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1.
Am J Hum Genet ; 105(3): 493-508, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31447100

RESUMO

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.

2.
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.

5.
Nat Commun ; 9(1): 4619, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30397230

RESUMO

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

7.
Genet Med ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30287924

RESUMO

PURPOSE: Several studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population. METHODS: We retrospectively evaluated all genetic NICU consultations in a 2-year period. RESULTS: In 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.4%) were made using standard genetic workup. Most diagnoses (65.6%) were made within 16 days. Diagnostic ES yield was 5/29 (17.2%). Genetic diagnoses had a direct effect on clinical management in 90.6% (29/32) of patients. CONCLUSIONS: Our study shows that exome sequencing has a place in NICU diagnostics, but given the associated costs and the high yield of alternative diagnostic strategies, we recommend to first perform clinical genetic consultation.

9.
Genet Med ; 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30206421

RESUMO

PURPOSE: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. METHODS: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. RESULTS: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. CONCLUSION: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

10.
Am J Hum Genet ; 102(6): 1195-1203, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861108

RESUMO

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

11.
Fam Cancer ; 17(3): 415-420, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29124495

RESUMO

Patients synchronously or metachronously presenting with ovarian and colon cancer can pose diagnostic challenges. A primary colon carcinoma can metastasize to one or both ovaries, two independent primary tumors can arise or an ovarian carcinoma can metastasize to the colon. Clinical and immunohistochemical characterization can aid the diagnosis. Recently, we reported that in difficult cases finding pathogenic APC variants supports a colonic origin.In this case report we describe the clinical history of a female patient suspected for Lynch syndrome. She was diagnosed with a bilateral ovarian cancer at age 44, followed by the detection of a colon carcinoma 12.5 months later. Lesions of both sites showed a DNA mismatch repair deficiency with immunohistochemical loss of MLH1 and PMS2 expression without MLH1 promoter hypermethylation. In absence of germline MMR gene variants identical somatic MLH1 and CTNNB1 gene variants were found, indicating a clonal relation. MMR germline mosaicism was made unlikely by ultra deep sequencing of the MLH1 variant in DNA isolated from normal mucosa, blood, urine and saliva. Although initially being suspect for Lynch syndrome it was eventually concluded that a metachronously diagnosed colon carcinoma that metastasized to both ovaries was most likely.

13.
Am J Hum Genet ; 99(1): 125-38, 2016 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-27374770

RESUMO

DNA replication precisely duplicates the genome to ensure stable inheritance of genetic information. Impaired licensing of origins of replication during the G1 phase of the cell cycle has been implicated in Meier-Gorlin syndrome (MGS), a disorder defined by the triad of short stature, microtia, and a/hypoplastic patellae. Biallelic partial loss-of-function mutations in multiple components of the pre-replication complex (preRC; ORC1, ORC4, ORC6, CDT1, or CDC6) as well as de novo stabilizing mutations in the licensing inhibitor, GMNN, cause MGS. Here we report the identification of mutations in CDC45 in 15 affected individuals from 12 families with MGS and/or craniosynostosis. CDC45 encodes a component of both the pre-initiation (preIC) and CMG helicase complexes, required for initiation of DNA replication origin firing and ongoing DNA synthesis during S-phase itself, respectively, and hence is functionally distinct from previously identified MGS-associated genes. The phenotypes of affected individuals range from syndromic coronal craniosynostosis to severe growth restriction, fulfilling diagnostic criteria for Meier-Gorlin syndrome. All mutations identified were biallelic and included synonymous mutations altering splicing of physiological CDC45 transcripts, as well as amino acid substitutions expected to result in partial loss of function. Functionally, mutations reduce levels of full-length transcripts and protein in subject cells, consistent with partial loss of CDC45 function and a predicted limited rate of DNA replication and cell proliferation. Our findings therefore implicate the preIC as an additional protein complex involved in the etiology of MGS and connect the core cellular machinery of genome replication with growth, chondrogenesis, and cranial suture homeostasis.


