proteínas Supressoras de Tumor
16.
Eur J Hum Genet ; 20(4): 381-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22126750

RESUMO

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Heterogeneidade Genética , Doenças Hematológicas/genética , Mutação , Proteínas de Neoplasias/genética , Fenótipo , Doenças Vestibulares/genética , Estudos de Coortes , Face/anormalidades , Feminino , Humanos , Análise de Sequência de DNA
17.
Science ; 332(6026): 240-3, 2011 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-21474761

RESUMO

The spliceosome, a ribonucleoprotein complex that includes proteins and small nuclear RNAs (snRNAs), catalyzes RNA splicing through intron excision and exon ligation to produce mature messenger RNAs, which, in turn serve as templates for protein translation. We identified four point mutations in the U4atac snRNA component of the minor spliceosome in patients with brain and bone malformations and unexplained postnatal death [microcephalic osteodysplastic primordial dwarfism type 1 (MOPD 1) or Taybi-Linder syndrome (TALS); Mendelian Inheritance in Man ID no. 210710]. Expression of a subgroup of genes, possibly linked to the disease phenotype, and minor intron splicing were affected in cell lines derived from TALS patients. Our findings demonstrate a crucial role of the minor spliceosome component U4atac snRNA in early human development and postnatal survival.


Assuntos
Mutação Puntual , Processamento de RNA , RNA Nuclear Pequeno/genética , Spliceossomos/genética , Pareamento de Bases , Linhagem Celular , Pré-Escolar , Cromossomos Humanos Par 2/genética , Nanismo/genética , Nanismo/metabolismo , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/metabolismo , Humanos , Lactente , Íntrons , Sequências Repetidas Invertidas , Masculino , Microcefalia/genética , Microcefalia/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Conformação de Ácido Nucleico , Osteocondrodisplasias/genética , Osteocondrodisplasias/metabolismo , Linhagem , Sítios de Splice de RNA , RNA Nuclear Pequeno/química , RNA Nuclear Pequeno/metabolismo , Spliceossomos/metabolismo
19.
Nat Genet ; 41(1): 95-100, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19079258

RESUMO

Abnormalities in WNT signaling are implicated in a broad range of developmental anomalies and also in tumorigenesis. Here we demonstrate that germline mutations in WTX (FAM123B), a gene that encodes a repressor of canonical WNT signaling, cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (OSCS; MIM300373). This condition is typically characterized by increased bone density and craniofacial malformations in females and lethality in males. The mouse homolog of WTX is expressed in the fetal skeleton, and alternative splicing implicates plasma membrane localization of WTX as a factor associated with survival in males with OSCS. WTX has also been shown to be somatically inactivated in 11-29% of cases of Wilms tumor. Despite being germline for such mutations, individuals with OSCS are not predisposed to tumor development. The observed phenotypic discordance dependent upon whether a mutation is germline or occurs somatically suggests the existence of temporal or spatial constraints on the action of WTX during tumorigenesis.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/patologia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Lesões Pré-Cancerosas/genética , Proteínas Supressoras de Tumor/genética , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Adulto , Processamento Alternativo/genética , Animais , Doenças do Desenvolvimento Ósseo/complicações , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 11/genética , Embrião de Mamíferos/metabolismo , Feminino , Humanos , Lactente , Masculino , Camundongos , Pessoa de Meia-Idade , Fenótipo , Mutação Puntual , Estrutura Terciária de Proteína , Esclerose , Proteínas Supressoras de Tumor/química , Tumor de Wilms/genética , Inativação do Cromossomo X/genética
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