Assuntos
Proteínas de Ciclo Celular/genética , Microtia Congênita/genética , Craniossinostoses/genética , Transtornos do Crescimento/genética , Micrognatismo/genética , Mutação , Patela/anormalidades , Adolescente , Adulto , Alelos , Processamento Alternativo/genética , Sequência de Aminoácidos , Âmnio/citologia , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Células Cultivadas , Criança , Pré-Escolar , Análise Mutacional de DNA , Replicação do DNA , Exoma/genética , Éxons/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Modelos Moleculares , Conformação Proteica , Síndrome , Adulto Jovem
14.
Am J Hum Genet ; 93(5): 932-44, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-24183451

RESUMO

Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. Here, by using exome sequencing and a targeted next-generation sequencing panel, we identified a total of 11 mutations in WDR34 in 9 families with the clinical diagnosis of Jeune syndrome (asphyxiating thoracic dystrophy). WDR34 encodes a WD40 repeat-containing protein orthologous to Chlamydomonas FAP133, a dynein intermediate chain associated with the retrograde intraflagellar transport motor. Three-dimensional protein modeling suggests that the identified mutations all affect residues critical for WDR34 protein-protein interactions. We find that WDR34 concentrates around the centrioles and basal bodies in mammalian cells, also showing axonemal staining. WDR34 coimmunoprecipitates with the dynein-1 light chain DYNLL1 in vitro, and mining of proteomics data suggests that WDR34 could represent a previously unrecognized link between the cytoplasmic dynein-1 and IFT dynein-2 motors. Together, these data show that WDR34 is critical for ciliary functions essential to normal development and survival, most probably as a previously unrecognized component of the mammalian dynein-IFT machinery.


Assuntos
Proteínas de Transporte/genética , Dineínas do Citoplasma/genética , Síndrome de Ellis-Van Creveld/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Animais , Grupo com Ancestrais do Continente Asiático/genética , Axonema/genética , Criança , Chlamydomonas/genética , Cílios/genética , Cílios/metabolismo , Citoesqueleto/genética , Citoesqueleto/metabolismo , Síndrome de Ellis-Van Creveld/patologia , Grupo com Ancestrais do Continente Europeu/genética , Exoma , Éxons , Humanos , Lactente , Recém-Nascido , Mutação , Conformação Proteica , Proteômica
15.
Eur J Hum Genet ; 20(2): 166-70, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21915152

RESUMO

In several laboratories, genome-wide array analysis has been implemented as the first tier diagnostic test for the identification of copy number changes in patients with mental retardation and/or congenital anomalies. The identification of a pathogenic copy number variant (CNV) is not only important to make a proper diagnosis but also to enable the accurate estimation of the recurrence risk to family members. Upon the identification of a de novo interstitial loss or gain, the risk recurrence is considered very low. However, this risk is 50% if one of the parents is carrier of a balanced insertional translocation (IT). The apparently de novo imbalance in a patient is then the consequence of the unbalanced transmission of a derivative chromosome involved in an IT. To determine the frequency with which insertional balanced translocations would be the origin of submicroscopic imbalances, we investigated the potential presence of an IT in a consecutive series of 477 interstitial CNVs, in which the parental origin has been tested by FISH, among 14,293 patients with developmental abnormalities referred for array. We demonstrate that ITs underlie ~2.1% of the apparently de novo, interstitial CNVs, indicating that submicroscopic ITs are at least sixfold more frequent than cytogenetically visible ITs. This risk estimate should be taken into account during counseling, and warrant parental and proband FISH testing wherever possible in patients with an apparently de novo, interstitial aberration.


Assuntos
Anormalidades Múltiplas/genética , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Mutagênese Insercional , Translocação Genética , Anormalidades Múltiplas/diagnóstico , Deficiências do Desenvolvimento/diagnóstico , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Linhagem
16.
Arthritis Rheum ; 58(8): 2460-9, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18668574

RESUMO

OBJECTIVE: In patients with systemic lupus erythematosus (SLE) and lupus nephritis, the presence of antiphospholipid antibodies (aPL) is considered to be an indication of increased risk of thrombotic microangiopathy, a serious complication of SLE. Previous studies have demonstrated a critical role for activation of the classical pathway of complement that leads to thrombotic injury in the presence of aPL. This study was undertaken to investigate whether C4d deposition in lupus nephritis is related to circulating aPL and the presence of renal microthrombi. METHODS: Deposition patterns of C4d in 44 renal biopsy samples obtained from 38 patients with biopsy-proven lupus nephritis were determined by staining with a polyclonal anti-C4d antibody. A phosphotungstic acid-hematoxylin stain was used to identify fibrin microthrombi. Clinical data (serum creatinine levels and presence or absence of aPL) were obtained and correlated with findings in the renal biopsy specimens. Patients were categorized as having aPL (n = 20) or not having aPL (n = 18). RESULTS: A strong relationship between the intensity of glomerular C4d staining and the presence of microthrombi was found (P < 0.002). Intense glomerular C4d deposition was present in 7 of 8 biopsy samples showing renal microthrombi. Neither C4d deposition nor the presence of microthrombi was correlated with aPL status. CONCLUSION: Our findings suggest that activation of the classical pathway of complement plays a pathogenic role in the development of renal tissue injury leading to thrombosis, irrespective of the type of circulating antibodies present. Immunodetection of glomerular C4d deposition in renal biopsy samples could be a convenient method of identifying patients at risk of thrombotic microangiopathy.


Assuntos
Complemento C4b/metabolismo , Glomérulos Renais/metabolismo , Nefrite Lúpica/diagnóstico , Fragmentos de Peptídeos/metabolismo , Trombose/diagnóstico , Doenças Vasculares/diagnóstico , Adolescente , Adulto , Idoso , Anticorpos Antifosfolipídeos/sangue , Biomarcadores/metabolismo , Biópsia , Complemento C1q/metabolismo , Complemento C3/metabolismo , Feminino , Humanos , Imunoglobulina A/metabolismo , Imunoglobulina G/metabolismo , Imunoglobulina M/metabolismo , Glomérulos Renais/patologia , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Trombose/metabolismo , Trombose/patologia , Doenças Vasculares/metabolismo , Doenças Vasculares/patologia
17.
J Reprod Immunol ; 78(1): 68-75, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18329105

RESUMO

Chimerism indicates the presence of cells from one individual in another. Pregnancy and blood transfusions are considered the main sources for chimerism. Chimeric cells have been attributed a pathogenic role in various autoimmune diseases. However, data on the occurrence of chimeric cells in normal organs are scarce. In order to gain insight into the possible pathogenic potential of chimeric cells in autoimmune disease, it is necessary to determine the prevalence of chimeric cells in organs not affected by autoimmune disease. In situ hybridization for the Y-chromosome was performed on organs obtained at autopsy of 51 women. We investigated 44 thyroid, 38 lung, 21 skin and 7 lymph node samples. All women had sons, and data from their blood transfusion histories were retrieved for at least 10 years before death. Slides were scored semi-quantitatively for chimerism as low (1-3 Y-chromosome-positive cells per slide), moderate (4-10 positive cells per slide) or high (more than 10 positive cells per slide). Y-chromosome-positive cells were found in 8 thyroid, 10 lung, 3 skin and 1 lymph node samples of 18 women. There was no association between the presence of chimeric cells and blood transfusion history. Most organs in which chimerism was present contained a small to moderate level. Thus, chimerism can occur in normal organs of women without autoimmune disease. Our results indicate that chimerism is not necessarily associated with disease.


Assuntos
Quimerismo , Pulmão , Linfonodos , Troca Materno-Fetal , Pele , Glândula Tireoide , Adulto , Doenças Autoimunes/genética , Cromossomos Humanos Y/genética , Feminino , Humanos , Hibridização In Situ , Masculino , Troca Materno-Fetal/genética , Gravidez
18.
Ann Rheum Dis ; 66(12): 1568-73, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17584805

RESUMO

BACKGROUND: Chimerism indicates the presence of cells from one individual in another individual, and has been associated with several autoimmune diseases. Although this finding may point towards a role for chimerism in the induction of SLE, it could also indicate that chimerism is the result of repair mechanisms after injury. OBJECTIVE: To perform a post-mortem investigation for the presence of chimerism in 48 organs from seven women with SLE and establish whether there was a relationship between chimerism and injury. METHODS: Chimeric male cells in female tissue specimens were identified by in situ hybridisation of the Y-chromosome. Organs were categorised into four different groups according to injury experienced. RESULTS: were compared with those for unaffected control organs. Results: Chimerism was found in all seven patients with SLE. Y-chromosome-positive cells were present in 24 of 48 organs from women with SLE, which was significantly more than in control organs (p<0.001). Chimerism occurred more often in organs from patients with SLE who had experienced injury than in normal control organs, irrespective of whether the injury experienced was SLE-related, non-SLE-related or both. CONCLUSIONS: This is the first report of the distribution of chimerism in a large number of organs from women with SLE. It shows that the occurrence of chimerism is related to injury. The data support the hypothesis that tissue chimerism is the result of a repair process.


Assuntos
Quimerismo , Cromossomos Humanos Y , Lúpus Eritematoso Sistêmico/genética , Autoanticorpos/imunologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Humanos , Hibridização In Situ/métodos , Rim/patologia , Fígado/patologia , Pulmão/patologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Linfonodos/patologia , Masculino , Miocárdio/patologia , Pele/patologia , Baço/patologia , Glândula Tireoide/patologia , Fatores de Tempo
20.
Arthritis Rheum ; 54(9): 2944-50, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16948133

RESUMO

OBJECTIVE: Systemic lupus erythematosus (SLE) is an immune-mediated disease that particularly affects the kidneys, causing lupus nephritis. In experimental mouse models, lupus nephritis can be mimicked by inducing a chimeric state through the injection of parental T cells in offspring. In humans, pregnancy-induced chimerism may play a role in the pathogenesis of autoimmune diseases such as SLE, but it is likely that only certain chimeric cells have pathogenic potential. In this study, we investigated whether the distribution of chimeric cells is different in the kidneys of women with SLE from that in normal kidneys, and we examined the phenotype of chimeric cells in women with SLE. METHODS: The presence of chimeric cells was investigated by in situ hybridization targeting the Y chromosome in 57 renal biopsy samples from 49 women with lupus nephritis. Fifty-one kidney autopsy specimens without histomorphologic lesions served as controls. Double-staining for the Y chromosome in combination with CD3 and CD34 markers was performed in 5 kidney specimens with lupus nephritis to identify the phenotype of the chimeric cells. RESULTS: Y chromosome-positive cells were found in 27 of 49 patients with lupus nephritis and in 13 of 51 normal controls (P < 0.01). Both CD3+ and CD34+ chimeric cells were identified in lupus nephritis kidney specimens. CONCLUSION: Chimeric cells are present significantly more often in kidneys with lupus nephritis than in normal kidneys, and some of these chimeric cells are T cells. This finding is interesting in light of experimental models demonstrating that lupus nephritis is initiated by chimeric T cells.


Assuntos
Quimerismo , Rim/patologia , Lúpus Eritematoso Sistêmico/patologia , Adulto , Autopsia , Biópsia , Cromossomos Humanos Y , Feminino , Humanos , Hibridização In Situ , Lúpus Eritematoso Sistêmico/genética , Valores de Referência , Aberrações dos Cromossomos Sexuais
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